US20190133971A1 - Pharmaceutical Combination - Google Patents
Pharmaceutical Combination Download PDFInfo
- Publication number
- US20190133971A1 US20190133971A1 US16/238,990 US201916238990A US2019133971A1 US 20190133971 A1 US20190133971 A1 US 20190133971A1 US 201916238990 A US201916238990 A US 201916238990A US 2019133971 A1 US2019133971 A1 US 2019133971A1
- Authority
- US
- United States
- Prior art keywords
- composition
- matter
- dimethylamino
- propyl
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 claims abstract description 74
- 239000001961 anticonvulsive agent Substances 0.000 claims abstract description 57
- 230000003556 anti-epileptic effect Effects 0.000 claims abstract description 49
- -1 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound Chemical class 0.000 claims abstract description 39
- 208000002193 Pain Diseases 0.000 claims abstract description 34
- 230000036407 pain Effects 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000002552 dosage form Substances 0.000 claims abstract description 8
- 208000004296 neuralgia Diseases 0.000 claims abstract description 8
- 208000021722 neuropathic pain Diseases 0.000 claims abstract description 8
- 230000037361 pathway Effects 0.000 claims abstract description 8
- KWTWDQCKEHXFFR-SMDDNHRTSA-N tapentadol Chemical compound CN(C)C[C@H](C)[C@@H](CC)C1=CC=CC(O)=C1 KWTWDQCKEHXFFR-SMDDNHRTSA-N 0.000 claims description 38
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 34
- 229960001233 pregabalin Drugs 0.000 claims description 32
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 claims description 32
- 150000001875 compounds Chemical class 0.000 claims description 30
- 229960002623 lacosamide Drugs 0.000 claims description 27
- 229960004002 levetiracetam Drugs 0.000 claims description 27
- VPPJLAIAVCUEMN-GFCCVEGCSA-N lacosamide Chemical compound COC[C@@H](NC(C)=O)C(=O)NCC1=CC=CC=C1 VPPJLAIAVCUEMN-GFCCVEGCSA-N 0.000 claims description 26
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 claims description 26
- 229960001848 lamotrigine Drugs 0.000 claims description 24
- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 claims description 24
- 229960002870 gabapentin Drugs 0.000 claims description 19
- 229960004394 topiramate Drugs 0.000 claims description 18
- 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 17
- PCOBBVZJEWWZFR-UHFFFAOYSA-N ezogabine Chemical compound C1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 PCOBBVZJEWWZFR-UHFFFAOYSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 15
- 230000001419 dependent effect Effects 0.000 claims description 10
- 238000007912 intraperitoneal administration Methods 0.000 claims description 9
- 229960003312 retigabine Drugs 0.000 claims description 9
- 230000002195 synergetic effect Effects 0.000 claims description 9
- 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 8
- 239000012752 auxiliary agent Substances 0.000 claims description 8
- 229960000623 carbamazepine Drugs 0.000 claims description 8
- 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 8
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 claims description 8
- 229960002036 phenytoin Drugs 0.000 claims description 8
- BHJIBOFHEFDSAU-LBPRGKRZSA-N ralfinamide Chemical compound C1=CC(CN[C@@H](C)C(N)=O)=CC=C1OCC1=CC=CC=C1F BHJIBOFHEFDSAU-LBPRGKRZSA-N 0.000 claims description 8
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 claims description 8
- 229960000604 valproic acid Drugs 0.000 claims description 8
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 7
- 102100024426 Dihydropyrimidinase-related protein 2 Human genes 0.000 claims description 7
- 239000000480 calcium channel blocker Substances 0.000 claims description 7
- 108010022822 collapsin response mediator protein-2 Proteins 0.000 claims description 7
- 238000013270 controlled release Methods 0.000 claims description 6
- BMPDWHIDQYTSHX-AWEZNQCLSA-N (S)-MHD Chemical compound C1[C@H](O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 BMPDWHIDQYTSHX-AWEZNQCLSA-N 0.000 claims description 5
- KWTWDQCKEHXFFR-RISCZKNCSA-N 3-[(2s,3s)-1-(dimethylamino)-2-methylpentan-3-yl]phenol Chemical compound CN(C)C[C@@H](C)[C@H](CC)C1=CC=CC(O)=C1 KWTWDQCKEHXFFR-RISCZKNCSA-N 0.000 claims description 5
- 208000000094 Chronic Pain Diseases 0.000 claims description 5
- 101000584505 Homo sapiens Synaptic vesicle glycoprotein 2A Proteins 0.000 claims description 5
- 206010065390 Inflammatory pain Diseases 0.000 claims description 5
- 102100030701 Synaptic vesicle glycoprotein 2A Human genes 0.000 claims description 5
- 208000005298 acute pain Diseases 0.000 claims description 5
- 229960002161 brivaracetam Drugs 0.000 claims description 5
- MSYKRHVOOPPJKU-BDAKNGLRSA-N brivaracetam Chemical compound CCC[C@H]1CN([C@@H](CC)C(N)=O)C(=O)C1 MSYKRHVOOPPJKU-BDAKNGLRSA-N 0.000 claims description 5
- 229960004028 eslicarbazepine Drugs 0.000 claims description 5
- 238000001990 intravenous administration Methods 0.000 claims description 5
- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 claims description 5
- 108090000312 Calcium Channels Proteins 0.000 claims description 4
- 102000003922 Calcium Channels Human genes 0.000 claims description 4
- 206010058019 Cancer Pain Diseases 0.000 claims description 4
- 108091006146 Channels Proteins 0.000 claims description 4
- 229940086575 Glutamate release inhibitor Drugs 0.000 claims description 4
- 208000019695 Migraine disease Diseases 0.000 claims description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 claims description 4
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 claims description 4
- 230000002779 inactivation Effects 0.000 claims description 4
- 239000003446 ligand Substances 0.000 claims description 4
- 206010027599 migraine Diseases 0.000 claims description 4
- 239000003195 sodium channel blocking agent Substances 0.000 claims description 4
- 208000009935 visceral pain Diseases 0.000 claims description 4
- ALARQZQTBTVLJV-CYBMUJFWSA-N (5r)-5-ethyl-1-methyl-5-phenyl-1,3-diazinane-2,4,6-trione Chemical compound C=1C=CC=CC=1[C@]1(CC)C(=O)NC(=O)N(C)C1=O ALARQZQTBTVLJV-CYBMUJFWSA-N 0.000 claims description 3
- KWTWDQCKEHXFFR-FZMZJTMJSA-N 3-[(2r,3s)-1-(dimethylamino)-2-methylpentan-3-yl]phenol Chemical compound CN(C)C[C@H](C)[C@H](CC)C1=CC=CC(O)=C1 KWTWDQCKEHXFFR-FZMZJTMJSA-N 0.000 claims description 3
- KWTWDQCKEHXFFR-BXUZGUMPSA-N 3-[(2s,3r)-1-(dimethylamino)-2-methylpentan-3-yl]phenol Chemical compound CN(C)C[C@@H](C)[C@@H](CC)C1=CC=CC(O)=C1 KWTWDQCKEHXFFR-BXUZGUMPSA-N 0.000 claims description 3
- 108010060511 4-Aminobutyrate Transaminase Proteins 0.000 claims description 3
- 102100035923 4-aminobutyrate aminotransferase, mitochondrial Human genes 0.000 claims description 3
- 229940098747 AMPA receptor antagonist Drugs 0.000 claims description 3
- 239000000775 AMPA receptor antagonist Substances 0.000 claims description 3
- SIGSNYAYBSJATD-UHFFFAOYSA-N Ethadione Chemical compound CCN1C(=O)OC(C)(C)C1=O SIGSNYAYBSJATD-UHFFFAOYSA-N 0.000 claims description 3
- XWLUWCNOOVRFPX-UHFFFAOYSA-N Fosphenytoin Chemical compound O=C1N(COP(O)(=O)O)C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 XWLUWCNOOVRFPX-UHFFFAOYSA-N 0.000 claims description 3
- 102000005915 GABA Receptors Human genes 0.000 claims description 3
- 108010005551 GABA Receptors Proteins 0.000 claims description 3
- FWJKNZONDWOGMI-UHFFFAOYSA-N Metharbital Chemical compound CCC1(CC)C(=O)NC(=O)N(C)C1=O FWJKNZONDWOGMI-UHFFFAOYSA-N 0.000 claims description 3
- AJXPJJZHWIXJCJ-UHFFFAOYSA-N Methsuximide Chemical compound O=C1N(C)C(=O)CC1(C)C1=CC=CC=C1 AJXPJJZHWIXJCJ-UHFFFAOYSA-N 0.000 claims description 3
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 claims description 3
- VQASKUSHBVDKGU-UHFFFAOYSA-N Paramethadione Chemical compound CCC1(C)OC(=O)N(C)C1=O VQASKUSHBVDKGU-UHFFFAOYSA-N 0.000 claims description 3
- XPFRXWCVYUEORT-UHFFFAOYSA-N Phenacemide Chemical compound NC(=O)NC(=O)CC1=CC=CC=C1 XPFRXWCVYUEORT-UHFFFAOYSA-N 0.000 claims description 3
- AJOQSQHYDOFIOX-UHFFFAOYSA-N Pheneturide Chemical compound NC(=O)NC(=O)C(CC)C1=CC=CC=C1 AJOQSQHYDOFIOX-UHFFFAOYSA-N 0.000 claims description 3
- WLWFNJKHKGIJNW-UHFFFAOYSA-N Phensuximide Chemical compound O=C1N(C)C(=O)CC1C1=CC=CC=C1 WLWFNJKHKGIJNW-UHFFFAOYSA-N 0.000 claims description 3
- 108010052164 Sodium Channels Proteins 0.000 claims description 3
- 102000018674 Sodium Channels Human genes 0.000 claims description 3
- HMHVCUVYZFYAJI-UHFFFAOYSA-N Sultiame Chemical compound C1=CC(S(=O)(=O)N)=CC=C1N1S(=O)(=O)CCCC1 HMHVCUVYZFYAJI-UHFFFAOYSA-N 0.000 claims description 3
- 102000003691 T-Type Calcium Channels Human genes 0.000 claims description 3
- 108090000030 T-Type Calcium Channels Proteins 0.000 claims description 3
- 229960000343 amino(diphenylhydantoin) valeric acid Drugs 0.000 claims description 3
- PAJBBDCZSMDSFL-UHFFFAOYSA-N amino(diphenylhydantoin) valeric acid Chemical compound O=C1N(CCCC(N)C(O)=O)C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 PAJBBDCZSMDSFL-UHFFFAOYSA-N 0.000 claims description 3
- 229940124277 aminobutyric acid Drugs 0.000 claims description 3
- 239000002380 aminotransferase inhibitor Substances 0.000 claims description 3
- 239000005557 antagonist Substances 0.000 claims description 3
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 claims description 3
- 229960002910 barbexaclone Drugs 0.000 claims description 3
- MJCBWPMBFCUHBP-NPULLEENSA-N barbexaclone Chemical compound CN[C@@H](C)CC1CCCCC1.C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O MJCBWPMBFCUHBP-NPULLEENSA-N 0.000 claims description 3
- 229960005200 beclamide Drugs 0.000 claims description 3
- JPYQFYIEOUVJDU-UHFFFAOYSA-N beclamide Chemical compound ClCCC(=O)NCC1=CC=CC=C1 JPYQFYIEOUVJDU-UHFFFAOYSA-N 0.000 claims description 3
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 claims description 3
- 229960003120 clonazepam Drugs 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229960000262 ethadione Drugs 0.000 claims description 3
- 229960002767 ethosuximide Drugs 0.000 claims description 3
- HAPOVYFOVVWLRS-UHFFFAOYSA-N ethosuximide Chemical compound CCC1(C)CC(=O)NC1=O HAPOVYFOVVWLRS-UHFFFAOYSA-N 0.000 claims description 3
- SZQIFWWUIBRPBZ-UHFFFAOYSA-N ethotoin Chemical compound O=C1N(CC)C(=O)NC1C1=CC=CC=C1 SZQIFWWUIBRPBZ-UHFFFAOYSA-N 0.000 claims description 3
- 229960003533 ethotoin Drugs 0.000 claims description 3
- 229960003472 felbamate Drugs 0.000 claims description 3
- WKGXYQFOCVYPAC-UHFFFAOYSA-N felbamate Chemical compound NC(=O)OCC(COC(N)=O)C1=CC=CC=C1 WKGXYQFOCVYPAC-UHFFFAOYSA-N 0.000 claims description 3
- 229960000693 fosphenytoin Drugs 0.000 claims description 3
- 239000002843 gaba uptake inhibitor Substances 0.000 claims description 3
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 3
- GMHKMTDVRCWUDX-UHFFFAOYSA-N mephenytoin Chemical compound C=1C=CC=CC=1C1(CC)NC(=O)N(C)C1=O GMHKMTDVRCWUDX-UHFFFAOYSA-N 0.000 claims description 3
- 229960000906 mephenytoin Drugs 0.000 claims description 3
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- 229960002057 metharbital Drugs 0.000 claims description 3
- 229960001703 methylphenobarbital Drugs 0.000 claims description 3
- 229960001816 oxcarbazepine Drugs 0.000 claims description 3
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- 229960002695 phenobarbital Drugs 0.000 claims description 3
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 claims description 3
- 229960004227 phensuximide Drugs 0.000 claims description 3
- 229960002393 primidone Drugs 0.000 claims description 3
- DQMZLTXERSFNPB-UHFFFAOYSA-N primidone Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NCNC1=O DQMZLTXERSFNPB-UHFFFAOYSA-N 0.000 claims description 3
- 229960002752 progabide Drugs 0.000 claims description 3
- IBALRBWGSVJPAP-HEHNFIMWSA-N progabide Chemical compound C=1C(F)=CC=C(O)C=1C(=N/CCCC(=O)N)/C1=CC=C(Cl)C=C1 IBALRBWGSVJPAP-HEHNFIMWSA-N 0.000 claims description 3
- 229960003014 rufinamide Drugs 0.000 claims description 3
- POGQSBRIGCQNEG-UHFFFAOYSA-N rufinamide Chemical compound N1=NC(C(=O)N)=CN1CC1=C(F)C=CC=C1F POGQSBRIGCQNEG-UHFFFAOYSA-N 0.000 claims description 3
- 229960001897 stiripentol Drugs 0.000 claims description 3
- IBLNKMRFIPWSOY-FNORWQNLSA-N stiripentol Chemical compound CC(C)(C)C(O)\C=C\C1=CC=C2OCOC2=C1 IBLNKMRFIPWSOY-FNORWQNLSA-N 0.000 claims description 3
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- 229960001918 tiagabine Drugs 0.000 claims description 3
- 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 3
- 229960004453 trimethadione Drugs 0.000 claims description 3
- IRYJRGCIQBGHIV-UHFFFAOYSA-N trimethadione Chemical compound CN1C(=O)OC(C)(C)C1=O IRYJRGCIQBGHIV-UHFFFAOYSA-N 0.000 claims description 3
- OMOMUFTZPTXCHP-UHFFFAOYSA-N valpromide Chemical compound CCCC(C(N)=O)CCC OMOMUFTZPTXCHP-UHFFFAOYSA-N 0.000 claims description 3
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- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 claims description 3
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 claims description 2
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- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 claims description 2
- 238000001361 intraarterial administration Methods 0.000 claims description 2
- 238000007918 intramuscular administration Methods 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 1
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- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
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- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
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Classifications
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions
- the present invention relates to a combination comprising as components (a) at least one 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound, and (b) at least one antiepileptic, a pharmaceutical formulation and a dosage form comprising said combination as well as a method of treating pain, e.g. neuropathic pain, wherein components (a) and (b) are administered simultaneously or sequentially to a mammal, whereby component (a) may be administered before or after component (b) and whereby components (a) or (b) are administered to the mammal either via the same or a different pathway of administration.
- pain e.g. neuropathic pain
- WO 01/13904 describes substance combinations comprising a tramadol material and an anticonvulsant drug, which show super-additive effects upon administration. Due to the super-additive effect the overall dose and accordingly the risk of undesired side effects can be reduced.
- a combination comprising (a) at least one 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound, and (b) at least one antiepileptic exhibits an analgesic effect. If these components are present in the composition in such a weight ratio that a supra-additive or synergistic effect is observed upon administration to the patients, the overall administered dose may be lowered, so that fewer undesired side-effects will occur.
- the present invention relates to a pharmaceutical combination comprising as components
- the compound of formula (I) is selected from the group consisting of:
- component (a) includes 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, derivatives thereof and stereoisomers thereof in any possible form, thereby particularly including solvates and polymorphs, salts, in particular acid addition salts and corresponding solvates and polymorphs.
- derivative as used herein particularly includes prodrugs such as ethers and esters of the active substance.
- prodrugs such as ethers and esters of the active substance.
- Suitable methods for selecting and preparing a pro-drug of a given substance are for example described in “Textbook of Drug Design and Discovery”, 3 rd edition, 2002, chapter 14, pages 410-458, Editors: Krogsgaard-Larsen et al., Taylor and Francis. The respective parts of said literature description are incorporated by reference and form part of the present disclosure.
- component (a) is present as mixture of enantiomers, such a mixture may contain the enantiomers in racemic or non-racemic form.
- a non-racemic form could, for example, contain the enantiomers in a ratio of 60 ⁇ 5:40 ⁇ 5, 70 ⁇ 5:30 ⁇ 5, 80 ⁇ 5:20 ⁇ 5 or 90 ⁇ 5:10 ⁇ 5.
- stereoisomers e.g., enantiomers or diastereomers
- isolated means that the respective stereoisomer is separated from other stereoisomers but not necessarily from other substances.
- the compound 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol and its stereoisomers according to component (a) may be present in the inventive pharmaceutical composition in form of an acid addition salt, whereby any suitable acid capable of forming such an addition salt may be used.
- Suitable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid.
- Salt formation is preferably effected in a solvent, for example, diethyl ether, diisopropyl ether, alkyl acetates, acetone and/or 2-butanone.
- a solvent for example, diethyl ether, diisopropyl ether, alkyl acetates, acetone and/or 2-butanone.
- trimethylchlorosilane in aqueous solution is also suitable for the preparation of hydrochlorides.
- Voltage dependent calcium channel blockers such as blockers of the alpha 2 delta subunits, voltage dependent t-type calcium channel blockers, voltage dependent sodium channel blockers, compounds that exhibit enhancement of fast or slow inactivation of voltage dependent sodium channels, KCNQ channel openers, SV2A ligands, modulators of collapsin response mediator protein-2 (CRMP-2), glutamate release inhibitors, AMPA receptor antagonists, NMDA antagonists, GABA receptor modulators such as GABA A receptor inhibitors, GABA B receptor inhibitors, benzodiazepams and barbiturates, GABA aminotransferase inhibitors (GABA-transaminase inhibitors), GABA reuptake inhibitors and carbonic anhydrase inhibitors are well known to those skilled in the art. For these aforementioned compounds general ranges of potency with regard to the respective mechanisms are well known to persons skilled in the art, as are suitable assays for their determination.
- the potency of the voltage dependent calcium channel blockers such as blockers of the alpha 2 delta subunits, expressed in K i for the displacement of [3H-Gabapentin] in the respective binding test, may be in the range of 0.001 to 0.01 ⁇ M.
- the potency of the voltage dependent sodium channel blocker, expressed in IC 50 may be in the range of 0.1 to 500 ⁇ M.
- the potency of the carbonic anhydrase inhibitor may be in the range of 0.1 to 100 nM, IC 50 for the inhibition.
- the potency of the glutamate release inhibitor may be in the range of 1 to 50 ⁇ M, IC 50 for the inhibition.
- the potency of the SV2A ligand, expressed in pK i for the binding affinity to SV2A protein, can be in the range of 0.05 to 5 ⁇ M.
- the potency of the KCNQ channel opener expressed as EC 50 , can be in the range of 0.1 to 10 ⁇ M.
- the modulator of collapsin response mediator protein-2 may have a potency in the range of 1 to 50 ⁇ M, expressed as K for its respective binding affinity.
- the potency of the compound that exhibits enhancing slow inactivation of voltage gated sodium channels may be characterized by an IC 50 in the range of 10 to 500 ⁇ M.
- Antiepileptics which are often also referred to as anticonvulsants, are well known in the art and include, without limitation, barbiturates and derivatives, such as methylphenobarbital, phenobarbital, primidone, barbexaclone and metharbital; hydantoin derivatives such as ethotoin, phenytoin, amino(diphenylhydantoin) valeric acid, mephenytoin and fosphenytoin; oxazolidine derivatives such as paramethadione, trimethadione and ethadione; succinimide derivatives such as ethosuximide, phensuximide and mesuximide; benzodiazepine derivatives such as clonazepam, carboxamide derivatives such as carbamazepine, oxcarbazepine, eslicarbazepine and rufinamide; fatty acid derivatives such as valproic acid, valpro
- antiepileptics are known to be useful in the treatment of neuropathic pain.
- one or more of these antiepileptics is used as component (b).
- stereoisomers also included are stereoisomers, salts, solvates, polymorphs and derivatives of the antiepileptic component as well as mixtures of any of the foregoing.
- the antiepileptic according to component (b) is selected from the group consisting of pregabalin, gabapentin, topiramate, lamotrigine, carbamazepine, oxcarbamazepine, eslicarbazepine, mexiletin, lacosamide, phenytoin, levetiracetam, brivaracetam, selectracetam, retigabin, valproic acid and ralfinamide.
- the antiepileptic according to component (b) is selected from the group consisting of pregabalin, gabapentin, topiramate, lamotrigine, carbamazepine, mexiletin, lacosamide, phenytoin, levetiracetam, retigabin, valproic acid and ralfinamide.
- the antiepileptic according to component (b) is selected from the group consisting of pregabalin, gabapentin, topiramate, lamotrigine, lacosamide, levetiracetam and retigabine.
- the antiepileptic according to component (b) is pregabalin.
- the antiepileptic according to component (b) is (S)-pregabalin.
- the antiepileptic according to component (b) is gabapentin.
- the antiepileptic according to component (b) is topiramate.
- the antiepileptic according to component (b) is lamotrigine.
- the antiepileptic according to component (b) is lacosamide.
- the antiepileptic according to component (b) is levetiracetam.
- the antiepileptic according to component (b) is retigabine.
- the antiepileptic according to component (b) is retigabine dihydrochloride.
- a specific embodiment of the present invention is a combination comprising (a) (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof such as the hydrochloride addition salt, and (b) one or more antiepileptics selected from the group consisting of pregabalin, gabapentin, topiramate, lamotrigine, carbamazepine, oxcarbamazepine, eslicarbazepine, mexiletin, lacosamide, phenytoin, levetiracetam, brivaracetam, selectracetam, retigabin, valproic acid and ralfinamide.
- one or more antiepileptics selected from the group consisting of pregabalin, gabapentin, topiramate, lamotrigine, carbamazepine, oxcarbamazepine, eslicarbazepine, mexilet
- a specific embodiment of the present invention is a combination comprising (a) (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof such as the hydrochloride addition salt, and (b) one or more antiepileptics selected from the group consisting of pregabalin, gabapentin, topiramate, lamotrigine, carbamazepine, mexiletin, lacosamide, phenytoin, levetiracetam, retigabin, valproic acid and ralfinamide.
- Another specific embodiment of the present invention is a combination comprising (a) (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof such as the hydrochloride addition salt, and (b) one or more antiepileptics selected from the group consisting of pregabalin, gabapentin, topiramate, lamotrigine, lacosamide, levetiracetam and retigabine.
- Another specific embodiment of the present invention is a combination comprising (a) (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof such as the hydrochloride addition salt, and (b) pregabalin.
- Yet another specific embodiment of the present invention is a combination comprising (a) (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof such as the hydrochloride addition salt, and (b) (S)-pregabalin.
- Some antiepileptics comprise functional groups, for example, acidic groups such as carboxy groups which are capable of forming salts with the 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol component of formula (I), thereby incorporating both components (a) and (b) in one and the same salt.
- the inventive combination comprises components (a) and (b) in form of a salt formed from these two components.
- Such a salt formation may be partial, i.e. the inventive composition comprises one or both of these components also in their non-salt form, or the salt formation may essentially be complete.
- Both components (a) and (b) as part of the inventive combination may be administered in amounts up to their maximum daily dosage, which is known to those skilled in the art.
- the compound Pregabalin may preferably be administered to a patient in a daily dosage of 1 to 1200 mg
- the compound Gabapentin may preferably be administered to a patient in a daily dosage of 1 to 5000 mg.
- the compound Topiramate may preferably be administered to a patient in a daily dosage of 1-800 mg; the compound Levetiracetam may preferably be administered to a patient in a daily dosage of 1-4500 mg; the compound Lacosamide may preferably be administered to a patient in a daily dosage of 1-800 mg; the compound Lamotrigine may preferably be administered to a patient in a daily dosage of 1-1200 mg, and the compound Retigabine may preferably be administered to a patient in a daily dosage of 1-2400 mg.
- the compound (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol may preferably be administered to a patient in a daily dosage of 25 to 1000 mg, particularly preferably in a dosage of 50 to 800 mg, more particularly preferably in a dosage of 100 to 600 mg.
- the compound (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol may preferably be administered to a patient in a daily dosage of 5 to 1000 mg, particularly preferably in a dosage of 25 to 800 mg, more particularly preferably in a dosage of 50 to 600 mg.
- the inventive combination may comprise 1 to 500 mg Tapentadol and 1 to 660 mg Pregabalin. This combination may, for example, be administered to the patient once daily, twice daily or three times daily.
- the inventive combination may comprise 1 to 500 mg Tapentadol and 1 to 1000 mg Gabapentin. This combination may, for example, be administered to the patient once daily, twice daily or three times daily.
- the inventive combination may comprise 1 to 500 mg Tapentadol and 1 to 400 mg Topiramate. This combination may, for example, be administered to the patient once daily, twice daily or three times daily.
- the inventive combination may comprise 1 to 500 mg Tapentadol and 1 to 600 mg Lamotrigine. This combination may, for example, be administered to the patient once daily, twice daily or three times daily.
- the inventive combination may comprise 1 to 500 mg Tapentadol and 1 to 400 mg Lacosamide. This combination may, for example, be administered to the patient once daily, twice daily or three times daily.
- the inventive combination may comprise 1 to 500 mg Tapentadol and 1 to 1000 mg Levetiracetam. This combination may, for example, be administered to the patient once daily, twice daily or three times daily.
- the inventive combination may comprise 1 to 500 mg Tapentadol and 1 to 1000 mg Retigabine. This combination may, for example, be administered to the patient once daily, twice daily or three times daily.
- the administered amount per day of component (a) and/or component (b) may be less than the respective maximum daily dosage and be, for example, 75 ⁇ 15 wt.-%, 75 ⁇ 10 wt.-%, 75 ⁇ 5 wt.-%, 50 ⁇ 15 wt.-%, 50 ⁇ 10 wt.-%, 50 ⁇ 5 wt.-%, 25 ⁇ 15 wt.-%, 25 ⁇ 10 wt.-% and 25 ⁇ 5 wt.-% for each of the components.
- the inventive combination may contain components (a) and (b) essentially in an equieffective ratio.
- inventive combination components (a) and (b) are present in such a weight ratio that the resulting composition will exert a supra-additive or synergistic effect upon administration to a patient.
- Suitable weight ratios can be determined by methods well known to those skilled in the art.
- Both components (a) and (b) may also be present in the inventive combination in ratios deviating from the equieffective ratio.
- each of the components could be present in a range from 1/50 of the equieffective amount to 50 times the equieffective amount, from 1/20 of the equieffective amount to 20 times the equieffective amount, from 1/10 of the equieffective amount to 10 times the equieffective amount, from 1/5 of the equieffective amount to 5 times the equieffective amount, from 1/4 of the equieffective amount to 4 times the equieffective amount, from 1/3 of the equieffective amount to 3 times the equieffective amount, or from 1/2 of the equieffective amount to 2 times the equieffective amount.
- components (a) and (b) can be administered in a specific dosage regimen to treat pain, for example, neuropathic pain.
- Components (a) and (b) may be administered simultaneously or sequentially to one another, in each case via the same or different administration pathways.
- Another aspect of the present invention is therefore a method of treating pain, characterized in that components (a) and (b) are administered simultaneously or sequentially to a mammal, wherein component (a) may be administered before or after component (b) and wherein components (a) or (b) are administered to the mammal either via the same or a different pathway of administration.
- pain as used herein includes but is not limited to inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain and cancer pain.
- Suitable pathways of administration include but are not limited to oral, intravenous, intraarterial, intraperitoneal, intradermal, transdermal, intrathekal, intramuscular, intranasal, transmucosal, subcutaneous, and rectal administration.
- inventive combinations are toxicologically safe and are therefore suitable for the treatment of mammals, particularly humans including infants, children and grown-ups.
- the present invention relates to a pharmaceutical composition comprising an inventive combination as described herein and one or more auxiliary agents.
- the present invention relates to a pharmaceutical dosage form comprising an inventive combination as described herein and one or more auxiliary agents.
- inventive pharmaceutical dosage form additionally comprises caffeine.
- the pharmaceutical dosage form of the invention is suitable for being administered orally, intravenously, intraarterially, intraperitoneally, intradermally, transdermally, intrathekally, intramuscularly, intranasally, transmucosally, subcutaneously, or rectally.
- auxiliary agents for example, carriers, fillers, solvents, diluents, colorants and/or binders.
- auxiliary agents for example, carriers, fillers, solvents, diluents, colorants and/or binders.
- the selection of auxiliary agents and of the amounts of the same to be used depends, for example, on how the drug is to be administered, e.g. orally, intravenously, intraarterially, intraperitoneally, intradermally, transdermally, intramuscularly, intranasally or locally, for example for infections of the skin, of the mucous membranes or of the eye.
- Suitable auxiliary agents in the context of this invention include any substances known to persons skilled in the art to be useful for the preparation of galenical formulations.
- suitable auxiliary agents include, but are not limited to, water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, saccharose, dextrose, molasses, starch, modified starch, gelatine, sorbitol, inositol, mannitol, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, cellulose acetate, shellac, cetyl alcohol, polyvinyl pyrrolidone, paraffins, waxes, natural and synthetic gums, acacia gum, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glycerol stearate, sodium lau
- compositions in the form of tablets, effervescent tablets, chewing tablets, dragees, capsules, drops, juices or syrups are, for example, suitable for oral administration.
- Oral pharmaceutical formulations may also be in the form of multiparticulates such as granules, pellets, spheres, crystals and the like, optionally compressed into a tablet, filled into a capsule, filled into a sachet or suspended in a suitable liquid medium.
- Oral pharmaceutical formulations may also be equipped with an enteric coating.
- compositions that are suitable for parenteral, topical and inhalative administration include but are not limited to solutions, suspensions, easily reconstitutable dry preparations and sprays.
- Suppositories are a suitable pharmaceutical formulation for rectal administration.
- Formulations in a deposit, in dissolved form, for example, in a patch optionally with the addition of agents to promote skin penetration, are examples of suitable formulations for percutaneous administration.
- One or both of the components (a) and (b) may be present in the inventive pharmaceutical formulation at least partially in controlled-release form.
- any controlled release/immediate release combination of said components may also be present in the inventive pharmaceutical formulation.
- one or both of the components may be released from the inventive formulations with a certain delay, e.g. if administered orally, rectally or percutaneously.
- Such formulations are particularly useful for “once-daily” or “twice-daily” preparations, which only have to be taken once a day, respectively, twice a day.
- Suitable controlled-release materials are well known to those skilled in the art.
- the pharmaceutical formulations of the invention may be produced using materials, means, devices and processes that are well known in the prior art of pharmaceutical formulations, as described for example in “Remington's Pharmaceutical Sciences”, A. R. Gennaro (ed.), 17 th edition, Mack Publishing Company, Easton, Pa. (1985), in particular in part 8, chapters 76 to 93.
- the components of the pharmaceutical composition may be granulated with a pharmaceutical carrier, for example conventional tablet ingredients such as corn starch, lactose, saccharose, sorbitol, talcum, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, for example water, in order to form a solid composition that contains the components in homogeneous distribution.
- a pharmaceutical carrier for example conventional tablet ingredients such as corn starch, lactose, saccharose, sorbitol, talcum, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, for example water
- a pharmaceutical carrier for example conventional tablet ingredients such as corn starch, lactose, saccharose, sorbitol, talcum, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, for example water
- the term “homogeneous distribution” is taken to mean that the components are distributed uniform
- compositions having a corresponding release profile may be prepared.
- An example of such a formulation is an osmotically driven release system for achieving a delayed release of one component via a coating that itself contains the other component which is accordingly released earlier.
- a release system of this kind which is particularly suitable for oral administration, at least part, and preferably all, of the surface of the release system, preferably those parts that will come into contact with the release medium, is/are semipermeable, preferably equipped with a semipermeable coating, so the surface(s) is/are permeable to the release medium, but substantially, preferably entirely, impermeable to the active ingredient, the surface(s) and/or optionally the coating comprising at least one opening for releasing the active ingredient.
- precisely that/those surface(s) that is/are in contact with the release medium is/are provided with a coating containing and releasing the other component.
- This is preferably taken to mean a system in tablet form comprising a release opening, an osmotic pharmaceutical composition core, a semipermeable membrane and a polymer portion that exerts pressure upon swelling.
- a suitable example of this kind of system is the system distributed by ALZA Corporation, USA under the tradenames OROS®, in particular, the OROS® Push-PullTM System, the OROS® Delayed Push-PullTM System, the OROS® Multi-Layer Push-PullTM system, the OROS® Push-Stick System and also, in specific cases, the L-OROSTM.
- Embodiments and examples of osmotically driven release systems are, for example, disclosed in U.S. Pat. Nos. 4,765,989, 4,783,337 and 4,612,008, the entire disclosure of each of which is incorporated herein by reference.
- a further example of a suitable pharmaceutical formulation is a gel-matrix tablet, such as the products developed by Penwest Pharmaceuticals (for example, under TimeRX). Suitable examples are provided in U.S. Pat. Nos. 5,330,761, 5,399,362, 5,472,711 and 5,455,046, the entire disclosure of each of which is incorporated herein by reference.
- Particularly suitable is a retarding matrix formulation, with an inhomogeneous distribution of the pharmaceutically active composition, whereby, for example, one component can be distributed in the outer region (the portion that comes into contact with the release medium most quickly) of the matrix and the other component is distributed inside the matrix.
- the outer matrix layer On contact with the release medium, the outer matrix layer initially (and rapidly) swells and firstly releases the first component, followed by the significantly (more) retarded release of the other component.
- a suitable matrix include matrices with 1 to 80% by weight of one or more hydrophilic or hydrophobic polymers as pharmaceutically acceptable matrix formers.
- a further example of a suitable matrix may be inferred from U.S. Pat. No. 4,389,393 the respective contents of which hereby being incorporated by reference and forming part of the disclosure of the present invention.
- the amount of the inventive pharmaceutically active combination to be administered to the patient may vary depending on different factors well known to those skilled in the art, for example, the weight of the patient, the route of administration, or the severity of the illness.
- the present invention relates to the use of an inventive combination as described herein for the treatment of pain, said pain preferably including but not being limited to inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain and cancer pain.
- the present invention relates to the use of an inventive combination as described herein for the preparation of a medicament for the treatment of pain, said pain preferably including but not being limited to inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain and cancer pain.
- the present invention relates to a method of treating pain in a mammal, preferably a human, which comprises administering an effective amount of an inventive combination as described herein to the mammal.
- the weight ratios of components (a) and (b) that will lead to a supra-additive effect/synergistic effect of the inventive compositions may be determined in the test of Kim & Chung as described in Kim S H, Chung J M. An experimental model for peripheral mononeuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992; 50: 355-63. Said reference is hereby incorporated by reference and forms part of the disclosure.
- tapentadol hydrochloride or tapentadol-HCl
- S-pregabalin as well as the inventive combination of tapentadol-HCl and (S)-pregabalin were each dissolved in 0.9% NaCl solution and injected by the intravenous (i.v.) route (application volume 5 ml/kg).
- Tapentadol hydrochloride (0.1, 0.316, 1, 3.16 and 10 mg/kg i.v.) showed a dose dependent increase in the withdrawal threshold of the ipsi-lateral hind paw with an efficacy of 94% MPE and an ED 50 -value (95% confidence interval) of 1.65 (1.20-2.35) mg/kg i.v. calculated from the peak effect vs. control values at 30 min. after administration.
- (S)-Pregabalin (0.1, 3.16 and 10 mg/kg i.v.) showed a dose dependent increase in the withdrawal threshold of the ipsi-lateral hind paw with an efficacy of 67% MPE and an ED 50 -value (95% confidence interval) of 4.20 (3.37-5.43) mg/kg i.v. calculated from the peak effect vs. control values at 30 min. after administration.
- Tapentadol hydrochloride and (S)-pregabalin show a potency difference which amounts to a factor 2.5 based on the ED 50 values 30 minutes after administration.
- Combinations in a fixed ratio of 1:2.5 (tapentadol hydrochloride:(S)-pregabalin) were tested in doses of 0.1 mg/kg+0.25 mg/kg; 0.3 mg/kg+0.75 mg/kg, 1 mg/kg+2.5 mg/kg i.v. tapentadol hydrochloride+(S)-pregabalin, respectively. These combinations showed a dose dependent increase in the withdrawal threshold of the ipsi-lateral hind paw. The highest dose combination tested showed full efficacy with 89% MPE. Potency was quantified by an ED 50 value (95% confidence interval) of 0.83 (0.74-0.92) mg/kg i.v. calculated from the peak effect vs control values at 30 min after administration.
- the experimental ED 50 value (95% confidence interval) of 0.83 (0.74-0.92) mg/kg i.v. of the inventive combination is below the theoretical additive ED 50 value (95% confidence interval) of 2.91 (2.28-3.54) mg/kg i.v. and is statistically significant (p ⁇ 0.001) as compared to the line of additivity.
- the interaction of tapentadol hydrochloride and (S)-pregabalin is synergistic.
- mice After operation, animals were allowed to recover for one week. Animals develop tactile allodynia which is stable for at least five weeks. For the assessment of tactile allodynia the rats were placed on a metal mesh covered with a plastic dome and were allowed to habituate until the exploratory behaviour diminished. Threshold for tactile allodynia was measured with an electronic von Frey anesthesiometer (Somedic, Sweden). Animals randomly assigned to groups of 10 for each test dose and vehicle, were tested 0.5h before administration and on several time points after administration. The median of the withdrawal threshold for each animal at a given time is calculated from five individual stimulations with the electronic von Frey filament.
- the effect of each compound and vehicle is calculated for each testing time point (e.g. 0.5, 1, 3h post administration) as interindividual % MPE value ( ⁇ SEM).
- Anti-allodynic efficacy is defined as increase of ipsi-lateral withdrawal threshold without effect on contra-lateral withdrawal threshold. Ten animals have been used in each group.
- the weight ratios of the components (a) and (b) that will lead to a supra-additive effect (synergistic effect) of the inventive pharmaceutical composition may be determined via the test of Randall and Selitto as described in Arch. Int. Pharmacodyn., 1957, 111, 409 to 419, which is a model for inflammatory pain.
- the respective part of the literature is hereby incorporated by reference and forms part of the present disclosure.
- Acute inflammation is induced by an intraplantar injection of 0.1 ml of a carrageenan solution (0.5% in distilled water) into one hind paw.
- the mechanical nociceptive threshold is measured 4 hours after carrageenan injection using an Algesiometer (Ugo Basile, Italy).
- the device generates a mechanical force with a linear increase over time.
- the force is applied to the dorsal surface of the inflamed rat hind paw via a cone-shaped stylus with a rounded tip (2 mm tip diameter).
- the nociceptive threshold is defined as the force (in grams) at which the rat vocalises (cut-off force 250 g).
- the mechanical nociceptive threshold is measured at different timepoints after the drug or vehicle administration.
- the antinociceptive and antihyperalgesic activity of the tested substance is expressed as percentages of the maximal possible effect (% MPE).
- the route of administration was intravenous (i.v.) for Tapentadol hydrochloride (A) and intraperitoneal (i.p.) for the anticonvulsants (antiepileptics) Lamotrigine, Lacosamide, Levetiracetam and Retigabine dihydrochloride.
- A Tapentadol hydrochloride
- i.p. intraperitoneal
- the anticonvulsants antiepileptics
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Abstract
A composition of matter comprising in combination as component (a) at least one 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound, and as component (b) at least one antiepileptic, a pharmaceutical formulation and a dosage form comprising said composition of matter, and a method of treating pain, e.g. neuropathic pain, in which components (a) and (b) are administered simultaneously or sequentially to a mammal, whereby component (a) may be administered before or after component (b) and whereby components (a) or (b) are administered to the mammal either via the same or a different pathway of administration.
Description
- This application is a continuation of U.S. application Ser. No. 14/927,585 filed Oct. 30, 2015, now allowed, which is a continuation of U.S. application Ser. No. 12/693,747, filed Jan. 26, 2010, now abandoned, which is a continuation-in-part of U.S. application Ser. No. 12/554,235, filed Sep. 4, 2009, now abandoned, which claims priority from U.S. Provisional Patent Application No. 61/094,787, filed Sep. 5, 2008. Priority is also claimed based on European patent application no. EP 08 015 625.0, filed Sep. 5, 2008.
- The present invention relates to a combination comprising as components (a) at least one 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound, and (b) at least one antiepileptic, a pharmaceutical formulation and a dosage form comprising said combination as well as a method of treating pain, e.g. neuropathic pain, wherein components (a) and (b) are administered simultaneously or sequentially to a mammal, whereby component (a) may be administered before or after component (b) and whereby components (a) or (b) are administered to the mammal either via the same or a different pathway of administration.
- The treatment of chronic and acute pain conditions is extremely important in medicine. There is currently a worldwide demand for additional, not exclusively opioid-based, but highly effective pain treatment. The urgent need for action for patient-oriented and purposeful treatment of pain conditions, this being taken to mean the successful and satisfactory treatment of pain for the patient, is documented in the large number of scientific papers which have recently appeared in the field of applied analgesics and fundamental research work on nociception.
- Even if the analgesics that are currently used for treating pain, for example opioids, NA- and 5HT-reuptake inhibitors, NSAIDS and COX inhibitors, are analgesically effective, side effects nevertheless sometimes occur. WO 01/13904 describes substance combinations comprising a tramadol material and an anticonvulsant drug, which show super-additive effects upon administration. Due to the super-additive effect the overall dose and accordingly the risk of undesired side effects can be reduced.
- Thus, it was an object of the present invention to find further combinations having improved properties. It was also an object of the present invention to find further combinations that are suitable for the treatment of pain and which preferably exhibit fewer undesired side effects compared to its individual components, if administered in effective doses.
- It has been found that a combination comprising (a) at least one 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound, and (b) at least one antiepileptic exhibits an analgesic effect. If these components are present in the composition in such a weight ratio that a supra-additive or synergistic effect is observed upon administration to the patients, the overall administered dose may be lowered, so that fewer undesired side-effects will occur.
- Accordingly, the present invention relates to a pharmaceutical combination comprising as components
- (a) 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula (I)
-
- optionally in form of one of its pure stereoisomers, in particular an enantiomer or a diastereomer, a racemate or in form of a mixture of its stereoisomers, in particular enantiomers and/or diastereomers in any mixing ratio, or any corresponding acid addition salt thereof, and
- (b) at least one antiepileptic.
- In another embodiment the present invention relates to a pharmaceutical combination comprising as components
- (a) 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula (I)
-
- optionally in form of one of its pure stereoisomers, in particular an enantiomer or a diastereomer, a racemate or in form of a mixture of its stereoisomers, in particular enantiomers and/or diastereomers in any mixing ratio, or any corresponding acid addition salt thereof, and
- (b) at least one antiepileptic and/or at least one compound selected from the group consisting of voltage dependent calcium channel blockers, voltage dependent t-type calcium channel blockers, voltage dependent sodium channel blockers, compounds that exhibit enhancement of fast or slow inactivation of voltage dependent sodium channels, KCNQ channel openers, SV2A ligands, modulators of collapsin response mediator protein-2 (CRMP-2), glutamate release inhibitors, AMPA receptor antagonists, NMDA antagonists, GABA receptor modulators, GABA aminotransferase inhibitors, GABA reuptake inhibitors and carbonic anhydrase inhibitors.
- In one embodiment of the inventive combination the compound of formula (I) is selected from the group consisting of:
- (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,
- (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,
- (1R,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,
- (1S,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and
any mixture thereof. - In another embodiment of the inventive combination the compound of formula (I) is selected from
- (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and
- (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and
- any mixture thereof.
- In yet another embodiment the inventive combination comprises
- (a) the compound (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula (I′),
-
- or an acid addition salt thereof, and
- (b) at least one antiepileptic.
- The compound 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula (I), its stereoisomers and corresponding salts thereof as well as methods for their preparation are well known, for example, from U.S. Pat. No. 6,248,737 B1, the entire disclosure of which is incorporated herein by reference.
- The definition of component (a) as used herein includes 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, derivatives thereof and stereoisomers thereof in any possible form, thereby particularly including solvates and polymorphs, salts, in particular acid addition salts and corresponding solvates and polymorphs.
- The term derivative as used herein particularly includes prodrugs such as ethers and esters of the active substance. Suitable methods for selecting and preparing a pro-drug of a given substance are for example described in “Textbook of Drug Design and Discovery”, 3rd edition, 2002, chapter 14, pages 410-458, Editors: Krogsgaard-Larsen et al., Taylor and Francis. The respective parts of said literature description are incorporated by reference and form part of the present disclosure.
- If component (a) is present as mixture of enantiomers, such a mixture may contain the enantiomers in racemic or non-racemic form. A non-racemic form could, for example, contain the enantiomers in a ratio of 60±5:40±5, 70±5:30±5, 80±5:20±5 or 90±5:10±5.
- The term “isolated” as used herein with regard to stereoisomers (e.g., enantiomers or diastereomers) means that the respective stereoisomer is separated from other stereoisomers but not necessarily from other substances.
- The compound 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol and its stereoisomers according to component (a) may be present in the inventive pharmaceutical composition in form of an acid addition salt, whereby any suitable acid capable of forming such an addition salt may be used.
- The conversion of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol into a corresponding addition salt, for example, via reaction with a suitable acid may be effected in a manner known to persons skilled in the art. Suitable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid. Salt formation is preferably effected in a solvent, for example, diethyl ether, diisopropyl ether, alkyl acetates, acetone and/or 2-butanone. Moreover, trimethylchlorosilane in aqueous solution is also suitable for the preparation of hydrochlorides.
- Voltage dependent calcium channel blockers such as blockers of the alpha 2 delta subunits, voltage dependent t-type calcium channel blockers, voltage dependent sodium channel blockers, compounds that exhibit enhancement of fast or slow inactivation of voltage dependent sodium channels, KCNQ channel openers, SV2A ligands, modulators of collapsin response mediator protein-2 (CRMP-2), glutamate release inhibitors, AMPA receptor antagonists, NMDA antagonists, GABA receptor modulators such as GABA A receptor inhibitors, GABA B receptor inhibitors, benzodiazepams and barbiturates, GABA aminotransferase inhibitors (GABA-transaminase inhibitors), GABA reuptake inhibitors and carbonic anhydrase inhibitors are well known to those skilled in the art. For these aforementioned compounds general ranges of potency with regard to the respective mechanisms are well known to persons skilled in the art, as are suitable assays for their determination.
- In one embodiment the potency of the voltage dependent calcium channel blockers such as blockers of the alpha 2 delta subunits, expressed in Ki for the displacement of [3H-Gabapentin] in the respective binding test, may be in the range of 0.001 to 0.01 μM.
- In another embodiment the potency of the voltage dependent sodium channel blocker, expressed in IC50 may be in the range of 0.1 to 500 μM.
- In yet another embodiment the potency of the carbonic anhydrase inhibitor may be in the range of 0.1 to 100 nM, IC50 for the inhibition.
- In still another embodiment the potency of the glutamate release inhibitor may be in the range of 1 to 50 μM, IC50 for the inhibition.
- In a further embodiment the potency of the SV2A ligand, expressed in pKi for the binding affinity to SV2A protein, can be in the range of 0.05 to 5 μM.
- In another embodiment the potency of the KCNQ channel opener, expressed as EC50, can be in the range of 0.1 to 10 μM.
- In a further embodiment the modulator of collapsin response mediator protein-2 (CRMP-2) may have a potency in the range of 1 to 50 μM, expressed as K for its respective binding affinity.
- In another embodiment the potency of the compound that exhibits enhancing slow inactivation of voltage gated sodium channels may be characterized by an IC50 in the range of 10 to 500 μM.
- Antiepileptics, which are often also referred to as anticonvulsants, are well known in the art and include, without limitation, barbiturates and derivatives, such as methylphenobarbital, phenobarbital, primidone, barbexaclone and metharbital; hydantoin derivatives such as ethotoin, phenytoin, amino(diphenylhydantoin) valeric acid, mephenytoin and fosphenytoin; oxazolidine derivatives such as paramethadione, trimethadione and ethadione; succinimide derivatives such as ethosuximide, phensuximide and mesuximide; benzodiazepine derivatives such as clonazepam, carboxamide derivatives such as carbamazepine, oxcarbazepine, eslicarbazepine and rufinamide; fatty acid derivatives such as valproic acid, valpromide, aminobutyric acid, vigabatrin, progabide and tiagabine; or other antiepileptics such as sultiame, phenacemide, lamotrigine, felbamate, topiramate, gabapentin, pheneturide, levetiracetam, brivaracetam, selectracetam, zonisamide, pregabalin, stiripentol, lacosamide and beclamide.
- These aforementioned classes of antiepileptics and most of their individual representatives are, for example, listed in the Anatomical Therapeutic Chemical (ATC) classification under [N03] as used by the WHO for classification of pharmaceutically active ingredients (preferred edition: January 2008 or 2009). With regard to further details of the ATC-index reference is made to U. Fricke, J. Günther, Anatomisch-therapeutisch-chemische Klassifikation mit Tagesdosen für den deutschen Arzneimittelmarkt: Methodik der ATC-Klassifikation and DDD-Festlegung. ATC-Index mit DDD-Angaben, Wissenschaftliches Institut der AOK, and Swiss Pharmaceutical Society, Index Nominum: International Drug Directory, CRC Press; 18th edition (Jan. 31, 2004). Other suitable antiepileptics include, for example, mexiletin, retigabin and ralfinamide.
- Some antiepileptics are known to be useful in the treatment of neuropathic pain. In one embodiment of the present invention one or more of these antiepileptics is used as component (b).
- Also included are stereoisomers, salts, solvates, polymorphs and derivatives of the antiepileptic component as well as mixtures of any of the foregoing.
- In one embodiment of the inventive combination the antiepileptic according to component (b) is selected from the group consisting of pregabalin, gabapentin, topiramate, lamotrigine, carbamazepine, oxcarbamazepine, eslicarbazepine, mexiletin, lacosamide, phenytoin, levetiracetam, brivaracetam, selectracetam, retigabin, valproic acid and ralfinamide.
- In another embodiment of the inventive combination the antiepileptic according to component (b) is selected from the group consisting of pregabalin, gabapentin, topiramate, lamotrigine, carbamazepine, mexiletin, lacosamide, phenytoin, levetiracetam, retigabin, valproic acid and ralfinamide.
- In still another embodiment of the inventive combination the antiepileptic according to component (b) is selected from the group consisting of pregabalin, gabapentin, topiramate, lamotrigine, lacosamide, levetiracetam and retigabine.
- In another embodiment of the inventive combination the antiepileptic according to component (b) is pregabalin.
- In yet another embodiment of the inventive combination the antiepileptic according to component (b) is (S)-pregabalin.
- In a further embodiment of the inventive combination the antiepileptic according to component (b) is gabapentin.
- In yet another embodiment of the inventive combination the antiepileptic according to component (b) is topiramate.
- In still another embodiment of the inventive combination the antiepileptic according to component (b) is lamotrigine.
- In yet still another embodiment of the inventive combination the antiepileptic according to component (b) is lacosamide.
- In another embodiment of the inventive combination the antiepileptic according to component (b) is levetiracetam.
- In yet another embodiment of the inventive combination the antiepileptic according to component (b) is retigabine.
- In still another embodiment of the inventive combination the antiepileptic according to component (b) is retigabine dihydrochloride.
- A specific embodiment of the present invention is a combination comprising (a) (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof such as the hydrochloride addition salt, and (b) one or more antiepileptics selected from the group consisting of pregabalin, gabapentin, topiramate, lamotrigine, carbamazepine, oxcarbamazepine, eslicarbazepine, mexiletin, lacosamide, phenytoin, levetiracetam, brivaracetam, selectracetam, retigabin, valproic acid and ralfinamide.
- A specific embodiment of the present invention is a combination comprising (a) (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof such as the hydrochloride addition salt, and (b) one or more antiepileptics selected from the group consisting of pregabalin, gabapentin, topiramate, lamotrigine, carbamazepine, mexiletin, lacosamide, phenytoin, levetiracetam, retigabin, valproic acid and ralfinamide.
- Another specific embodiment of the present invention is a combination comprising (a) (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof such as the hydrochloride addition salt, and (b) one or more antiepileptics selected from the group consisting of pregabalin, gabapentin, topiramate, lamotrigine, lacosamide, levetiracetam and retigabine.
- Another specific embodiment of the present invention is a combination comprising (a) (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof such as the hydrochloride addition salt, and (b) pregabalin.
- Yet another specific embodiment of the present invention is a combination comprising (a) (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof such as the hydrochloride addition salt, and (b) (S)-pregabalin.
- Some antiepileptics comprise functional groups, for example, acidic groups such as carboxy groups which are capable of forming salts with the 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol component of formula (I), thereby incorporating both components (a) and (b) in one and the same salt. Thus, in another embodiment of the present invention the inventive combination comprises components (a) and (b) in form of a salt formed from these two components. Such a salt formation may be partial, i.e. the inventive composition comprises one or both of these components also in their non-salt form, or the salt formation may essentially be complete.
- Both components (a) and (b) as part of the inventive combination may be administered in amounts up to their maximum daily dosage, which is known to those skilled in the art. The compound Pregabalin may preferably be administered to a patient in a daily dosage of 1 to 1200 mg, the compound Gabapentin may preferably be administered to a patient in a daily dosage of 1 to 5000 mg. The compound Topiramate may preferably be administered to a patient in a daily dosage of 1-800 mg; the compound Levetiracetam may preferably be administered to a patient in a daily dosage of 1-4500 mg; the compound Lacosamide may preferably be administered to a patient in a daily dosage of 1-800 mg; the compound Lamotrigine may preferably be administered to a patient in a daily dosage of 1-1200 mg, and the compound Retigabine may preferably be administered to a patient in a daily dosage of 1-2400 mg.
- The compound (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol may preferably be administered to a patient in a daily dosage of 25 to 1000 mg, particularly preferably in a dosage of 50 to 800 mg, more particularly preferably in a dosage of 100 to 600 mg.
- In another embodiment the compound (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol may preferably be administered to a patient in a daily dosage of 5 to 1000 mg, particularly preferably in a dosage of 25 to 800 mg, more particularly preferably in a dosage of 50 to 600 mg.
- In one embodiment of the present invention the inventive combination may comprise 1 to 500 mg Tapentadol and 1 to 660 mg Pregabalin. This combination may, for example, be administered to the patient once daily, twice daily or three times daily.
- In another embodiment of the present invention the inventive combination may comprise 1 to 500 mg Tapentadol and 1 to 1000 mg Gabapentin. This combination may, for example, be administered to the patient once daily, twice daily or three times daily.
- In another embodiment of the present invention the inventive combination may comprise 1 to 500 mg Tapentadol and 1 to 400 mg Topiramate. This combination may, for example, be administered to the patient once daily, twice daily or three times daily.
- In another embodiment of the present invention the inventive combination may comprise 1 to 500 mg Tapentadol and 1 to 600 mg Lamotrigine. This combination may, for example, be administered to the patient once daily, twice daily or three times daily.
- In another embodiment of the present invention the inventive combination may comprise 1 to 500 mg Tapentadol and 1 to 400 mg Lacosamide. This combination may, for example, be administered to the patient once daily, twice daily or three times daily.
- In another embodiment of the present invention the inventive combination may comprise 1 to 500 mg Tapentadol and 1 to 1000 mg Levetiracetam. This combination may, for example, be administered to the patient once daily, twice daily or three times daily.
- In another embodiment of the present invention the inventive combination may comprise 1 to 500 mg Tapentadol and 1 to 1000 mg Retigabine. This combination may, for example, be administered to the patient once daily, twice daily or three times daily.
- When administered as part of the inventive combination the administered amount per day of component (a) and/or component (b) may be less than the respective maximum daily dosage and be, for example, 75±15 wt.-%, 75±10 wt.-%, 75±5 wt.-%, 50±15 wt.-%, 50±10 wt.-%, 50±5 wt.-%, 25±15 wt.-%, 25±10 wt.-% and 25±5 wt.-% for each of the components.
- In another embodiment of the present invention the inventive combination may contain components (a) and (b) essentially in an equieffective ratio.
- In yet a further embodiment of the inventive combination components (a) and (b) are present in such a weight ratio that the resulting composition will exert a supra-additive or synergistic effect upon administration to a patient. Suitable weight ratios can be determined by methods well known to those skilled in the art.
- Both components (a) and (b) may also be present in the inventive combination in ratios deviating from the equieffective ratio. For, example, each of the components could be present in a range from 1/50 of the equieffective amount to 50 times the equieffective amount, from 1/20 of the equieffective amount to 20 times the equieffective amount, from 1/10 of the equieffective amount to 10 times the equieffective amount, from 1/5 of the equieffective amount to 5 times the equieffective amount, from 1/4 of the equieffective amount to 4 times the equieffective amount, from 1/3 of the equieffective amount to 3 times the equieffective amount, or from 1/2 of the equieffective amount to 2 times the equieffective amount.
- In another embodiment of the present invention the components (a) and (b) can be administered in a specific dosage regimen to treat pain, for example, neuropathic pain. Components (a) and (b) may be administered simultaneously or sequentially to one another, in each case via the same or different administration pathways.
- Another aspect of the present invention is therefore a method of treating pain, characterized in that components (a) and (b) are administered simultaneously or sequentially to a mammal, wherein component (a) may be administered before or after component (b) and wherein components (a) or (b) are administered to the mammal either via the same or a different pathway of administration.
- The term pain as used herein includes but is not limited to inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain and cancer pain.
- Suitable pathways of administration include but are not limited to oral, intravenous, intraarterial, intraperitoneal, intradermal, transdermal, intrathekal, intramuscular, intranasal, transmucosal, subcutaneous, and rectal administration.
- The inventive combinations are toxicologically safe and are therefore suitable for the treatment of mammals, particularly humans including infants, children and grown-ups. Thus, in a further aspect the present invention relates to a pharmaceutical composition comprising an inventive combination as described herein and one or more auxiliary agents.
- In a further aspect the present invention relates to a pharmaceutical dosage form comprising an inventive combination as described herein and one or more auxiliary agents. In one embodiment the inventive pharmaceutical dosage form additionally comprises caffeine.
- In one embodiment, the pharmaceutical dosage form of the invention is suitable for being administered orally, intravenously, intraarterially, intraperitoneally, intradermally, transdermally, intrathekally, intramuscularly, intranasally, transmucosally, subcutaneously, or rectally.
- The formulations and dosage forms of the invention may contain auxiliary agents, for example, carriers, fillers, solvents, diluents, colorants and/or binders. The selection of auxiliary agents and of the amounts of the same to be used depends, for example, on how the drug is to be administered, e.g. orally, intravenously, intraarterially, intraperitoneally, intradermally, transdermally, intramuscularly, intranasally or locally, for example for infections of the skin, of the mucous membranes or of the eye.
- Suitable auxiliary agents in the context of this invention include any substances known to persons skilled in the art to be useful for the preparation of galenical formulations. Examples of suitable auxiliary agents include, but are not limited to, water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, saccharose, dextrose, molasses, starch, modified starch, gelatine, sorbitol, inositol, mannitol, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, cellulose acetate, shellac, cetyl alcohol, polyvinyl pyrrolidone, paraffins, waxes, natural and synthetic gums, acacia gum, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glycerol stearate, sodium lauryl sulfate, edible oils, sesame oil, coconut oil, peanut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and polypropylene fatty acid ester, sorbitan fatty acid ester, sorbic acid, benzoic acid, citric acid, ascorbic acid, tannic acid, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, magnesium oxide, zinc oxide, silicon dioxide, titanium oxide, titanium dioxide, magnesium sulfate, zinc sulfate, calcium sulfate, potash, calcium phosphate, dicalcium phosphate, potassium bromide, potassium iodide, talcum, kaolin, pectin, crosspovidone, agar and bentonite.
- Pharmaceutical formulations (dosage forms) in the form of tablets, effervescent tablets, chewing tablets, dragees, capsules, drops, juices or syrups are, for example, suitable for oral administration. Oral pharmaceutical formulations may also be in the form of multiparticulates such as granules, pellets, spheres, crystals and the like, optionally compressed into a tablet, filled into a capsule, filled into a sachet or suspended in a suitable liquid medium. Oral pharmaceutical formulations may also be equipped with an enteric coating.
- Pharmaceutical formulations that are suitable for parenteral, topical and inhalative administration include but are not limited to solutions, suspensions, easily reconstitutable dry preparations and sprays. Suppositories are a suitable pharmaceutical formulation for rectal administration. Formulations in a deposit, in dissolved form, for example, in a patch optionally with the addition of agents to promote skin penetration, are examples of suitable formulations for percutaneous administration.
- One or both of the components (a) and (b) may be present in the inventive pharmaceutical formulation at least partially in controlled-release form. Moreover, any controlled release/immediate release combination of said components may also be present in the inventive pharmaceutical formulation. For example, one or both of the components may be released from the inventive formulations with a certain delay, e.g. if administered orally, rectally or percutaneously. Such formulations are particularly useful for “once-daily” or “twice-daily” preparations, which only have to be taken once a day, respectively, twice a day. Suitable controlled-release materials are well known to those skilled in the art.
- The pharmaceutical formulations of the invention may be produced using materials, means, devices and processes that are well known in the prior art of pharmaceutical formulations, as described for example in “Remington's Pharmaceutical Sciences”, A. R. Gennaro (ed.), 17th edition, Mack Publishing Company, Easton, Pa. (1985), in particular in part 8, chapters 76 to 93.
- In order to obtain a solid pharmaceutical formulation such as a tablet, for example, the components of the pharmaceutical composition may be granulated with a pharmaceutical carrier, for example conventional tablet ingredients such as corn starch, lactose, saccharose, sorbitol, talcum, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, for example water, in order to form a solid composition that contains the components in homogeneous distribution. The term “homogeneous distribution” is taken to mean that the components are distributed uniformly over the entire composition, so that said composition may easily be divided into equally effective unit dose forms, such as tablets, pills or capsules and the like. The solid composition is then divided into unit dose forms. The tablets or pills of the pharmaceutical composition according to the invention may also be coated or compounded in a different manner, in order to provide a dose form with a controlled release.
- If one of the components is to be released prior to the other component, for example at least 30 minutes or 1 hour beforehand, pharmaceutical formulations having a corresponding release profile may be prepared. An example of such a formulation is an osmotically driven release system for achieving a delayed release of one component via a coating that itself contains the other component which is accordingly released earlier. In a release system of this kind, which is particularly suitable for oral administration, at least part, and preferably all, of the surface of the release system, preferably those parts that will come into contact with the release medium, is/are semipermeable, preferably equipped with a semipermeable coating, so the surface(s) is/are permeable to the release medium, but substantially, preferably entirely, impermeable to the active ingredient, the surface(s) and/or optionally the coating comprising at least one opening for releasing the active ingredient. Moreover, precisely that/those surface(s) that is/are in contact with the release medium is/are provided with a coating containing and releasing the other component. This is preferably taken to mean a system in tablet form comprising a release opening, an osmotic pharmaceutical composition core, a semipermeable membrane and a polymer portion that exerts pressure upon swelling. A suitable example of this kind of system is the system distributed by ALZA Corporation, USA under the tradenames OROS®, in particular, the OROS® Push-Pull™ System, the OROS® Delayed Push-Pull™ System, the OROS® Multi-Layer Push-Pull™ system, the OROS® Push-Stick System and also, in specific cases, the L-OROS™.
- Embodiments and examples of osmotically driven release systems are, for example, disclosed in U.S. Pat. Nos. 4,765,989, 4,783,337 and 4,612,008, the entire disclosure of each of which is incorporated herein by reference.
- A further example of a suitable pharmaceutical formulation is a gel-matrix tablet, such as the products developed by Penwest Pharmaceuticals (for example, under TimeRX). Suitable examples are provided in U.S. Pat. Nos. 5,330,761, 5,399,362, 5,472,711 and 5,455,046, the entire disclosure of each of which is incorporated herein by reference. Particularly suitable is a retarding matrix formulation, with an inhomogeneous distribution of the pharmaceutically active composition, whereby, for example, one component can be distributed in the outer region (the portion that comes into contact with the release medium most quickly) of the matrix and the other component is distributed inside the matrix. On contact with the release medium, the outer matrix layer initially (and rapidly) swells and firstly releases the first component, followed by the significantly (more) retarded release of the other component. Examples of a suitable matrix include matrices with 1 to 80% by weight of one or more hydrophilic or hydrophobic polymers as pharmaceutically acceptable matrix formers. A further example of a suitable matrix may be inferred from U.S. Pat. No. 4,389,393 the respective contents of which hereby being incorporated by reference and forming part of the disclosure of the present invention.
- The amount of the inventive pharmaceutically active combination to be administered to the patient may vary depending on different factors well known to those skilled in the art, for example, the weight of the patient, the route of administration, or the severity of the illness.
- In a further aspect the present invention relates to the use of an inventive combination as described herein for the treatment of pain, said pain preferably including but not being limited to inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain and cancer pain.
- In another aspect the present invention relates to the use of an inventive combination as described herein for the preparation of a medicament for the treatment of pain, said pain preferably including but not being limited to inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain and cancer pain.
- In another aspect the present invention relates to a method of treating pain in a mammal, preferably a human, which comprises administering an effective amount of an inventive combination as described herein to the mammal.
- The weight ratios of components (a) and (b) that will lead to a supra-additive effect/synergistic effect of the inventive compositions may be determined in the test of Kim & Chung as described in Kim S H, Chung J M. An experimental model for peripheral mononeuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992; 50: 355-63. Said reference is hereby incorporated by reference and forms part of the disclosure.
- Ligatures were applied to the left L5/L6 spinal nerves of male Sprague-Dawley rats (140-160 g body weight, Janvier, Genest St. Isle, France). Animals developed tactile allodynia at the ipsilateral paw. Three to four weeks after the operation the tactile allodynia threshold baseline (withdrawal threshold) was measured on the ipsilateral and contralateral hind paw by an electronic von Frey anaesthesiometer (Somedic, Schweden). After test and measurement of the baseline, (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (hereinafter referred to as tapentadol hydrochloride or tapentadol-HCl), (S)-pregabalin as well as the inventive combination of tapentadol-HCl and (S)-pregabalin were each dissolved in 0.9% NaCl solution and injected by the intravenous (i.v.) route (application volume 5 ml/kg). Animals were randomly assigned to groups of 10 for each test dose and vehicle (0.9% NaCl solution) and tactile withdrawal thresholds were tested 0.5 h before administration and on several time points (0.5, 1 and 3 hours) after intravenous administration. Ipsi- and contralateral hindpaws were tested. The median of the withdrawal threshold for each animal at a given time is calculated from five individual stimulations with the electronic von Frey filament. Withdrawal thresholds of the injured paws are expressed as % MPE (Maximum possible effect) comparing predrug threshold of Chung-Animals (=0% MPE) and control threshold of sham-animals (100% MPE). A cut-off is set at 100% MPE. The effect of each compound and vehicle is calculated for each testing time point as interindividual % MPE value.
- Data (anti-allodynic efficacy (% MPE), ipsi-lateral, paw withdrawal threshold (g), ipsi- and conralateral) were analysed by means of a two-factor analysis of variance (ANOVA) with repeated measures. In case of a significant treatment effect, post hoc analysis with Bonferroni adjustment was performed. Results were considered statistically significant if P<0.05. ED50 values and 95% confidence intervals (95% Cl) were determined for the anti-allodynic efficacy (% MPE) at the time of the peak effect for each drug by regression analysis. The analysis of the results was carried out via statistical comparison of the theoretical additive ED50-value with the experimentally determined ED50-value of a so-called fixed ratio combination (isobolographic analysis according to Tallarida R J, Porreca F, and Cowan A. Statistical analysis of drug-drug and site-site interactions with isobolograms. Life Sci 1989; 45: 947-61, which is hereby incorporated by reference.
- Tapentadol hydrochloride (0.1, 0.316, 1, 3.16 and 10 mg/kg i.v.) showed a dose dependent increase in the withdrawal threshold of the ipsi-lateral hind paw with an efficacy of 94% MPE and an ED50-value (95% confidence interval) of 1.65 (1.20-2.35) mg/kg i.v. calculated from the peak effect vs. control values at 30 min. after administration.
- (S)-Pregabalin (0.1, 3.16 and 10 mg/kg i.v.) showed a dose dependent increase in the withdrawal threshold of the ipsi-lateral hind paw with an efficacy of 67% MPE and an ED50-value (95% confidence interval) of 4.20 (3.37-5.43) mg/kg i.v. calculated from the peak effect vs. control values at 30 min. after administration.
- Tapentadol hydrochloride and (S)-pregabalin show a potency difference which amounts to a factor 2.5 based on the ED50 values 30 minutes after administration. Combinations in a fixed ratio of 1:2.5 (tapentadol hydrochloride:(S)-pregabalin) were tested in doses of 0.1 mg/kg+0.25 mg/kg; 0.3 mg/kg+0.75 mg/kg, 1 mg/kg+2.5 mg/kg i.v. tapentadol hydrochloride+(S)-pregabalin, respectively. These combinations showed a dose dependent increase in the withdrawal threshold of the ipsi-lateral hind paw. The highest dose combination tested showed full efficacy with 89% MPE. Potency was quantified by an ED50 value (95% confidence interval) of 0.83 (0.74-0.92) mg/kg i.v. calculated from the peak effect vs control values at 30 min after administration.
- The results of the isobolographic analysis are summarized in the following Table 1.
-
TABLE 1 Experimental ED50 values of tapentadol hydrochloride and (S)-pregabalin and isobolographic analysis of the interaction between tapentadol hydrochloride and (S)-pregabalin: Theoretical Experimental ED50 of the ED50 of the combination combination of tapentadol- of tapentadol- tapentadol- (S)- HCl and (S)- HCl and (S)- HCl pregabalin pregabalin pregabalin interaction Substance/ED50 1.65 (1.20- 4.20 (3.37- 2.91 (2.28- 0.83 (0.74- synergistic [mg/kg i.v.] 2.35) 5.43) 3.54) 0.92) (p < 0.001) (95% confidence interval) p: Level of statistical significance - The experimental ED50 value (95% confidence interval) of 0.83 (0.74-0.92) mg/kg i.v. of the inventive combination is below the theoretical additive ED50 value (95% confidence interval) of 2.91 (2.28-3.54) mg/kg i.v. and is statistically significant (p<0.001) as compared to the line of additivity. Thus, the interaction of tapentadol hydrochloride and (S)-pregabalin is synergistic.
- Analysis of contra-lateral paw withdrawal thresholds reveal significant anti-nociceptive effects of tapentadol hydrochloride and (S)-pregabalin at 10 mg/kg i.v. while no significant anti-nociceptive effect was seen at the highest dose of the inventive combination. Thus, synergistic anti-allodynic activity of tapentadol hydrochloride and (S)-pregabalin result in reduced anti-nociceptive side effects.
- Under pentobarbital anaesthesia (Narcoren®, 60 mg/kg i.p., Merial GmbH, Hallbergmoos, Germany), the L5, L6 spinal nerves were tightly ligated (Kim and Chung, Pain 1992; 50: 355). The left L5 and L6 spinal nerves were exposed by removing a small piece of the paravertebral muscle and a part of the left spinous process of the L5 lumbar vertebra. The L5 and L6 spinal nerves were then carefully isolated and tightly ligated with silk (NC-silk black, USP 5/0, metric 1, Braun Melsungen A G, Melsungen, F R G). After checking hemostasis, the muscle and the adjacent fascia were closed with sutures and the skin was closed with sutures.
- After operation, animals were allowed to recover for one week. Animals develop tactile allodynia which is stable for at least five weeks. For the assessment of tactile allodynia the rats were placed on a metal mesh covered with a plastic dome and were allowed to habituate until the exploratory behaviour diminished. Threshold for tactile allodynia was measured with an electronic von Frey anesthesiometer (Somedic, Sweden). Animals randomly assigned to groups of 10 for each test dose and vehicle, were tested 0.5h before administration and on several time points after administration. The median of the withdrawal threshold for each animal at a given time is calculated from five individual stimulations with the electronic von Frey filament. Withdrawal thresholds of the injured paws are expressed as % maximal possible effect (% MPE) comparing predrug threshold of Chung-animals (=0% MPE) and control threshold of sham-animals (=100% MPE). A cut-off is set at 100% MPE. The effect of each compound and vehicle is calculated for each testing time point (e.g. 0.5, 1, 3h post administration) as interindividual % MPE value (±SEM). Anti-allodynic efficacy is defined as increase of ipsi-lateral withdrawal threshold without effect on contra-lateral withdrawal threshold. Ten animals have been used in each group.
- Effects of drug combinations are compared to the theoretical sum of the effects of each drug tested alone. Drug combination effects which are clearly greater than the sum of the single drug effects are considered to be supra-additive.
-
TABLE 2 Effect % MPE (time after Treatment administration Compound A Compound B of Tapentadol Dose mg/kg Dose mg/kg hydrochloride) Comment Example 2.1 (combination of Tapentadol hydrochloride with Topiramate or Levetiracetam) Tapentadol 18 ± 4% hydrochloride (30 min) 1 mg/kg iv Topiramate 22 ± 3% 1 mg/kg iv (30 min) Tapentadol Topiramate 87 ± 3% Supra-additive vs hydrochloride 1 mg/kg iv (30 min) 18 + 22 = 40 1 mg/kg iv Levetiracetam 16 ± 4% 20 mg/kg iv (30 min) Tapentadol Levetiracetam 48 ± 3% Supra-additive vs hydrochloride 20 mg/kg iv (30 min) 18 + 16 = 34 1 mg/kg iv Example 2.2 (combination of Tapentadol hydrochloride with Gabapentin) Tapentadol 13 ± 5% hydrochloride (30 min) 1 mg/kg iv Gabapentin 3 ± 3% 10 mg/kg iv (30 min) (20 min before Tapentadol hydrochloride) Tapentadol Gabapentin 34 ± 5% Supra-additive vs hydrochloride 10 mg/kg iv (30 min) 13 + 3 = 16 1 mg/kg iv (20 min before Tapentadol hydrochloride) Example 2.3 (combination of Tapentadol with Lacosamide) Tapentadol 13 ± 5% hydrochloride (30 min) 1 mg/kg iv Lacosamide 24 ± 4% 3 mg/kg iv (30 min) Tapentadol Lacosamide 39 ± 9% Additive vs hydrochloride 3 mg/kg iv (30 min) 13 + 24 = 37 1 mg/kg iv - The weight ratios of the components (a) and (b) that will lead to a supra-additive effect (synergistic effect) of the inventive pharmaceutical composition may be determined via the test of Randall and Selitto as described in Arch. Int. Pharmacodyn., 1957, 111, 409 to 419, which is a model for inflammatory pain. The respective part of the literature is hereby incorporated by reference and forms part of the present disclosure.
- Acute inflammation is induced by an intraplantar injection of 0.1 ml of a carrageenan solution (0.5% in distilled water) into one hind paw. The mechanical nociceptive threshold is measured 4 hours after carrageenan injection using an Algesiometer (Ugo Basile, Italy). The device generates a mechanical force with a linear increase over time. The force is applied to the dorsal surface of the inflamed rat hind paw via a cone-shaped stylus with a rounded tip (2 mm tip diameter). The nociceptive threshold is defined as the force (in grams) at which the rat vocalises (cut-off force 250 g). The mechanical nociceptive threshold is measured at different timepoints after the drug or vehicle administration. The antinociceptive and antihyperalgesic activity of the tested substance is expressed as percentages of the maximal possible effect (% MPE). The group size is n=10.
- The analysis of the results with respect to a supra-additive effect of the inventive pharmaceutical composition comprising the components (a) and (b) is carried out via statistical comparison of the theoretical additive ED50-value with the experimentally determined ED50-value of a so-called fixed ratio combination (isobolographic analysis according to Tallarida J T, Porreca F, and Cowan A. Statistical analysis of drug-drug and site-site interactions with isobolograms. Life Sci 1989; 45: 947-961, which is hereby incorporated by reference).
- The interactions studies presented herein were performed using equieffective doses of the two components, calculated from the ratio of the respective ED50 values of the components if administered alone.
- The route of administration was intravenous (i.v.) for Tapentadol hydrochloride (A) and intraperitoneal (i.p.) for the anticonvulsants (antiepileptics) Lamotrigine, Lacosamide, Levetiracetam and Retigabine dihydrochloride. When A was applied alone, the peak effect was reached 15 min p. appl. (timepoint of first measurement) and an ED50-value of 1.75 (1.69-1.81) mg/kg i.v. was calculated. The anticonvulsants induced dose-dependent analgesic effects with ED50-values of 35.3 (32.7-38.1) mg/kg i.p. (Lamotrigine), 35.85 (34.74-36.89) mg/kg i.p. (Lacosamide), 986.0 (854.0-1137.3) (Levetiracetam) mg/kg i.p. and 5.09 (4.68-5.50) mg/kg i.p. (Retigabine dihydrochloride), reaching the peak effect 15 min p. appl. According to their respective timepoint of peak effect, A was applied 15 min and the anticonvulsant component 15 min before timepoint of measurement of the interaction-experiments (i. e. both components were applied simultaneously). Thus, the time point of ED50 calculation of the combination corresponds to the timepoint of the peak effect of the respective compound. The isobolographic analysis revealed that the experimental ED50-values of the combinations were significantly lower than the respective theoretical ED50-values. Thus, the combination studies demonstrate superadditive/supraadditive interaction of A with all of the anticonvulsants, Lamotrigine, Lacosamide, Levetiracetam and Retigabine dihydrochloride.
- The results of the isobolographic analysis are summarized in the following Table 3:
- Experimental ED50 values of A, Lamotrigine, Lacosamide, Levetiracetam and Retigabine dihydrochloride and isobolographic analysis of the interaction between A with these anticonvulsants, respectively.
-
TABLE 3 Experimental ED50 values of Tapentadol (A), Lamotrigine, Lacosamide, Levetiracetam and Retigabine dihydrochloride, and isobolographic analysis of the interaction between A with, Lamotrigine, Lacosamide, Levetiracetam or Retigabine dihydrochloride, respectively. Theoretical Experimental Substance/ Retigabine ED50 of the ED50 of ED50 [mg/kg] A Lamotrigine Lacosamide Levetiracetam dihydrochloride combination combination Interaction A + 1.747 (1.689- 35.25 (32.74- — — — 18.50 (17.74- 17.51 (16.69- additive to Lamotrigine 1.805) * 38.08) 19.26) 18.40) supra- additive (p < 0.05) A + 1.747 (1.689- — 35.85 (34.74- — — 18.80 (18.38- 15.24 (14.42- supra- Lacosamide 1.805) * 36.89) 19.21) 15.95) additive (p < 0.001) A + 1.747 (1.689- — — 986.0 (854.0- — 493.8 (458.0- 416 (393.5- supra- Levetiracetam 1.805) * 1137.3) 529.7) 442.4) additive (p < 0.001) A + 1.749 (1.646- — — — 5.09 (4.68- 3.42 (3.25- 1.82 (1.71- supra- Retigabine 1.849) 5.50) 3.59) 1.94) additive dihydrochloride (p < 0.001) * identical single-substance group with A for these combinations p: level of statistical significance of supra-additive interaction - The weight ratios of A to the respective anticonvulsant component used in the afore mentioned experiments were as follows:
-
Combination of A with Ratio Lamotrigine 1:20.2 Lacosamide 1:20.5 Levetiracetam 1:564 Retigabine dihydrochloride 1:2.9 - The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.
Claims (41)
2. A composition of matter as claimed in claim 1 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound is present in the form of an isolated stereoisomer.
3. A composition of matter as claimed in claim 1 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound is present in the form of a mixture of stereoisomers in any mixing ratio.
4. A composition of matter as claimed in claim 3 , wherein said mixture is a racemic mixture.
5. A composition of matter as claimed in claim 1 , wherein the compound of formula (I) is selected from the group consisting of:
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,
(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,
(1R,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,
(1S,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and
mixtures of two or more of the foregoing.
6. A composition of matter as claimed in claim 5 , wherein said compound of formula (I) is selected from the group consisting of:
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,
(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and
mixtures thereof.
8. A composition of matter as claimed in claim 7 , wherein said compound of formula (I) is a hydrochloride salt of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol.
9. A composition of matter as claimed in claim 1 , wherein the antiepileptic is selected from the group consisting of methylphenobarbital, phenobarbital, primidone, barbexaclone, metharbital, ethotoin, phenytoin, amino(diphenylhydantoin) valeric acid, mephenytoin, fosphenytoin, paramethadione, trimethadione, ethadione, ethosuximide, phensuximide, mesuximide, clonazepam, carbamazepine, oxcarbazepine, eslicarbazepine, rufinamide, valproic acid, valpromide, aminobutyric acid, vigabatrin, progabide, tiagabine, sultiame, phenacemide, lamotrigine, felbamate, topiramate, gabapentin, pheneturide, levetiracetam, brivaracetam, selectracetam, zonisamide, pregabalin, stiripentol, lacosamide, beclamide, mexiletin, retigabin and ralfinamide.
10. A composition of matter as claimed in claim 9 , wherein the antiepileptic is selected from the group consisting of pregabalin, gabapentin, topiramate, lamotrigine, carbamazepine, mexiletin, lacosamide, phenytoin, levetiracetam, retigabin, valproic acid and ralfinamide.
11. A composition of matter as claimed in claim 10 , wherein the antiepileptic is selected from the group consisting of pregabalin, gabapentin, topiramate, lamotrigine, lacosamide, levetiracetam and retigabine.
12. A composition of matter as claimed in claim 11 , wherein the antiepileptic is pregabalin.
13. A composition of matter as claimed in claim 11 , wherein the antiepileptic is gabapentin.
14. A composition of matter as claimed in claim 11 , wherein the antiepileptic is, topiramate.
15. A composition of matter as claimed in claim 11 , wherein the antiepileptic is lamotrigine.
16. A composition of matter as claimed in claim 11 , wherein the antiepileptic is lacosamide.
17. A composition of matter as claimed in claim 11 , wherein the antiepileptic is, levetiracetam.
18. A composition of matter as claimed in claim 11 , wherein the antiepileptic is retigabine.
19. A composition of matter as claimed in claim 1 , wherein the two components (a) and (b) are present in the form of a salt formed from said two components.
20. A composition of matter as claimed in claim 1 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound or salt thereof and said antiepileptic are present in a weight ratio such that the composition exerts a synergistic effect upon administration to a patient.
21. A composition of matter as claimed in claim 1 , further comprising at least one pharmaceutical carrier or auxiliary agent.
22. A composition of matter as claimed in claim 21 , wherein said composition is formed into a dosage form suitable for oral, intravenous, intraarterial, intraperitoneal, intradermal, transdermal, intrathekal, intramuscular, intranasal, transmucosal, subcutaneous, or rectal administration.
23. A composition of matter as claimed in claim 22 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound or said antiepileptic, or both, is present in controlled-release form.
24. A composition of matter as claimed in claim 21 , wherein said composition comprises caffeine.
25. A method of treating or inhibiting pain in a subject in need thereof, said method comprising administering to said subject a pharmacologically effective amount of a composition as claimed in claim 1 .
26. A method as claimed in claim 25 , wherein said pain is selected from the group consisting of inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain and cancer pain.
27. A method as claimed in claim 25 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound and said antiepileptic are administered simultaneously either by the same or by different pathways of administration.
28. A method as claimed in claim 25 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound and said antiepileptic are administered sequentially either by the same or by different pathways of administration, with the 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound being administered before the antiepileptic.
29. A method as claimed in claim 25 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound and said antiepileptic are administered sequentially either by the same or by different pathways of administration, with the 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound being administered after the antiepileptic.
30. A composition of matter comprising in combination:
(a) a 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound corresponding to formula (I):
or a pharmaceutically acceptable salt thereof, and
(b) at least one antiepileptic and/or at least one compound selected from the group consisting of voltage dependent calcium channel blockers, voltage dependent t-type calcium channel blockers, voltage dependent sodium channel blockers, compounds that exhibit enhancement of fast or slow inactivation of voltage dependent sodium channels, KCNQ channel openers, SV2A ligands, modulators of collapsin response mediator protein-2, glutamate release inhibitors, AMPA receptor antagonists, NMDA antagonists, GABA receptor modulators, GABA aminotransferase inhibitors, GABA reuptake inhibitors and carbonic anhydrase inhibitors.
31. A composition of matter as claimed in claim 30 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound is present in the form of an isolated stereoisomer.
32. A composition of matter as claimed in claim 30 , wherein said 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound is present in the form of a mixture of stereoisomers in any mixing ratio.
33. A composition of matter as claimed in claim 32 , wherein said mixture is a racemic mixture.
34. A composition of matter as claimed in claim 30 , wherein the compound of formula (I) is selected from the group consisting of:
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,
(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,
(1R,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,
(1S,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and
mixtures of two or more of the foregoing.
36. A composition of matter as claimed in claim 30 , wherein the antiepileptic is selected from the group consisting of methylphenobarbital, phenobarbital, primidone, barbexaclone, metharbital, ethotoin, phenytoin, amino(diphenylhydantoin) valeric acid, mephenytoin, fosphenytoin, paramethadione, trimethadione, ethadione, ethosuximide, phensuximide, mesuximide, clonazepam, carbamazepine, oxcarbazepine, eslicarbazepine, rufinamide, valproic acid, valpromide, aminobutyric acid, vigabatrin, progabide, tiagabine, sultiame, phenacemide, lamotrigine, felbamate, topiramate, gabapentin, pheneturide, levetiracetam, brivaracetam, selectracetam, zonisamide, pregabalin, stiripentol, lacosamide, beclamide, mexiletin, retigabin and ralfinamide.
37. A composition of matter as claimed in claim 30 , wherein the two components (a) and (b) are present in the form of a salt formed from said two components.
38. A composition of matter as claimed in claim 30 , wherein the two components (a) and (b) are present in a weight ratio such that the composition exerts a synergistic effect upon administration to a patient.
39. A composition of matter as claimed in claim 30 , further comprising at least one pharmaceutical carrier or auxiliary agent.
40. A composition of matter as claimed in claim 22 , wherein component (a) or component (b), or both, is/are present in controlled-release form.
41. A method of treating or inhibiting pain in a subject in need thereof, said method comprising administering to said subject a pharmacologically effective amount of a composition as claimed in claim 30 .
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-
2015
- 2015-10-30 US US14/927,585 patent/US10206890B2/en not_active Expired - Fee Related
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2019
- 2019-01-03 US US16/238,990 patent/US20190133971A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4656177A (en) * | 1982-07-22 | 1987-04-07 | Analgesic Associates | Analgesic and anti-inflammatory compositions comprising caffeine and methods of using same |
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US20100190752A1 (en) | 2010-07-29 |
US10206890B2 (en) | 2019-02-19 |
US20160045458A1 (en) | 2016-02-18 |
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