ZA200509247B - Pharmaceutical combination comprising modafinil and another drug - Google Patents
Pharmaceutical combination comprising modafinil and another drug Download PDFInfo
- Publication number
- ZA200509247B ZA200509247B ZA200509247A ZA200509247A ZA200509247B ZA 200509247 B ZA200509247 B ZA 200509247B ZA 200509247 A ZA200509247 A ZA 200509247A ZA 200509247 A ZA200509247 A ZA 200509247A ZA 200509247 B ZA200509247 B ZA 200509247B
- Authority
- ZA
- South Africa
- Prior art keywords
- modafinil
- drug
- analeptic
- composition
- administration
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims description 157
- 229940079593 drug Drugs 0.000 title claims description 141
- 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 title claims description 103
- 229960001165 modafinil Drugs 0.000 title claims description 99
- 239000002269 analeptic agent Substances 0.000 claims description 104
- 230000003555 analeptic effect Effects 0.000 claims description 96
- 239000000203 mixture Substances 0.000 claims description 49
- 239000002246 antineoplastic agent Substances 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 37
- 238000002651 drug therapy Methods 0.000 claims description 33
- 230000000694 effects Effects 0.000 claims description 30
- 241001465754 Metazoa Species 0.000 claims description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
- 208000035475 disorder Diseases 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 16
- -1 cisplatinum Chemical compound 0.000 claims description 15
- 208000024891 symptom Diseases 0.000 claims description 15
- 230000002411 adverse Effects 0.000 claims description 12
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 10
- 229930012538 Paclitaxel Natural products 0.000 claims description 10
- 229960003668 docetaxel Drugs 0.000 claims description 10
- 229960001592 paclitaxel Drugs 0.000 claims description 10
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 10
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 10
- 229960004528 vincristine Drugs 0.000 claims description 10
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 10
- 208000020401 Depressive disease Diseases 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 claims description 6
- 230000003247 decreasing effect Effects 0.000 claims description 6
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 claims description 6
- 230000002708 enhancing effect Effects 0.000 claims description 6
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 206010019280 Heart failures Diseases 0.000 claims description 4
- 108010050904 Interferons Proteins 0.000 claims description 4
- 102000014150 Interferons Human genes 0.000 claims description 4
- 229960001918 tiagabine Drugs 0.000 claims description 4
- PBJUNZJWGZTSKL-MRXNPFEDSA-N tiagabine Chemical compound C1=CSC(C(=CCCN2C[C@@H](CCC2)C(O)=O)C2=C(C=CS2)C)=C1C PBJUNZJWGZTSKL-MRXNPFEDSA-N 0.000 claims description 4
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 claims description 3
- SGUAFYQXFOLMHL-UHFFFAOYSA-N 2-hydroxy-5-{1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl}benzamide Chemical compound C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 SGUAFYQXFOLMHL-UHFFFAOYSA-N 0.000 claims description 3
- 239000002083 C09CA01 - Losartan Substances 0.000 claims description 3
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 claims description 3
- 108010061435 Enalapril Proteins 0.000 claims description 3
- 108010005716 Interferon beta-1a Proteins 0.000 claims description 3
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 claims description 3
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 claims description 3
- 230000003556 anti-epileptic effect Effects 0.000 claims description 3
- 230000000118 anti-neoplastic effect Effects 0.000 claims description 3
- 239000001961 anticonvulsive agent Substances 0.000 claims description 3
- 229960003965 antiepileptics Drugs 0.000 claims description 3
- 229940034982 antineoplastic agent Drugs 0.000 claims description 3
- 239000000164 antipsychotic agent Substances 0.000 claims description 3
- 229940005529 antipsychotics Drugs 0.000 claims description 3
- 229960002802 bromocriptine Drugs 0.000 claims description 3
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 claims description 3
- 229960000830 captopril Drugs 0.000 claims description 3
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 claims description 3
- 229960000623 carbamazepine Drugs 0.000 claims description 3
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 claims description 3
- 239000000544 cholinesterase inhibitor Substances 0.000 claims description 3
- 229960004170 clozapine Drugs 0.000 claims description 3
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 claims description 3
- 229960005156 digoxin Drugs 0.000 claims description 3
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 claims description 3
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 claims description 3
- 229960004166 diltiazem Drugs 0.000 claims description 3
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 claims description 3
- 229960003530 donepezil Drugs 0.000 claims description 3
- 229940052760 dopamine agonists Drugs 0.000 claims description 3
- 239000003136 dopamine receptor stimulating agent Substances 0.000 claims description 3
- 229960000873 enalapril Drugs 0.000 claims description 3
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 claims description 3
- 229960002870 gabapentin Drugs 0.000 claims description 3
- 229960003980 galantamine Drugs 0.000 claims description 3
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 claims description 3
- 229960003161 interferon beta-1b Drugs 0.000 claims description 3
- 229940047124 interferons Drugs 0.000 claims description 3
- 229960001632 labetalol Drugs 0.000 claims description 3
- 229960001848 lamotrigine Drugs 0.000 claims description 3
- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 claims description 3
- 229960004773 losartan Drugs 0.000 claims description 3
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 claims description 3
- 238000002483 medication Methods 0.000 claims description 3
- 229960001597 nifedipine Drugs 0.000 claims description 3
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims description 3
- 229960005017 olanzapine Drugs 0.000 claims description 3
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 claims description 3
- 229960004851 pergolide Drugs 0.000 claims description 3
- 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 claims description 3
- 229960002036 phenytoin Drugs 0.000 claims description 3
- 229960003089 pramipexole Drugs 0.000 claims description 3
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 claims description 3
- 229960001289 prazosin Drugs 0.000 claims description 3
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 claims description 3
- 229960001534 risperidone Drugs 0.000 claims description 3
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 claims description 3
- 229960001879 ropinirole Drugs 0.000 claims description 3
- UHSKFQJFRQCDBE-UHFFFAOYSA-N ropinirole Chemical compound CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 claims description 3
- 229960004394 topiramate Drugs 0.000 claims description 3
- 229960001722 verapamil Drugs 0.000 claims description 3
- 108010005714 Interferon beta-1b Proteins 0.000 claims description 2
- 229960004461 interferon beta-1a Drugs 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims 37
- 238000004519 manufacturing process Methods 0.000 claims 7
- 229940079322 interferon Drugs 0.000 claims 1
- 206010041349 Somnolence Diseases 0.000 description 22
- 208000032140 Sleepiness Diseases 0.000 description 17
- 201000003631 narcolepsy Diseases 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 13
- 239000002552 dosage form Substances 0.000 description 12
- 230000037321 sleepiness Effects 0.000 description 12
- 238000002560 therapeutic procedure Methods 0.000 description 11
- 239000003826 tablet Substances 0.000 description 10
- 206010016256 fatigue Diseases 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 8
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 201000002859 sleep apnea Diseases 0.000 description 6
- 206010062519 Poor quality sleep Diseases 0.000 description 5
- 206010046543 Urinary incontinence Diseases 0.000 description 5
- 239000000853 adhesive Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 208000019116 sleep disease Diseases 0.000 description 5
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 230000000977 initiatory effect Effects 0.000 description 4
- 208000028867 ischemia Diseases 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 208000018737 Parkinson disease Diseases 0.000 description 3
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 208000001797 obstructive sleep apnea Diseases 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 241000282465 Canis Species 0.000 description 2
- 241000282412 Homo Species 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229940124533 adjunct drug Drugs 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000013583 drug formulation Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 206010020765 hypersomnia Diseases 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 238000013271 transdermal drug delivery Methods 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 206010000372 Accident at work Diseases 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 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 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010002942 Apathy Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 208000001573 Cataplexy Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010054089 Depressive symptom Diseases 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 208000030814 Eating disease Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000034347 Faecal incontinence Diseases 0.000 description 1
- 208000019454 Feeding and Eating disease Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 206010037213 Psychomotor retardation Diseases 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 206010040981 Sleep attacks Diseases 0.000 description 1
- 208000005439 Sleep paralysis Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 150000003869 acetamides Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 206010001584 alcohol abuse Diseases 0.000 description 1
- 208000025746 alcohol use disease Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000036626 alertness Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000002253 anti-ischaemic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 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
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 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
- 210000004556 brain Anatomy 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 150000001840 cholesterol esters Chemical class 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 125000005131 dialkylammonium group Chemical group 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 235000014632 disordered eating Nutrition 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 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 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000005414 inactive ingredient Substances 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
- 206010022437 insomnia Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 231100000863 loss of memory Toxicity 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000422 nocturnal effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229940117394 provigil Drugs 0.000 description 1
- 230000008430 psychophysiology Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000004461 rapid eye movement Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 229920000260 silastic Polymers 0.000 description 1
- 208000020685 sleep-wake disease Diseases 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000013759 synthetic iron oxide Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
PHARMACEUTICAL COMBINATION COMPRISING MODAFINIL AND ANOTHER DRUG
1. Modafinil
Modafinil, CsH;sNO,S, also known as 2-(benzhydrylsulfinyl) acetamide, or 2-[(diphenylmethyl) sulfinyl] acetamide, is a synthetic acetamide derivative with wake-promoting activity, the structure of which has been described in French Patent
No. 78 05 510 and in U.S. Patent No. 4,177,290 (290), and which has been approved by the United States Food and Drug Administration for use in the treatment of excessive daytime sleepiness associated with narcolepsy. A method of preparation of a racemic mixture is described in the 290 patent and a method of preparation of a levorotatory isomer is described in U.S. Patent No. 4,927,855 (both incorporated : herein by reference). The levorotatory isomer is reported to be useful for treatment of hypersomnia, depression, Alzheimer's disease and to have activity towards the symptoms of dementia and loss of memory, especially in the elderly.
The primary pharmacological activity of modafinil is to promote wakefulness.
Modafinil promotes wakefulness in rats (Touret et al., 1995; Edgar and Seidel, 1997), cats (Lin et al., 1992), canines (Shelton et al., 1995) and non-human primates (Hemant et al, 1991) as well as in models mimicking clinical situations, such as sleep apnea (English bulldog sleep disordered breathing model) (Panckeri et al, 1996) and narcolepsy (narcoleptic canine) (Shelton et al, 1995).
Modafinil has also been described as an agent with activity in the central ) nervous system, and as a useful agent in the treatment of Parkinson's disease (U.S.
Patent No. 5,180,745); in the protection of cerebral tissue from ischemia (U.S. Patent
No. 5,391,576); in the treatment of urinary and fecal incontinence (U.S. Patent No. 5,401,776); and in the treatment of sleep apneas and disorders of central origin (U.S.
Patent No. 5,612,379). U.S. Patent No. 5,618,845 describes modafinil preparations of a defined particle size less than about 200 microns. In addition, modafinil may be used in the treatment of eating disorders, or to promote weight gain or stimulate appetite in humans or animals (U.S. Patent No. 6,455,588, incorporated herein by reference), or in the treatment of attention deficit hyperactivity disorder (ADHD) (U.S. Patent No. 6,346,548, incorporated herein by reference), or fatigue, especially fatigue associated with multiple sclerosis (U.S. Patent No. 6,488,164, incorporated herein by reference).
Modafinil has been shown to be effective in treating narcolepsy, sleepiness, excessive sleepiness (e.g., sleepiness associated with disorders of sleep and wakefulness), excessive daytime sleepiness associated with narcolepsy, Parkinson's disease, urinary incontinence, multiple sclerosis fatigue, ADHD, Alzheimer's disorder, sleep apnea, obstructive sleep apnea, depression, and ischemia.
Narcolepsy is a chronic disorder characterized by intermittent sleep attacks, persistent, excessive daytime sleepiness and abnormal rapid eye movement (“REM”) sleep manifestations, such as sleep-onset REM periods, cataplexy, sleep paralysis and hypnagogic hallucinations, or both (Assoc. of Sleep Disorders Centers, Sleep 2:1 (1979). Most patients with narcolepsy also have disrupted nocturnal sleep (Montplaisir, in Guilleminault et al. eds., Narcolepsy, Spectrum Pub., New York, pp. 43-56). Pathological somnolence, whether due to narcolepsy or other causes, is disabling and potentially dangerous. Causes of pathological somnolence, other than narcolepsy, include chronic sleep loss (Carskadon et al., Sleep, 5:73 (1982);
Carskadon et al., Psychophysiology, 18:107 (1981)); sleep apnea (Kryger et al.,
Principles and Practice of Sleep Medicine, W. B. Saunders Co., Philadelphia, Pa. (1989)); and other sleep disorders (International Classification of Sleep Disorders:
Diagnostic and Coding Manual, American Sleep Disorder Association, Rochester,
Minn. (1990)). Whether due to narcolepsy or other causes, pathological somnolence ‘ produces episodes of unintended sleep, reduced attention, and performance errors.
Consequently, it is linked to a variety of transportation and industrial accidents (Mitler et al., Sleep 11:100 (1988)). A therapeutic agent that reduces or eliminates pathological somnolence would have important implications not only for individual patients, but also for public health and safety.
Other uses of modafinil have been presented. U.S. Pat. No. 5,180,745 discloses the use of modafinil for providing a neuroprotective effect in humans, and in particular for the therapy of Parkinson's disease. The levorotatory form of modafinil, i.e, (-) benzhydrylsulfinyl-acetamide, may have potential benefit for therapy of depression, hypersomnia and Alzheimer's disease (U.S. Pat. No. 4,927,855).
European Published Application 547952 (published Jun. 23, 1993) discloses the use of modafinil as an anti-ischemic agent. European Published Application 594507 (published Apr. 27, 1994) discloses the use of modafinil to treat urinary incontinence.
U.S. Pat. No. RE37,516 discloses pharmaceutical compositions having a defined particle size, and in particular compositions wherein 95% of the cumulative total of the effective amount of modafinil particles in the composition have a diameter less than about 200 microns.
In one embodiment, a composition can include therapeutically effective amounts of two or more active compounds, including but not limited to 1) an analeptic, and 2) one or more other drugs. The actives can be combined together and optionally include a pharmaceutically acceptable carrier or the actives can be administered separately. Co
In another embodiment, the present invention includes using modafinil in combination with one or more other drugs to treat and/or ameliorate one or more symptom associated with a condition which can be treated by the other drug and/or to treat and/or ameliorate one or more side effects associated with treatment or therapy with the other drug.
J
The present invention is directed to compositions and methods of treating symptoms and side effects associated with various drug therapies and further enhancing the activity of the drug involved in the drug therapy. The symptoms and/or side effects can include but are not limited to narcolepsy, sleepiness, excessive sleepiness (e.g., sleepiness associated with disorders of sleep and wakefulness), excessive daytime sleepiness associated with narcolepsy, urinary incontinence, fatigue, ADHD, sleep apnea, obstructive sleep apnea, depression, and ischemia.
The compositions and methods of the present invention include an analeptic, including but not limited to modafinil, and at least one other drug that has adverse side effects associated with its administration, especially fatigue, sleepiness, sad mood — lack of pleasure, anxiety, worry, irritability, agitation, excessive sleepiness, somnolence, sedation, low energy, lack of motivation, and difficulty in thinking, concentrating and/or remembering.
1. Analeptic Agents
Analeptics are drugs that principally act as or are used as a central nervous system stimulant. Preferred for use in the practice of the invention are analeptics that operate on the sleep-wake centers of the brain and that lack the pharmacological effects of amphetamines. Preferred analeptic agents have the pharmacological profile of modafinil. Thus, in a preferred embodiment of the invention, the analeptic used in the practice of the invention is Provigil® (modafinil). 2. Other Drugs
Any drug that induces or is known to cause as a side effect of its administration, either directly or indirectly, one or more of narcolepsy, sleepiness, excessive sleepiness (e.g., sleepiness associated with disorders of sleep and wakefulness), excessive daytime sleepiness associated with narcolepsy, urinary incontinence, fatigue, ADHD, sleep apnea, obstructive sleep apnea, depression, and/or ischemia, can be used with the present invention.
For example, antipsychotics such as risperidone, clozapine and olanzapine can be used. Further, cholinesterase inhibitors such as donepezil, galantamine, and interferons such as interferon beta-1a and interferon beta-1b can be used. Also, included within the scope of acceptable drugs are dopamine agonists such as ropinirole, bromocriptine, pergolide, and pramipexole. Antiepileptics such as tiagabine, topiramate, phenytoin, carbamazepine, lamotrigine, and gabapentin are also considered within the scope of the present invention. Additionally, heart failure medications such as digoxin, captopril, enalapril, verapamil, diltiazem, nifedipine, losartan, prazosin, and labetalol can also be used. Furthermore, antineoplastics such as taxol, docetaxel, cisplatinum, and vincristine can be used. Generally, the particular drugs and types or classes of drugs suitable for adjunct therapy with modafinil are referred to herein as “modafinil adjunct drugs” or “M-drugs.” An M-drug can include, but is not limited to, a compound set forth above. 3. Variants, Analogs, Salts, Different Forms
Drugs not listed above, including but not limited to structural! analogs of the above compounds, that are safe and effective, are also useful in the practice of the invention.
S
Included within the scope of this invention are the various individual stereoisomers, including diastereomers and enantiomers (e.g., the L and/or R-isomer of modafinil) as well as mixtures thereof. In addition, compounds useful in this invention also include any pharmaceutically acceptable salts, for example: alkali metal salts, such as sodium and potassium; ammonium salts; monoalkylammonium salts; dialkylammonium salts; trialkylammonium salts; tetraalkylammonium salts; and tromethamine salts. Hydrates, solvates, and polymorphs of the compounds described above are included within the scope of this invention. Combinations of analeptics and of M-drugs can also be employed. The compounds can be substantially pure or mixed with other ingredients. 4, Treatment Disorders
The invention is useful in the treatment of disorders and/or side effects associated with an M-drug therapy, including fatigue and sleepiness that may be caused by any of a number of factors, including, for example, depression associated with alcohol or drug abuse. The invention is also useful in the treatment of other disorders for which such M-drugs are sometimes prescribed. These include, for example, epilepsy, heart failure, and psychosis. Such disorders, for which the drugs and types of drugs described herein have been shown to have clinically beneficial effects, are herein referred to collectively as "disorders." 5. Therapeutically Effective Amounts of Analeptics and M-Drugs
In one embodiment of the present invention, an amount of analeptic, e.g. modafinil, administered to a patient can include from about 5 to 400 mg., more preferably 5, 10, 15, 20, 30, 40, 50, 60, 70, 75, 80, 90, 100, 200, 300 and/or 400 mg. of modafinil, or combinations thereof. Typically, modafinil can be administered in 50,75, 100 and 200 mg. amounts. However, when used in combination with one or more M-drugs, as described herein, the amount of modafinil necessary to alleviate all or a portion of the symptoms associated with M-drug therapy can be reduced.
Accordingly, one embodiment of the present invention includes 100 mg. or less of modafinil when administered with an M-drug, either as a combined unit dose with the
M-drug or as a separate dose. A single unit dose containing both modafinil and an M- drug is a preferred composition of the present invention, as described below.
Typically, one or more M-drugs can be administered in the amounts known to be effective for that particular drug or type of drug. More specifically, in the present invention, a drug can be administered in an amount effective to alter the state of an animal subject, i.e., the amount of the M-drug that would be administered to the animal subject if the M-drug was administered alone. Suitable amounts are typically ion the range of 0.1 to 1,000 mg, depending upon the selection of M-drug. For most
M-drugs, the amount can be 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300 and/or 400 mg. of a particular M-drug, or combinations thereof. However, in the present invention, when used in combination with one or more analeptics such as modafinil, the overall amount of an administered M-drug can be reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, while still providing a therapeutic effect.
Accordingly, one embodiment of the present invention includes administering less than an amount of M-drug relative to the amount of M-drug administered to an animal subject if administered alone.
Generally, for daily oral doses of active compounds, the combined total of one : or more analeptics and one or more M-drugs will be from about 0.01 mg/kg per day to about 100 mg/kg per day. It is expected that IV doses in the range of about 1 to 1000 mg/cm’ per day will be effective.
In some embodiments of the present invention, the respective weight ratio of analeptic to M-drug can be from 0.01: 1 to 1:1 to 100:1, possibly 1000:1. In some embodiments the weight ratio can be 1:1 to 7:1 or 10:1, most preferably 1:1 to 5:1.
A dosage form containing an above described amount of an analeptic (e.g, modafinil) and one or more M-drugs can provide to a patient improved fatigue symptoms, as well as improve waking functioning, as demonstrated by the effects of fatigue, energy, alertness and cognitive function (e.g. psychomotor retardation). 6. Preparation of a Composition of the Present Invention
To prepare a pharmaceutical composition of this invention, an analeptic, including but not limited to modafinil, and an M-drug, including but not limitedto one or more of the modafinil adjunct drugs described above, can be intimately admixed. The mixture can further optionally include a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral, by suppository, or parenteral. The amount of each active component in the composition can correspond to the amounts described above.
Pharmaceutically acceptable carriers include, e.g., stabilizers binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, colors, diluents, etc. Such a composition, when used for the therapy of a depressive disorder preferably can include therapeutically effective amounts of an analeptic and M-drug.
In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. : For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
In one embodiment, a pharmaceutical composition of the present invention can be administered in a tablet or capsule form or other suitable unit dose form. A tablet or capsule of the present invention can contain one or more of the following inactive ingredients: lactose hydrous, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, carnauba wax, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, synthetic iron oxide, and polysorbate 80.
Accordingly, a pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder injection, teaspoonful, suppository and the like from about 5 to about 1000 mg, or more, of an analeptic and M-drug. In on embodiment of the invention, each single dosage unit (or unit dose) includes both an amount of an analeptic and an amount of an M-drug. In such an embodiment, it is not necessary that each single dosage unit include an effective amount so long as the total amount of drug administered to a patient is an effective amount of each. Therefore, for example, a patient may require 2 or more single dosage units to receive effective amounts of both agents. )
When administered, the formulations of the invention are applied in pharmaceutically acceptable amounts and in pharmaceutically acceptable compositions. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic ingredients. When used in medicine the salts should be pharmaceutically acceptable, but non- pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof and are not excluded from the scope of the invention. Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulfonic, tartaric, citric, methane sulfonic, formic, malonic, succinic, naphthalene-2-sulfonic, and benzene sulfonic. Also, pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.
Suitable buffering agents include: acetic acid and a salt (1-2% W/V); citric acid and a salt (1-3% W/V); boric acid and a salt (0.5-2.5% W/V); and phosphoric acid and a salt (0.8-2% W/V). Suitable preservatives include benzalkonium chloride (0.003-0.03% W/V); chlorobutanol (0.3-0.9% W/V); parabens (0.01-0.25% W/V) and thimerosal (0.004-0.02% W/V). :
Dosage may be adjusted appropriately to achieve desired drug levels, locally or systemically. As noted above, generally, daily oral doses of active compounds will be from about 0.01 mg/kg per day to 2000 mg/kg per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Continuous IV dosing over, for example 24 hours or multiple doses per day is contemplated to achieve appropriate systemic levels of compounds.
A variety of administration routes are available. The particular mode selected will depend of course, upon the particular drug selected, the severity of the disease state(s) being treated and the dosage required for therapeutic efficacy. The methods of this invention, generally speaking, may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse
S effects. Such modes of administration include oral, rectal, sublingual, topical, nasal, transdermal or parenteral routes. The term “parenteral” includes subcutaneous, intravenous, intramuscular, or infusion.
The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. In general, the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
Compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active compound. Other compositions include suspensions in aqueous liquors or non-aqueous liquids such as a syrup, an elixir, or an emulsion.
Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the active compounds of the invention, increasing convenience to the subject and the physician. They include polymer based systems such as polylactic and polyglycolic acid, polyanhydrides and polycaprolactone; nonpolymer systems that are lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-, di and triglycerides; hydrogel release systems; silastic systems; peptide based systems; wax coatings, compressed tablets using conventional binders and excipients, partially fused implants and the like. In addition, a pump-based hardware delivery system can be used, some of which are adapted for implantation.
Another embodiment of the present invention provides a kit or device which can facilitate the administration of an amount of an analeptic and an M-drug to treat a disorder. Specifically, a kit according to the present invention includes at least one dosage form containing an analeptic, including but not limited to modafinil, and a separate dosage form containing at least one M-drug. One suitable kit of the present invention includes a blister pack having a unit dose of modafinil and a separate unit dose of an M-drug. Most preferably, the unit dose of modafinil includes a 50, 75, 100 or 200 mg. tablet of modafinil and the unit dose of an M-drug includes a 10, 20, 30, 40 or 50 mg. tablet of antidepressant. The kit or device can also include instructions conceming administration of the analeptic and M-drug. Preferably, the instructions provide administration guidance according to one or more of the administration schemes set forth below.
The analeptic and/or M-drug can be in any suitable dosage form, including but not limited to solid dosage forms including tablets, capsules, pills, troches, cachets, and the like, and/or liquid dosage forms such as an oral elixir or an IV fluid. The dosage form of the analeptic can be the same type or a different type than the M-drug.
In yet another embodiment, the present invention includes a transdermal drug delivery system ("TDDS"). A TDDS suitable for use with the invention in patch form typically contains at least: (1) a backing layer and (2) a carrier formulated with an effective amount of an M-drug and optionally modafinil.
Preferred patches include (1) the matrix type patch; (2) the reservoir type patch; (3) the multi-laminate drug-in-adhesive type patch; and (4) the monolithic drug-in-adhesive type patch; and (Ghosh, T. K.; Pfister, w. R.; Yum, S. IL
Transdermal and Topical Drug Delivery Systems, Interpharm Press, Inc. p. 249-297, incorporated herein by reference). These patches are generally available commercially.
For practice of the invention, the matrix type and the drug-in-adhesive type patches are especially preferred. The more preferred drug-in-adhesive patch is the monolithic type.
Transdermal drug delivery systems other than standard patches can also be used. These include, for example, osmotic pump systems, ultrasonic systems, ointments, pastes, gels, medicated powders, creams, lotions, aerosols, sprays, foams, medicated adhesives and the like. 7. Method of Treatment/Therapy
A. Administration Schemes and Timing of Treatment of an Analeptic and
M-drug
An analeptic and an M-drug can be combined together into a single unit dose, but can also be administered separately as two or more distinct doses.
Thus, in some embodiments of the invention, a treatment of a disorder related to depression can be through the use of separate dosage forms — one or more analeptic doses and one or more M-drug doses. Accordingly, a dose of an analeptic can be administered at a different time relative to the M-drug dose or simultaneously (i.e., analeptic dose administration within less than 1 hour before or after administration of the M-drug). However, if simultaneous, the administration of the analeptic and M- drug can also be through the use of a single unit dose including both an analeptic and
M-drug.
In patients that are beginning M-drug therapy, i.e. patients that are substantially free of M-drugs or patients that have been free of M-drug therapy for about 1 week, 2 weeks, more preferably about 4 or more weeks, the dosage form containing the analeptic can be administered before and/or at about the same time as an initial administration of the M-drug. In such an embodiment, one or more administrations of an analeptic can be within 72 hours, preferably within 48 hours, more preferably within 24 hours, most preferably within 1 hour or moments before an initial administration/dosing of an M-drug. After the initial administration of the analeptic and M-drug, subsequent dosings of the analeptic and M-drug can continue at atypical rate, e.g., typically one or two 50, 75, 100 to 200 mg. doses of modafinil per day and 10, 20, 30, 40 to 50 mg. of M-drug per day. Further, after the initial administration of the M-drug, the dosings of the analeptic and M-drug can be in separate dosage forms or in a single unit dose. However, if a dose of an analeptic is to be administered before a subsequent dose of an M-drug, separate dosage forms for each are preferred.
Additionally, in patients that are substantially free of M-drugs, the initial administration of the analeptic can coincide with or be nearly simultaneous with the initial administration of an M-drug. This can be accomplished through the use of separate dosage forms of an analeptic and M-drug which can then be administered together simultaneously (i.e., within 1 hour or less, before or after the M-drug) or through the use of a single unit dose including both an analeptic and an M-drug, as noted above.
Further, an analeptic, including but not limited to modafinil, can also be administered to a patient that has already received at least an initial dose of an M- drug. In one embodiment, the initial administration of an analeptic can be within 72 hours, preferably within 48 hours, more preferably within 24 hours, most preferably within 1 hour or within moments after the initial administration of an M-drug. In this timing scheme, modafinil is administered at about the same time as an M-drug, but subsequent to at least one administration of an M-drug. After the initial dosing ofan analeptic, the dosing of the analeptic and M-drug can continue in a typical manner. In one particularly preferred embodiment, initial administration of an analeptic and subsequent administrations of an analeptic can be accomplished through the use of a single unit dose including both an analeptic and an M-drug.
In a further embodiment, initial administration of an analeptic to a patient can occur and/or continue after M-drug therapy has ended. Preferably, this is accomplished by administering an amount of the analeptic to the patient and the administration of which can continue for 1, 2, 5, 10, 20, or 30 days, or more, after M- "drug therapy cessation. "In embodiments where the analeptic and M-drug are in separate dosage forms, the administration of the analeptic can preferably occur within moments, or in less than 1 hour, or less than 5 hours, or less than 24 hours or less than 48 hours, or less than 72 hours before or after administration of the M-drug, unless otherwise indicated by a particular method of treatment below.
In one embodiment, an M-drug can be administered before administration of an analeptic.
B. Administration of an Analeptic To Reduce Side Effects Associated With
M-drug Treatment Cessation :
Administration of a combination of an analeptic such as modafinil and one or more M-drugs can significantly reduce the adverse side effects associated with the discontinuation of M-drug therapy. In such an embodiment, an effective amount of modafinil can be administered simultaneously with an M-drug and/or after M-drug therapy has been discontinued.
In one embodiment, the present invention includes a method of reducing adverse symptoms in an animal subject associated with the cessation of M-drug therapy. The method includes administering an effective amount of one or more analeptics, including but not limited to modafinil, to the animal subject, preferably a human, to reduce the adverse symptoms, wherein the analeptic is administered before and/or during and/or after M-drug therapy cessation, according to one or more of the timing schemes set forth above. The amount of analeptic and duration of analeptic therapy can vary from subject to subject.
However, in one embodiment, the amount of analeptic includes an effective amount, typically from about 100 mg to about 200 mg of modafinil administered once or twice daily during M-drug therapy. In another embodiment, administration of an . analeptic can occur within a period of 2 days, preferably less than 10 days, prior to the cessation of therapy of the M-drug with which it is desired to have a reduction of adverse symptoms. The administration of both modafinil and an M-drug can significantly reduce the adverse side effects associated with the discontinuation of M- drug therapy.
In one embodiment, the analeptic can be administered after M-drug treatment cessation. In such an embodiment, the administration of an analeptic can continue for a period of 1, 2, 5, 10, 20, or 30 days or more after the cessation of M-drug therapy.
In such an embodiment, the modafinil can be administered orally, nasally, rectally, intravenously, epidurally, intraperitoneally, subcutaneously, intramuscularly or intrathecally.
C. Disorder Treatment Generally
In one embodiment, the present invention includes a method of treating a depressive disorder by providing a pharmacolo gically active composition to a subject in need of the composition, preferably a human subject. The pharmacologically active composition can include an amount of an analeptic, preferably a therapeutically effective amount of an analeptic, and one or more M-drugs. The composition can optionally further include a pharmaceutically acceptable carrier, as described above.
The pharmacologically active composition can then be administered to an animal subject.
The analeptics and other drugs can be administered to a patient simultaneously or at different times, as described above, and can follow one or more of the administration schemes set forth above.
The pharmacologically active composition and/or combination can be administered via any acceptable route, including but not limited to orally, nasally, rectally, intravenously, epidurally, intraperitoneally, subcutaneously, intramuscularly or intrathecally.
In one embodiment, the administered analeptic is modafinil or a salt thereof.
In another embodiment, the M-drug can include one or more of the M-drugs described above, including but not limited to tiagabine.
In one embodiment, one or more analeptics are in a single unit dose form and one or more M-drugs are in a separate unit dose form. Each unit dose form can be administered simultaneously or at different times, according to one or more of the administration schemes described above. In a preferred embodiment, the pharmacologically active composition contains both an analeptic and an M-drug ina single unit dose form.
In a further embodiment, a therapy method for treating a depressive disorder in an animal subject includes topically applying a pharmaceutically acceptable drug formulation having at least one M-drug to the skin of an animal, wherein the pharmaceutically acceptable drug formulation is contained in a patch. An additional effective amount of one or more analeptics, including but not limited to modafinil, can be provided to the animal, either in a matrix included in the patch or via administration of the analeptic through any other acceptable route, including but not limited to orally, nasally, rectally, intravenously, epidurally, intraperitoneally, subcutaneously, intramuscularly or intrathecally.
D. Reduction of Disorder Side Effects
In one embodiment, the present invention includes a method of treating a : subject for depression and other disorders for which M-drugs are indicated, whereby side effects of M-drug therapy are reduced. The method includes the steps of administering to the subject an effective amount of an analeptic agent in addition to administering to the patient an effective amount of an M-drug. The therapy can occur according to one or more timing schemes set forth above. -
In another embodiment, the present invention includes a method for enhancing activity of an M-drug, whereby side effects are reduced. The method includes the steps of administering to the subject an effective amount of an analeptic agent in addition to administering to the patient an effective amount of an M-drug according to one or more of the administration schemes set forth above.
In yet another embodiment, the present invention includes a method of decreasing onset time of an M-drug, whereby side effects are reduced. The method includes administering to the subject an effective amount of an analeptic agent in addition to administering to the patient an effective amount of an M-drug according to one or more of the administration schemes set forth above.
In a further embodiment, the present invention includes a method for "enhancing activity of an M-drug and decreasing onset time of an M-drug, whereby side effects are reduced. The method includes the steps of administering to the subject an effective amount of an analeptic agent in addition to administering to the patient an effective amount of an M-drug according to one or more of the administration schemes set forth above.
E. Enhancing M-drug Activity
In one embodiment, the present invention includes a method of enhancing the activity of an M-drug in an animal subject, preferably a human. The method includes the step of pre-treating the subject with an effective amount of one or more analeptics, including but not limited to modafinil. The amount of analeptic and duration of pretreatment can vary from subject to subject, but typically conforms to the amounts described above and one or more of the timing schemes set forth above.
However, in one particular embodiment, the amount of analeptic includes an effective amount, typically from about 100 mg to about 200 mg of modafinil administered once or twice daily for a period of less than 2 days, preferably less than 10 days, prior to the initiation of M-drug therapy. The administration of the analeptic can also optionally continue during M-drug therapy and also continue for a period of time after the cessation of M-drug therapy, as described above.
The analeptic can be administered orally, nasally, rectally, intravenously, epidurally, intraperitoneally, subcutaneously, intramuscularly or intrathecally.
v 16
FE. Reduction of Onset Time of M-drug Effect
The time lapse between initiation of M-drug therapy and alleviation of associated M-drug therapy symptoms can be shortened. In one embodiment of the present invention, depressive symptoms can be improved after the initiation of administration of an analeptic, including but not limited to modafinil, before or during
M-drug therapy or by following one or more of the timing schemes set forth above. ~The time of improvement can be from 1, 2, 4, 7, 10, and 14 days relative to M- drug therapy alone.
In a further embodiment, the present invention includes a method of decreasing the onset time of an M-drug in an animal subject. The method includes the step of pre-treating the subject with an effective amount of one or more analeptics, : including but not limited to modafinil and/or co-administering an effective amount of one or more analeptics, including, but not limited to modafinil with an M-drug. The amount of analeptic and duration of pretherapy can vary from subject to subject.
However, it is preferred that the timing of administration of the analeptic follow one or more of the timing schemes set forth above.
In one embodiment, the amount of analeptic includes an effective amount of modafinil, typically from about 100 mg to about 200 mg of modafinil administered once or twice daily for a period of less than 2 days, preferably less than 10 days, prior to the initiation therapy of the M-drug with which it is desired to have a decrease in onset time. In another embodiment, the first administration of an analeptic can be within 72 hours, preferably within 48 hours, more preferably within 24 hours, most preferably within 1 hour or within moments before initial administration of an M- drug. As noted above, the administration of the analeptic can also optionally continue during M-drug therapy.
The analeptic can be administered orally, nasally, rectally, intravenously, epidurally, intraperitoneally, subcutaneously, intramuscularly or intrathecally.
GG Reduction of Adverse Symptoms
In one embodiment, the present invention includes a method of reducing adverse symptoms in an animal subject associated with M-drug therapy. The method includes administering an effective amount of one or more analeptics, including but
Claims (44)
1. A pharmaceutical composition for the treatment of a depressive disorder comprising an analeptic, an M-drug, and a pharmaceutically acceptable carrier.
2. The composition according to claim 1 wherein the analeptic comprises modafinil.
3. The composition of claim 1 wherein the analeptic is a pharmaceutically acceptable salt of modafinil.
4, The composition of claim 1 wherein the analeptic is a substantially pure enantiomer of modafinil.
5. The composition according to claim 1 wherein the ratio of analeptic to M-drug is from 0.1 to 10:1, by weight.
6. "The composition of claim 5, wherein the ratio of analeptic to M-drug is from 1:1 to 5:1, by weight.
7. The composition of claim 1 wherein the M-~drug is selected from the group consisting of antipsychotics, cholinesterase inhibitors, interferons, dopamine agonists, antiepileptics, heart failure medications, and antineoplastics.
8. The composition of claim 1 wherein the M-drug is selected from the group consisting of risperidone, clozapine, olanzapine, donepezil, galantamine, interferon beta-1a, interferon beta-1b, ropinirole, bromocriptine, pergolide, pramipexole, tiagabine, topiramate, phenytoin, carbamazepine, lamotrigine,
gabapentin, digoxin, captopril, enalapril, verapamil, diltiazem, nifedipine, losartan, prazosin, labetalol, taxol, docetaxel, cisplatinum, and vincristine.
9. The composition of claim 1 wherein the amount of M-drug includes 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300 or 400 mg of M-drug.
10. The composition of claim 1 wherein the amount of analeptic includes 5, 10, 15, 20, 30, 40, 50, 60, 70, 75, 80, 90, 100, 200, 300 or 400 mg of analeptic.
11. The composition of claim 4 wherein the enantiomer is the R-isomer of modafinil.
12. The composition of claim 1 wherein the analeptic is administered before or simultaneously with administration of the M-drug.
13. A method for treating a depressive disorder in an animal subject comprising: (a) providing a pharmacologically active composition comprising therapeutically effective amounts of an analeptic and an M-drug; and (b) administering the pharmacologically active composition to the subject to treat a depressive disorder wherein the analeptic and M-drug are in a single unit dose or the administration of modafinil is prior to or at about the same time as the administration of the M-drug.
14. The method according to claim 13 wherein the analeptic comprises modafinil.
15. The method of claim 14 wherein the M-drug is selected from the group consisting of antipsychotics, cholinesterase inhibitors, interferons, dopamine agonists, antiepileptics, heart failure medications, and antineoplastics.
16. The method of claim 13 wherein the M-drug is selected from the group consisting of risperidone, clozapine, olanzapine, donepezil, galantamine, interferon : beta-1a, interferon beta-1b, ropinirole, bromocriptine, pergolide, pramipexole, tiagabine, topiramate, phenytoin, carbamazepine, lamotrigine, gabapentin, digoxin, captopril, enalapril, verapamil, diltiazem, nifedipine, losartan, prazosin, labetalol, taxol, docetaxel, cisplatinum, and vincristine.
17. The method of claim 13 wherein the amount of M-drug includes 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300 or 400 mg of M-drug.
18. The method of claim 13 wherein the amount of analeptic includes 5, 10, 15, 20, 30, 40, 50, 60, 70, 75, 80, 90, 100, 200, 300 or 400 mg of analeptic.
19. A method of reducing adverse symptoms associated with the cessation of M-drug therapy in an animal subject comprising administering an amount of modafinil sufficient to reduce the adverse symptoms to the subject.
20. A method of treating a subject for depression and other disorders for which M-drugs are indicated, whereby side effects are reduced comprising administering an effective amount of an analeptic agent and an M-drug to the subject.
21. A method for decreasing the onset time of an M-drug administered to an animal subject comprising treating the subject with an effective amount of modafinil prior to the administration of the M-drug.
22. The method of claim 21 wherein modafinil is administered one or more of 72 hours, 48 hours, 24 hours, 1 hour or within moments before administration of an M-drug.
PCT/US2004/015408 Claims:
1. A pharmaceutical composition comprising modafinil, an antineoplastic drug, and a pharmaceutically acceptable carrier.
2. The composition of claim 1 wherein the modafinil is a substantially pure enantiomer of modafinil.
3. The composition according to claim 1 wherein the ratio of modafinil to antineoplastic drug is from 1:1 to 10:1, by weight. 4, The composition of claim 3, wherein the ratio of modafinil to antineoplastic drug is from 1:1 to 5:1, by weight.
5. The composition of claim 1 whereir: the antineoplastic drug is selected from the group consisting of taxol, docetaxel, cisplatinum, and vincristine.
6. The composition of claim | wherein the amount of antineoplastic drug includes 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300 or 400 mg of antineoplastic drug.
7. The composition of claim | wherein the amount of modafinil includes 5, 10, 15, 20, 30, 40, 50, 60, 70, 75, 80, 90, 100, 200, 300 or 400 mg of modafinil.
8. The composition of claim 2 wherein the enantiomer is the R-isomer of modafinil.
9. The composition of claim | wherein the modafinil is administered before or simultaneously with administration of the antineoplastic drug. AMENDED SHEET
PCT/US2004/015408
10. Use of a modafinil and an antineopastic drug in the manufacture of a medicament for the treatment of disorders or side effects associated with antineoplastic drug therapy in an animal subject.
11. Use of modafinil in the manufacture of a medicament for use with an antineoplastic drug for the treatment of disorders or side effects associated with antineoplastic drug therapy wherein the medicament is administrable prior to or at about the same time as administration of the antineoplastic drug.
12. Use according to claim 10 or claim 11 wherein the disorder or side effect associated with antineoplastic drug therapy is fatigue.
13. Use of claim 10 or claim 11 wherein the antineoplastic drug is selected from the group consisting of taxol, docetaxel, cisplatinum, and vincristine.
14. Use of claim 10 or claim 11 wherein the amount of antineoplastic drug includes 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300 or 400 mg of antineoplastic drug.
15. Use of claim 10 or claim 11 wherein the amount of modafinil includes 5, 10, 15, 20, 30, 40, 50, 60, 70, 75, 80, 90, 100, 200, 300 or 400 mg of modafinil.
16. Use of modafinil in the manufacture of a medicament for reducing adverse symptoms associated with the cessation of antineoplastic drug therapy in an animal subject.
17. Use of modafinil and an antineoplastic drug in the manufacture of a medicament for treating a subject for disorders for which antineoplastic drugs are indicated, whereby side effects are reduced.
18. Use of a modafinil in the manufacture of a medicament for decreasing the onset time of an antineoplastic drug administered to an animal subject wherein said medicament is AMENDED SHEET hd vr, PCT/US2004/015408 administrable to the subject in an effective amount prior to administration of the antineoplastic drug.
19. Use of claim 18 wherein said medicament is administrable one or more of 72 hours, 48 hours, 24 hours, 1 hour or within moments before administration of an antineoplastic drug.
20. The composition of claim 1 wherein the modafinil and antineoplastic drug are in a unit dose form suitable for simultaneous administration.
21. Use according to claim 10 or claim 11 wherein the modafinil is the R-isomer of modafinil.
22. Use of claim 10 or claim 11 wherein the modafinil is administrable before or simultaneously with administration of the antineoplastic drug.
23. Use of claim 17 wherein the subject is treated with an effective amount of the R- isomer of modafinil.
24. Use of claim 17 wherein the side effect that is reduced is fatigue.
25. Use of claim 17 wherein the antineoplastic drug is selected from the group consisting of taxol, docetaxel, cisplatinum, and vincristine.
26. Use of claim 17 wherein the medicament is administrable before or simultaneously with administration of the antineoplastic drug.
27. Use of claim 18 wherein the modafinil is the R-isomer of modafinil. AMENDED SHEET
¥ PCT/US2004/015408
28. Use of claim 18 wherein the antineoplastic drug is selected from the group consisting of taxol, docetaxel, cisplatinum, and vincristine.
29. Use of claim 18 wherein the modafinil is administrable before or simultaneously with administration of the antineoplastic drug.
30. Use of claim 19 wherein modafinil is an R-isomer of modafinil.
31. Use of claim 19 wherein the antineoplastic drug is selected from the group consisting of taxol, docetaxel, cisplatinum, and vincristine.
32. Use of claim 19 wherein the medicament is administrable before or simultaneously with administration of the antineoplastic drug.
33. Use of claim 19 wherein the medicament is administrable during the antineoplastic drug therapy.
34. Use of modafinil in the manufacture of a medicament for enhancing the activity of an antineoplastic drug in an animal.
35. Use of claim 34 wherein the modafinil is an R-isomer of modafinil.
36. Use of claim 34 wherein the antineoplastic drug is selected from the group consisting of taxol, docetaxel, cisplatinum, and vincristine.
37. Use of claim 34 wherein the medicament is administrable before or simultaneously with administration of the antineoplastic drug.
38. Use of modafinil in the manufacture of a medicament for decreasing the onset time of an antineoplastic drug used in drug therapy of an animal subject. AMENDED SHEET
” PCT/US2004/015408
39. Use of claim 38 wherein the modafinil is an R-isomer of modafinil.
40. Use of claim 38 wherein the antineoplastic drug is selected from the group consisting of taxol, docetaxel, cisplatinum, and vincristine.
41. Use of claim 38 wherein the modafinil is administrable before or simultaneously with an initial administration of an antineoplastic drug.
42. Use of claim 38 wherein the modafinil is administrable after antineoplastic drug therapy cessation.
43. A composition according to any one of claims 1 to 9 or 20, substantially as herein described with reference to and as illustrated in any of the examples.
44. Use according to any one of claims 10 to 19 or 21 to 42, substantially as herein described with reference to and as illustrated in any of the examples. AMENDED SHEET
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US47130203P | 2003-05-16 | 2003-05-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200509247B true ZA200509247B (en) | 2007-07-25 |
Family
ID=36788723
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200509247A ZA200509247B (en) | 2003-05-16 | 2005-11-15 | Pharmaceutical combination comprising modafinil and another drug |
Country Status (4)
Country | Link |
---|---|
CN (1) | CN1791397A (en) |
AR (1) | AR044360A1 (en) |
CL (1) | CL2004001071A1 (en) |
ZA (1) | ZA200509247B (en) |
-
2004
- 2004-05-17 AR ARP040101682 patent/AR044360A1/en not_active Application Discontinuation
- 2004-05-17 CL CL2004001071A patent/CL2004001071A1/en unknown
- 2004-05-17 CN CN 200480013407 patent/CN1791397A/en active Pending
-
2005
- 2005-11-15 ZA ZA200509247A patent/ZA200509247B/en unknown
Also Published As
Publication number | Publication date |
---|---|
CN1791397A (en) | 2006-06-21 |
AR044360A1 (en) | 2005-09-07 |
CL2004001071A1 (en) | 2005-03-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20040229943A1 (en) | Analeptic and drug combinations | |
US20200179336A1 (en) | Methods of treating neurological and psychiatric disorders | |
JP2007518763A (en) | Α-Aminoamide derivatives useful for the treatment of lower urinary tract disorders | |
NO334448B1 (en) | A pharmaceutical composition comprising modafinil and an antidepressant | |
US20040242698A1 (en) | Analeptic and antidepressant combinations | |
US20040229941A1 (en) | Analeptic and antidepressant combinations | |
US20040229940A1 (en) | Analeptic and antidepressant combinations | |
ZA200509247B (en) | Pharmaceutical combination comprising modafinil and another drug | |
US10576045B2 (en) | Low dosage combinations of fluoxetine and reboxetine for treating obesity | |
SK3272001A3 (en) | A new composition | |
ZA200510099B (en) | Combination of the analeptic modafinil and an anti-depressant for the treatment of depression | |
US8399708B2 (en) | Compounds useful for treating bipolar disorders | |
WO2007088473A2 (en) | Treatment and prevention of depression with pain, depression secondary to pain, and of neuropathic pain | |
WO2024052895A1 (en) | Combinations comprising psychedelics for the treatment of schizophrenia and other neuropsychiatric and neurologic disorders | |
WO2003072093A1 (en) | METHOD OF TREATMENT OF HYPERTENSION USING SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SSRIs) |