MX2008006610A - Pharmaceutical compositions - Google Patents
Pharmaceutical compositionsInfo
- Publication number
- MX2008006610A MX2008006610A MXMX/A/2008/006610A MX2008006610A MX2008006610A MX 2008006610 A MX2008006610 A MX 2008006610A MX 2008006610 A MX2008006610 A MX 2008006610A MX 2008006610 A MX2008006610 A MX 2008006610A
- Authority
- MX
- Mexico
- Prior art keywords
- pharmaceutically acceptable
- acceptable composition
- composition according
- further characterized
- acid
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title description 2
- 239000000203 mixture Substances 0.000 claims abstract description 105
- 230000036592 analgesia Effects 0.000 claims abstract description 28
- 201000008125 pain agnosia Diseases 0.000 claims abstract description 28
- 229960001736 buprenorphine Drugs 0.000 claims description 28
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 18
- 229960004063 Propylene glycol Drugs 0.000 claims description 16
- 230000000202 analgesic Effects 0.000 claims description 16
- 235000013772 propylene glycol Nutrition 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- -1 diethylisorbide Chemical compound 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 10
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical group CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 9
- LQZZUXJYWNFBMV-UHFFFAOYSA-N Dodecanol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 claims description 9
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 9
- 230000001939 inductive effect Effects 0.000 claims description 9
- 230000037242 Cmax Effects 0.000 claims description 8
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Ilacox Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 claims description 8
- QELSKZZBTMNZEB-UHFFFAOYSA-N Propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 8
- 230000035852 Tmax Effects 0.000 claims description 8
- 239000008346 aqueous phase Substances 0.000 claims description 8
- 229960001929 meloxicam Drugs 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- 239000003961 penetration enhancing agent Substances 0.000 claims description 8
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 8
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 8
- 239000003963 antioxidant agent Substances 0.000 claims description 7
- 230000035515 penetration Effects 0.000 claims description 7
- 239000003755 preservative agent Substances 0.000 claims description 7
- 239000003381 stabilizer Substances 0.000 claims description 7
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 6
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 6
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 6
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 6
- 229940079593 drugs Drugs 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- 229940121367 non-opioid analgesics Drugs 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- SFKUIGDOGVNRJK-UHFFFAOYSA-N sodium;3-sulfanylpropane-1,2-diol Chemical compound [Na].OCC(O)CS SFKUIGDOGVNRJK-UHFFFAOYSA-N 0.000 claims description 6
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 5
- HNJBEVLQSNELDL-UHFFFAOYSA-N 2-Pyrrolidone Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 5
- CZBZUDVBLSSABA-UHFFFAOYSA-N Butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 5
- 229960004873 LEVOMENTHOL Drugs 0.000 claims description 5
- 229940041616 Menthol Drugs 0.000 claims description 5
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 5
- 235000011187 glycerol Nutrition 0.000 claims description 5
- 229920000642 polymer Polymers 0.000 claims description 5
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (-)-propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 4
- MEJYDZQQVZJMPP-ULAWRXDQSA-N (3S,3aR,6R,6aR)-3,6-dimethoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound CO[C@H]1CO[C@@H]2[C@H](OC)CO[C@@H]21 MEJYDZQQVZJMPP-ULAWRXDQSA-N 0.000 claims description 4
- WAZQAZKAZLXFMK-UHFFFAOYSA-N Deracoxib Chemical compound C1=C(F)C(OC)=CC=C1C1=CC(C(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 WAZQAZKAZLXFMK-UHFFFAOYSA-N 0.000 claims description 4
- 229960005293 Etodolac Drugs 0.000 claims description 4
- XFBVBWWRPKNWHW-UHFFFAOYSA-N Etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 claims description 4
- FULAPETWGIGNMT-UHFFFAOYSA-N Firocoxib Chemical compound C=1C=C(S(C)(=O)=O)C=CC=1C=1C(C)(C)OC(=O)C=1OCC1CC1 FULAPETWGIGNMT-UHFFFAOYSA-N 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- DKYWVDODHFEZIM-UHFFFAOYSA-N Ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims description 4
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical group N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 claims description 4
- 229940026235 PROPYLENE GLYCOL MONOLAURATE Drugs 0.000 claims description 4
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 4
- 229960003314 deracoxib Drugs 0.000 claims description 4
- LLRANSBEYQZKFY-UHFFFAOYSA-N dodecanoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCCCCCCCC(O)=O LLRANSBEYQZKFY-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229960002524 firocoxib Drugs 0.000 claims description 4
- NOOCSNJCXJYGPE-UHFFFAOYSA-N flunixin Chemical compound C1=CC=C(C(F)(F)F)C(C)=C1NC1=NC=CC=C1C(O)=O NOOCSNJCXJYGPE-UHFFFAOYSA-N 0.000 claims description 4
- 229960000588 flunixin Drugs 0.000 claims description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- 150000002334 glycols Chemical class 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 4
- 229960000991 ketoprofen Drugs 0.000 claims description 4
- 230000002335 preservative Effects 0.000 claims description 4
- 229960003415 propylparaben Drugs 0.000 claims description 4
- XYKWNRUXCOIMFZ-UHFFFAOYSA-N tepoxalin Chemical compound C1=CC(OC)=CC=C1N1C(C=2C=CC(Cl)=CC=2)=CC(CCC(=O)N(C)O)=N1 XYKWNRUXCOIMFZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000001069 triethyl citrate Substances 0.000 claims description 4
- 235000013769 triethyl citrate Nutrition 0.000 claims description 4
- KLIVRBFRQSOGQI-UHFFFAOYSA-N 2-(11-oxo-6H-benzo[c][1]benzothiepin-3-yl)acetic acid Chemical compound S1CC2=CC=CC=C2C(=O)C2=CC=C(CC(=O)O)C=C12 KLIVRBFRQSOGQI-UHFFFAOYSA-N 0.000 claims description 3
- PYIHCGFQQSKYBO-UHFFFAOYSA-N 2-(11-oxo-6H-benzo[c][1]benzoxepin-3-yl)acetic acid Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC=C(CC(=O)O)C=C12 PYIHCGFQQSKYBO-UHFFFAOYSA-N 0.000 claims description 3
- DCXHLPGLBYHNMU-UHFFFAOYSA-N 2-[1-(4-azidobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(N=[N+]=[N-])C=C1 DCXHLPGLBYHNMU-UHFFFAOYSA-N 0.000 claims description 3
- TYCOFFBAZNSQOJ-UHFFFAOYSA-N 2-[4-(3-fluorophenyl)phenyl]propanoic acid Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC(F)=C1 TYCOFFBAZNSQOJ-UHFFFAOYSA-N 0.000 claims description 3
- JIEKMACRVQTPRC-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)-2-phenyl-1,3-thiazol-5-yl]acetic acid Chemical compound OC(=O)CC=1SC(C=2C=CC=CC=2)=NC=1C1=CC=C(Cl)C=C1 JIEKMACRVQTPRC-UHFFFAOYSA-N 0.000 claims description 3
- XKSAJZSJKURQRX-UHFFFAOYSA-N 2-acetyloxy-5-(4-fluorophenyl)benzoic acid Chemical compound C1=C(C(O)=O)C(OC(=O)C)=CC=C1C1=CC=C(F)C=C1 XKSAJZSJKURQRX-UHFFFAOYSA-N 0.000 claims description 3
- FIKVYIRIUOFLLR-UHFFFAOYSA-N 4-[4-(2,4-difluorophenyl)phenyl]-2-methyl-4-oxobutanoic acid Chemical compound C1=CC(C(=O)CC(C)C(O)=O)=CC=C1C1=CC=C(F)C=C1F FIKVYIRIUOFLLR-UHFFFAOYSA-N 0.000 claims description 3
- SYCHUQUJURZQMO-UHFFFAOYSA-N 4-hydroxy-2-methyl-1,1-dioxo-N-(1,3-thiazol-2-yl)-1$l^{6},2-benzothiazine-3-carboxamide Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=CS1 SYCHUQUJURZQMO-UHFFFAOYSA-N 0.000 claims description 3
- OIRAEJWYWSAQNG-UHFFFAOYSA-N 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylic acid Chemical compound ClC=1C=C2C(C(=O)O)CCC2=CC=1C1CCCCC1 OIRAEJWYWSAQNG-UHFFFAOYSA-N 0.000 claims description 3
- 229960004892 Acemetacin Drugs 0.000 claims description 3
- FSQKKOOTNAMONP-UHFFFAOYSA-N Acemetacin Chemical compound CC1=C(CC(=O)OCC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 FSQKKOOTNAMONP-UHFFFAOYSA-N 0.000 claims description 3
- FPHLBGOJWPEVME-UHFFFAOYSA-N Alminoprofen Chemical compound OC(=O)C(C)C1=CC=C(NCC(C)=C)C=C1 FPHLBGOJWPEVME-UHFFFAOYSA-N 0.000 claims description 3
- IVUMCTKHWDRRMH-UHFFFAOYSA-N Carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 claims description 3
- RZEKVGVHFLEQIL-UHFFFAOYSA-N Celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 claims description 3
- 229950010886 Clidanac Drugs 0.000 claims description 3
- HUPFGZXOMWLGNK-UHFFFAOYSA-N Diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 claims description 3
- 229950007979 FLUFENISAL Drugs 0.000 claims description 3
- 229960001419 Fenoprofen Drugs 0.000 claims description 3
- RDJGLLICXDHJDY-UHFFFAOYSA-N Fenoprofen Chemical compound OC(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-UHFFFAOYSA-N 0.000 claims description 3
- 229960004369 Flufenamic Acid Drugs 0.000 claims description 3
- LPEPZBJOKDYZAD-UHFFFAOYSA-N Flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 claims description 3
- 229950001284 Fluprofen Drugs 0.000 claims description 3
- SYTBZMRGLBWNTM-UHFFFAOYSA-N Flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 claims description 3
- RJMIEHBSYVWVIN-UHFFFAOYSA-N Indoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-UHFFFAOYSA-N 0.000 claims description 3
- OZWKMVRBQXNZKK-UHFFFAOYSA-N Ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 claims description 3
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 claims description 3
- HYYBABOKPJLUIN-UHFFFAOYSA-N Mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 claims description 3
- OJGQFYYLKNCIJD-UHFFFAOYSA-N Miroprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C1=CN(C=CC=C2)C2=N1 OJGQFYYLKNCIJD-UHFFFAOYSA-N 0.000 claims description 3
- 229950006616 Miroprofen Drugs 0.000 claims description 3
- CMWTZPSULFXXJA-VIFPVBQESA-N Naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 3
- 229960000916 Niflumic Acid Drugs 0.000 claims description 3
- JZFPYUNJRRFVQU-UHFFFAOYSA-N Niflumic acid Chemical compound OC(=O)C1=CC=CN=C1NC1=CC=CC(C(F)(F)F)=C1 JZFPYUNJRRFVQU-UHFFFAOYSA-N 0.000 claims description 3
- MITFXPHMIHQXPI-UHFFFAOYSA-N Oraflex Chemical compound N=1C2=CC(C(C(O)=O)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 MITFXPHMIHQXPI-UHFFFAOYSA-N 0.000 claims description 3
- OFPXSFXSNFPTHF-UHFFFAOYSA-N Oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 claims description 3
- 229950005708 Oxepinac Drugs 0.000 claims description 3
- 229960002895 Phenylbutazone Drugs 0.000 claims description 3
- QYSPLQLAKJAUJT-UHFFFAOYSA-N Piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 claims description 3
- PIDSZXPFGCURGN-UHFFFAOYSA-N Pirprofen Chemical compound ClC1=CC(C(C(O)=O)C)=CC=C1N1CC=CC1 PIDSZXPFGCURGN-UHFFFAOYSA-N 0.000 claims description 3
- 229950005175 SUDOXICAM Drugs 0.000 claims description 3
- 229960000894 Sulindac Drugs 0.000 claims description 3
- MLKXDPUZXIRXEP-MFOYZWKCSA-N Sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 claims description 3
- 229960004492 Suprofen Drugs 0.000 claims description 3
- MDKGKXOCJGEUJW-UHFFFAOYSA-N Suprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-UHFFFAOYSA-N 0.000 claims description 3
- 229950002345 TIOPINAC Drugs 0.000 claims description 3
- YEZNLOUZAIOMLT-UHFFFAOYSA-N Tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 claims description 3
- UPSPUYADGBWSHF-UHFFFAOYSA-N Tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 claims description 3
- 229950007802 Zidometacin Drugs 0.000 claims description 3
- ZXVNMYWKKDOREA-UHFFFAOYSA-N Zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 claims description 3
- 229960004663 alminoprofen Drugs 0.000 claims description 3
- 229960005430 benoxaprofen Drugs 0.000 claims description 3
- 229960003184 carprofen Drugs 0.000 claims description 3
- 229960000590 celecoxib Drugs 0.000 claims description 3
- 229960001259 diclofenac Drugs 0.000 claims description 3
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 3
- 229960000616 diflunisal Drugs 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229960002679 fentiazac Drugs 0.000 claims description 3
- 229960002390 flurbiprofen Drugs 0.000 claims description 3
- 150000004676 glycans Polymers 0.000 claims description 3
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 claims description 3
- 229920000591 gum Polymers 0.000 claims description 3
- 229960004187 indoprofen Drugs 0.000 claims description 3
- YYUAYBYLJSNDCX-UHFFFAOYSA-N isoxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC=1C=C(C)ON=1 YYUAYBYLJSNDCX-UHFFFAOYSA-N 0.000 claims description 3
- 229950002252 isoxicam Drugs 0.000 claims description 3
- 229960004752 ketorolac Drugs 0.000 claims description 3
- 229960003803 meclofenamic acid Drugs 0.000 claims description 3
- 229960003464 mefenamic acid Drugs 0.000 claims description 3
- XCWIEIVORUMFMV-UHFFFAOYSA-N methyl 4-hydroxybenzoate Chemical compound COC(=O)C1=CC=C(O)C=C1.COC(=O)C1=CC=C(O)C=C1 XCWIEIVORUMFMV-UHFFFAOYSA-N 0.000 claims description 3
- BLXXJMDCKKHMKV-UHFFFAOYSA-N nabumeton Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 claims description 3
- 229960004270 nabumetone Drugs 0.000 claims description 3
- 229960002009 naproxen Drugs 0.000 claims description 3
- 229960002739 oxaprozin Drugs 0.000 claims description 3
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 claims description 3
- 229960002702 piroxicam Drugs 0.000 claims description 3
- 229960000851 pirprofen Drugs 0.000 claims description 3
- 229920001282 polysaccharide Polymers 0.000 claims description 3
- 239000005017 polysaccharide Substances 0.000 claims description 3
- 150000004804 polysaccharides Polymers 0.000 claims description 3
- 229960002905 tolfenamic acid Drugs 0.000 claims description 3
- 229960001017 tolmetin Drugs 0.000 claims description 3
- 229960003414 zomepirac Drugs 0.000 claims description 3
- RMRJXGBAOAMLHD-CTAPUXPBSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-CTAPUXPBSA-N 0.000 claims 6
- 238000004519 manufacturing process Methods 0.000 claims 4
- 230000003364 opioid Effects 0.000 abstract description 25
- 241000282326 Felis catus Species 0.000 abstract description 22
- 229940005483 OPIOID ANALGESICS Drugs 0.000 abstract description 14
- 241000282472 Canis lupus familiaris Species 0.000 abstract description 3
- 241000124008 Mammalia Species 0.000 abstract description 3
- 238000009472 formulation Methods 0.000 description 25
- RMRJXGBAOAMLHD-IHFGGWKQSA-N Buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 22
- 208000002193 Pain Diseases 0.000 description 14
- 230000036407 pain Effects 0.000 description 12
- 210000002381 Plasma Anatomy 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 239000000730 antalgic agent Substances 0.000 description 5
- 239000003623 enhancer Substances 0.000 description 5
- 230000002708 enhancing Effects 0.000 description 5
- 239000000014 opioid analgesic Substances 0.000 description 5
- 210000001519 tissues Anatomy 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 230000036912 Bioavailability Effects 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N Oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
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Abstract
A method of providing systemic analgesia to cats, dogs and other small mammals by the otic or transdermal administration of opioids is disclosed. Compositions for use in such a method are also disclosed.
Description
PHARMACEUTICAL COMPOSITIONS COMPRISING BUPRENORPHINE
FIELD OF THE INVENTION
The present invention relates to compositions and methods for providing systemic analgesia, and more particularly to the otic and transdermal administration of opioid analgesics to cats, dogs and other mammals.
BACKGROUND OF THE INVENTION
All patents, applications, publications, test methods, and other materials cited herein are incorporated by reference. Pain activates the hormonal systems of the body's stress and contributes to morbidity and mortality. Pain relief (analgesia) in animals can be safely provided by titrated opioids to cause effect. Opioids can provide deep analgesia with minimal cardiovascular side effects, are safe alone and in combination with anesthetics, and are reversed if an adverse event occurs. Historically, pharmacological agents, including opioids, have been administered through systemic injection (subcutaneous,
intramuscular or intravenous), epidurally, intrathecally (in the subarachnoid space), sublingually, orally, rectally and transdermally to provide analgesia. With the exception of epidural and intrathecal supply, administration of these agents provides systemic drug delivery to produce analgesic effects. Epidural and intrathecal administration involves the direct administration of an analgesic agent to receptors in the spinal cord involved in the spinal transmission of pain (for example opioid receptors), avoiding the need for systemic exposure to the pharmacological agent in question. Opioids produce analgesia by binding with opioid receptors within the nervous system to block the transmission of the pain impulse to the higher brain centers, thus decreasing or blocking the perception of pain. There are three types of well-characterized opioid receptors: mu, kappa and delta. Most clinically useful opioid medications are mu agonists. TORBUGESIC-SA (butorphanol tartrate) is a veterinary product approved in the United States for perioperative analgesia. Butorphanol is an opioid agonist / antagonist. Complete opioid agonists such as oxymorphone, morphine, meperidine and fentanyl can provide deep analgesia to animals and are safe to use in combination with anesthetics. For example, hydromorphone is used in veterinary practice as a perioperative analgesic via the injectable route of administration. Without
However, parenteral administration is not practical for use by owners of animals that do not have veterinary training. Oral formulations of many opioids are also available, but opioid agonists have low systemic availability when administered orally due to extensive hepatic first pass metabolism. Fentanyl has been administered transdermally by means of drug-loaded adhesive patches, but such patches are expensive and inconvenient to use in fur-coated animals. Furthermore, transdermal patches require up to six hours to achieve a therapeutic effect, and in the meantime analgesia must be provided through other means. In addition to the deficiencies of the present methods for the administration of opioids to animals that were raised above, the possibility of overdose and the potential for abuse by humans has limited its use in animals. U.S. Patent No. 5,589,480 relates to a method for inducing analgesia in inflamed skin by topically administering to the skin an opioid analgesic agent in an amount that is not effective for the induction of systemic analgesia. According to this patent, effective analgesia must be induced in "substantial absence of transdermal delivery of the opioid analgesic agent to the systemic circulation." U.S. Patent No. 6,01 1, 022 refers to a
method for inducing analgesia in the mucosal or cutaneous tissue, comprising administering via the eyes an analgesic agent that affects the peripheral muscarinic receptors, said amount is systemically ineffective for the induction of analgesia, and therefore the analgesia of the mucosal or cutaneous tissue it is induced in the substantial absence of transdermal or transmucosal delivery of the analgesic agent to the central nervous system. While oxymorphone and morphine are mentioned as analgesic agents that can be used in conjunction with an analgesic muscarinic receptor agonist, they are not themselves muscarinic receptor agonists. "Mucous tissue" is defined specifically in the descriptive report excluding the conjunctiva of the eye. The administration of certain veterinary drugs through the otic route is also known, but not for the provision of systemic analgesia. For example, methymazole is administered to the ear pavilion of cats to control hyperthyroidism. U.S. Patent No. 5,543,434 relates to the nasal or ocular administration of ketamine to control chronic pain. US Patent No. 6,191, 126 B1 is directed to the administration of kappa opioid agonists to the eye to treat ocular pain. This patent emphasizes that kappa opioids act on receptors in peripheral tissue, while mu opioids relieve pain by activating receptors in the brain. It is said that the local action of the kappa opioids constitutes an advantage with respect to the systemic action. Accordingly, this invention is only suitable for the treatment of pain in the
Ophthalmic tissues, not systemic analgesia. In view of the foregoing limitations and deficiencies of prior art formulations and methods, as well as other disadvantages not specifically mentioned above, it is clear that there is still a need in the art for improved means to induce analgesia systemically.
BRIEF DESCRIPTION OF THE INVENTION
Accordingly, pharmaceutically acceptable compositions for otic and transdermal administration to an animal and methods for the use thereof are disclosed. Said compositions comprise buprenorphine, a pharmaceutically acceptable carrier system comprising a solvent consisting of an aqueous phase and an organic phase, at least one penetration enhancing agent and, optionally, a stabilizing agent, a preservative, an antioxidant, an agent which increases the viscosity and / or a tonicity regulating agent. The present composition may also optionally include a non-opioid analgesic, such as a non-spheroid anti-inflammatory drug (NSAID), an N-methyl-d-aspartate (NMDA) receptor antagonist, an alpha-2 adrenergic receptor agonist, a Sodium channel blocker, or ligand of the transient receptor potential ion channel (TRP).
With the foregoing objects, advantages and features of the invention and others which will become apparent hereinafter, the nature of the invention can be understood more clearly by reference to the following detailed description of the invention and the appended claims.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 is a graph showing the mean buprenorphine concentration (+ 1 DS) in plasma versus time in five healthy cats after the otic administration of a buprenorphine formulation at a dose of 0.25-0.50 mg / kg. Figure 2 is a graph showing the average pain assessed by Visual Analogue Scale (VAS) for cats after the debulking procedure and treatment either with subcutaneous meloxicam, a post-operative analgesic for cats approved by the FDA, or with otic buprenorphine. The cats with meloxicam are represented by the dotted line and have +1 DS that is shown for each time point. Cats with buprenorphine are represented by the continuous line and have -1 SD shown for each time point. Figure 3 is a graph showing the mean plasma buprenorphine concentration versus time in six healthy cats after transdermal administration of a buprenorphine formulation to a
dose either 0.17 - 0.35 mg / kg or 0.35 - 0.70 mg / kg. Data for cats with doses of 0.17 - 0.35 mg / kg are represented by the dotted line and have -1 SD displayed for each time point; The data for cats with doses of 0.35 - 0.70 mg / kg are represented by the continuous line and have +1 DS that is shown for each time point.
DETAILED DESCRIPTION OF THE INVENTION
It has been found that effective opioid concentrations in the systemic circulation for the purpose of providing systemic analgesia can be achieved by otic or transdermal routes of administration. When using the otic or transdermal route of administration, intestinal / hepatic wall metabolism ("first step") of the opioid is avoided, which may improve bioavailability in relation to oral dosing. The present invention relates to an opioid analgesic product for providing systemic analgesia, for example, preventive and perioperative analgesia, for mammals such as cats and dogs. The present invention comprises at least one opioid analgesic in a pharmaceutically acceptable vehicle. The compositions of the present invention can be used to simultaneously prevent or reduce the pain associated with surgery or injuries. Also contemplated is the use for the treatment of chronic pain associated with, for example, neoplasia, osteoarthritis, pruritis, etc.
The terms "otic" and "through the ear" are used interchangeably in the present to denote that they refer to the ear. As used herein, "opiate" means any preparation or derivative of opium. The term "opioid" refers to both opiates and synthetic or semi-synthetic narcotics that resemble opiates. As used herein, the term "aqueous phase" means a solvent system composed of water, isotonic solution, a pH regulator system and / or any solvent miscible with water. As used herein, the term "organic phase" means a solvent system composed of any solvent system or organic solvent miscible or immiscible with water. Active ingredients include opioid analgesics, in particular those which possess mu-opioid receptor agonist activity, such as buprenorphine, morphine, diamorphine, meperidine, methadone, etorphine, levorphanol, fentanyl, alfentanil, sufentanil, oxycodone, hydrocodone, codeine, and oxymorphone. . Buprenorphine is particularly preferred because of a wider safety margin and a longer duration of activity. In the preferred embodiment, the formulation is long-acting, for example it is administered up to three times a day as needed. Because this is a long-acting formulation, as opposed to a quick-acting formulation, a particular advantage of the
present invention consists of the reduced dosage frequency, which offers convenience for the person administering the product. It will also be appreciated that the present invention comprises, in one aspect, methods for alleviating pain by administering, for example, a pharmaceutically acceptable composition comprising, for example, buprenorphine, to an animal by otic or transdermal administration. Administration of the dosage can also be achieved, for example, by applying multiple or individual drops to the ear or skin of the animal. For example, concentrations of buprenorphine in plasma, after single-dose otic administration at a dose of about 0.05 to about 0.1 mg / kg achieved a Cmax approximately greater than 5 ng / ml at a Tmax of about 60 minutes, and at a At a dose of about 0.1 to about 0.2 mg / kg, a Cmax of approximately greater than 7 ng / ml was achieved at a Tmax of about 30 minutes. In another example, concentrations of buprenorphine in plasma, after single-dose otic administration at a dose of from about 0.3 to about 0.6 mg / kg achieved a Cmax of about 28 ng / ml at a Tmax of about 90 minutes, and a Dosage of about 0.25 to about 0.5 mg / kg, an initial peak approximately greater than 10 ng / mL was achieved at about 30 minutes, followed by a Cmax approximately greater than 12 ng / mL at a Tmax of about 2 hours.
In yet another embodiment, plasma buprenorphine concentrations, following a single dose transdermal administration at a dose of about 0.35 to about 0.70 mg / kg achieved a Cmax of about 10 ng / ml at a Tmax of about 30 minutes. When a dose of from about 0.17 to about 0.35 mg / kg was used, a Cmax of approximately greater than 3 ng / mL was achieved at a Tmax of about 4 hours. Opioid analgesic metabolites that have analgesic activity can also be used. Such metabolites include, for example, analgesically active forms of sulfate and glucuronide of opioids such as morphine-6-glucuronide. Due to possible problems created by the unpleasant smell of the drug, the low bioavailability, or the potential for the local analgesic effect, it may be desirable to use a prodrug form of said opioid. Particularly preferred prodrug forms are those in which the 3-hydroxy phenolic group is esterified. Examples of prodrug derivatives suitable for use in the present invention include those disclosed in U.S. Patent Nos. 4,668,685 and 4,673,679, both assigned to DuPont. In another embodiment, the present invention contemplates the inclusion of a non-opioid analgesic, such as an NSAID. Preferred NSAIDs include acemetacin, acetylsalicylic acid (aspirin), alminoprofen, benoxaprofen, bucilloxic acid, carprofen, celecoxib, clidanac, deracoxib,
diclofenac, diflunisal, dipirona, etodolac, fenoprofen, fentiazac, firocoxib, flobufen, flufenamic acid, flufenisal, flunixin, fluprofen, flurbiprofen, ibuprofen, indomethacin, indoprofen, isoxicam, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, miroprofen, nabumetone , naproxen, niflumic acid, oxaprozin, oxepinac, phenylbutazone, piroxicam, pirprofen, pramoprofen, sudoxicam, sulindac, suprofen, tepoxaline, thiaprofenic acid, tiopinac, tolfenamic acid, tolmetin, trioxaprofen, zidometacin, or zomepirac, the pharmaceutically acceptable salts thereof and the mixtures thereof. Particularly preferred NSAIDS include carprofen, deracoxib, etodolac, firocoxib, flunixin, ketoprofen, meloxicam and tepoxaline. Preferred NMDA receptor antagonists include memantine, ketamine, tiletamine, and pharmaceutically acceptable salts thereof and mixtures thereof. A particularly preferred NMDA receptor antagonist is ketamine. Preferred alpha-2 adrenergic receptor agonists include clonidine, detomidine, dexmedetomidine, fadolmidine, medetomidine, moxonidine, romifidine, xylazine, and the pharmaceutically acceptable salts thereof and mixtures thereof. Particularly preferred alpha-2 adrenergic receptor agonists include detomidine and xylazine. Preferred sodium channel blockers include benzocaine, bupivacaine, lamotrigine, levobupivicaine, lidocaine, lignocaine, oxybuprocaine, prilocaine, proxymetacaine, ropivicaine, and the pharmaceutically acceptable salts of the
same and the mixtures thereof. Particularly preferred sodium channel blockers include bupivacaine and lidocaine. In general, the formulations of the present invention will contain from about 0.1 to about 10% of the opioid (s) in an otic or transdermally acceptable vehicle. The amount of the opioid (s) can be varied to alter the volume of the dose and / or the dosage schedule. The amount of a second analgesic, such as an NSAID, will depend on synergy with the opioid and bioavailability and will be titled to take effect. The compositions of the present invention can take various forms. For example, they can be a gel, liquid, or ointment. The solvent used in the composition consists of an aqueous and organic phase. Suitable solvents for the formulation include, but are not limited to, glyceryl formaldehyde, dimethylformamide, N-methyl-pyrrolidone, 2-pyrrolidone, glycol, propylene glycol, polyethylene glycol, diethylosorbide, water, ethanol, isopropanol, 1,2-propanediol, glycerin, triethyl citrate, benzyl alcohol , dimethylisosorbide, C2-C9 alkylene diols, for example, butylene diol, pentylene glycol, neopentyl diol, propylene glycol diethylene glycol, monoethyl ether or similar compounds such as dialkylene diol C2-C5, monoethers of C-C4 alkyl, for example, dipropylene glycol, mono propyl ether, mono propyl ether, and mono ethyl ether. Preferred solvents include 2-pyrrolidone, glyceryl formal, dimethylformamide, N-methyl-pyrrolidone, propylene glycol, polyethylene glycol, diethylosorbide, ethanol, isopropanol, 1,2-propanediol, glycerin, citrate
triethyl, benzyl alcohol, dimethyl isosorbide and water. A particularly preferred solvent is propylene glycol. Preferably, said solvent is present in an amount of up to about 80% by weight of the formulation. Preferably, said solvent is present at about 10% to about 75% of the formulation. Suitable penetration enhancers can include lipophilic and / or hydrophilic components. Suitable penetration enhancers can be, for example, an alcohol, an emulsifier or a non-ionic solubilizer. Suitable penetration enhancers include, but are not limited to, ethylene glycol, propylene glycol, dimethyl sulfoxide (DMSO), dimethyl polysiloxane (DMPX), oleic acid, caprylic acid, isopropyl alcohol, 1-octanol, ethanol (denatured or anhydrous), benzyl alcohol and other absolute or pharmaceutical grade alcohols with the exception of methanol. Other penetration enhancers include, water, sulfoxides and similar chemicals, such as DMSO, dimethylacetamide (DMA), dimethylformamide (DMF), etc., azone and related compounds, pyrrolidones, such as N-methyl-pyrrolidone (NMP), 2 -pyrrolidone (2-pyrrole), etc., fatty alcohols, fatty acids and related structures, such as oleyl alcohol, oleic acid, linoleic acid, isopropyl myristate, etc., alcohols and glycols, such as ethanol, propylene glycol, esters of lauryl alcohol, lauryl alcohol, etc., the propylene glycol esters, such as propylene glycol monolaurate, surfactants, such as sodium lauryl sulfate (SLS), etc., urea, essential oils,
terpenes and terpenoids, such as menthol, eucalyptus oil, 8-cineole, etc., phospholipids and solvents and related compounds, such as transcutol (ethoxydiglycol), etc. Preferred penetration enhancers are menthol, alcohols, benzyl alcohol, ethanol, water, glycols, propylene glycol esters, propylene glycol monolaurate, lauryl alcohol esters or lauryl alcohol. The viscosity of the vehicle can be increased or decreased as necessary by the use of several additional agents. The viscosity improving agent may be a polysaccharide gum, a water dispersible acid polymer, and / or a mixture thereof. Viscosity improving agents suitable for use in the compositions of the present invention include, but are not limited to, polyvinyl alcohol, polyvinyl pyrrolidone magnesium sulfate, propylene glycol, lanolin, glycerin, hydroxypropyl cellulose and other agents known to those skilled in the art. for being suitable for use in the ear. A preferred viscosity improving agent is hydroxypropylcellulose. Emulsifiers suitable for use in the compositions of the present invention include, for example, polyethylene glycol dipolyhydroxystearate (PEG) 30 (for example ARLICEL P135, available from ICI Surfactants, Wilmington, DE), sorbitan stearate oleate PEG-40 (e.g. CRILL 4, available from Croda, Inc., Parsippany, NJ), polysorbate 80 (for example TWEEN 80, available from ICI Surfactants.) A component of the organic solution consists of a solvent consisting of compounds, such as suitable surfactants for
the organic solution, which include, but are not limited to, monoglycerides or similar compounds such as glyceryl mono-oleate, -laurate, -behenate, -eicosadioate, -stearate, or other mono-substituted glycerides with fatty acids. Suitable film formers for the organic solution include, but are not limited to, polyacrylamide or other similar compounds, which act as thickening agents such as other acrylamide copolymers, polyacrylate copolymers, copolymers and cellulosic polymers, and copolymers and polymers of polyvinyl pyrrolidone. Other optional inert ingredients may be added to the present composition, as desired. These ingredients include, but are not limited to, preservatives, chelating agents, antioxidants and stabilizers. Exemplary preservatives include, but are not limited to, BHT, methyl p-hydroxybenzoate (methylparaben) and propyl p-hydroxybenzoate (propylparaben). It will also be estimated that the formulations of the present invention in another embodiment are self-preserving. Exemplary chelating agents include, but are not limited to, sodium edetate. Exemplary antioxidants include, but are not limited to, butylated hydroxyanisole (BHA), BHT and monothioglycerol sodium. Preferred stabilizers for preventing degradation of any of the active ingredients in the formulations of the present invention include, but are not limited to, BHT, BHA, monothioglycerol sodium, methyl p-hydroxybenzoate (methylparaben) and propyl p-hydroxybenzoate ( propylparaben). Other preferred stabilizers
include, but are not limited to, triethyl citrate, USP, NF, acetic acid, glacial acetic acid, fumaric acid, hydrochloric acid, dilute hydrochloric acid, malic acid, nitric acid, phosphoric acid, dilute phosphoric acid, sulfuric acid and tartaric acid . Particularly preferred stabilizers for use in the present invention include, but are not limited to, BHT, BHA, monothioglycerol sodium or citric acid in a concentration of about 5% or less and monothioglycerol in a concentration of about 0.1% to 2% p / v. Preferably the pH of the compositions of the present invention is regulated to maintain buprenorphine or buprenorphine HCl in solution. Preferably, the pH of the compositions of the present invention is between about 3 and about 10, preferably about 3.5 to about 6. An appropriate pH regulating agent can be added to maintain the pH. Suitable pH regulators include, but are not limited to, potassium chloride, sodium or potassium phosphates (monobasic and dibasic), sodium or potassium acetates, sodium or potassium borates (eg, sodium tetraborate decahydrate) , sodium or potassium citrates, sodium or potassium hydroxides and equivalents or mixtures thereof, and weak acids, such as acetic, boric, and phosphoric acids. For the purpose of preparing the composition of the present invention, the vehicle (s) or a portion of the vehicle (s) is (are) added to the compounding vessel, followed by the active and
the remaining excipients. The mixture is mixed until all the solids are dissolved or in suspension. Additional solvent (s) can be added to bring the composition to a final volume if necessary. The additives, such as those listed above, may also be included in the container and mixed within the formulation (the order of addition is not decisive). After the application of the formulation, the opioid present in the composition is absorbed systemically. It is an advantage of the method of the present invention that it can provide rapid initial absorption with some delayed release for continuous absorption of the active drug, thereby providing a better pharmacokinetic profile than intravenous or other parenteral routes for dosing. The onset of the analgesic action after the administration of the compositions of the present invention is initiated after 30 minutes of application, and the duration of the analgesic action generally lasts up to at least 8 hours. Another advantage of the present invention is that some of the formulations appear to have a rapid absorptive phase and a prolonged plateau phase (slow absorptive phase). In this way, the preceding desirable characteristics can be achieved with a formulation. Other advantages of the present invention consist in the fact that animals with pain and / or animals with an opiate can be aggressive. Accordingly, the administration of the present invention has the advantage that a person
that manages animals never have to go near the mouth / teeth of the animal, that is, an increased security for those who handle animals. The method of the present invention, and the formulations for carrying out the method, possess other advantages with respect to the existing products, such as the ease of administration for both the veterinary personnel and the owner of the animal, the reduction of the effects secondary, etc. In the case of an adverse event, the activity of the opioid is reversed by the administration of opioid antagonists, for example naloxone. It is believed that the route of administration can improve the bioavailability of many analgesic agents such as opioids that undergo gastrointestinal degradation and hepatic first pass metabolism when administered orally. It is possible that the metabolism of said compounds may be favorably affected by the route of administration. The appropriate dosage can be determined according to the weight of the animal. As one skilled in the art will estimateIf renal or hepatic function is compromised, it may be necessary to decrease the dosage of the drug to account for the decreased elimination. The compositions of the present invention can be packaged in many forms. Preferably the formulation is packaged as single-dose, single-use units. Said single-dose pack overcomes problems of bacterial contamination of the preparations with multiple doses and
minimizes the possibility of accidental acute overdose. The following examples are provided for the purpose of illustrating the present invention and should not be construed as limiting the scope or spirit of the invention.
Otica
This Example can be prepared according to customary procedures known to the person skilled in the art. In a specific embodiment, the formulation can be prepared and stored in two different solvent systems consisting of an organic phase system and an aqueous phase system to be combined to obtain the final formulation.
EXAMPLE 2
Five healthy cats were administered the formulation of Example 1 at a dosage of 0.25-0.50 mg / kg. Serial blood samples were drawn at hour 0 before dosing, then at 0.25, 0.5, 1, 1.5.
2, 4, 6, 8, and 24 hours after dosing. The concentrations of buprenorphine in plasma (ng / mL) versus time were reported and presented graphically. The results are shown in figure 1. Two plasma peaks are evident - the first approximately 4 ng / mL occurs at 90 minutes, while the second approximately 5 ng / mL occurs at 8 hours. These data show that the formulation described in Example 1 has a benefit, in the sense that buprenorphine is detected in the plasma shortly after dosing, which suggests that the analgesia will take place soon. Second, the plasma peak occurs at approximately 8 hours after dosing, suggesting that the analgesia will be long lasting.
EXAMPLE 3
Fourteen healthy cats were used in a study described below to evaluate the analgesic properties of the formulation described in the Example. The cats underwent general anesthesia and underwent bilateral oniquectomy (debulking) of the front legs by a licensed veterinarian. Prior to the induction of anesthesia, six of the cats received a subcutaneous injection (0.3 mg / kg) of meloxicam, which is approved in the United States for postoperative analgesia in cats. Eight cats were given a dose of 0.6 mg / kg of
the buprenorphine formulation described in Example 1. After surgery, all cats were evaluated for signs of pain using an Analog Visual Scale (VAS) at 0.5, 1, 2, 3, 4, 6, 8, and 24 hours. The mean VAS versus post-surgery time for cats treated with meloxicam or with buprenorphine was reported and plotted. The results are shown in Figure 2. These data suggest that the post-surgical analgesic profile of the formulation described in Example 1 is similar to that of a post-operative analgesic for cats approved by the FDA.
EXAMPLE 4 Otic
This Example can be prepared according to customary procedures known to the person skilled in the art. In a specific embodiment, the formulation can be prepared and stored in two different solvent systems consisting of an organic phase system and an aqueous phase system to be combined to obtain the final formulation.
EXAMPLE 5 Topical / transdermal
This Example can be prepared according to customary procedures known to the person skilled in the art. In a specific embodiment the formulation can be prepared and stored in two different solvent systems consisting of an organic phase system and an aqueous phase system to be combined to obtain the final formulation.
EXAMPLE 6
Six healthy cats were administered the formulation of Example 5 once using a dosage of 0.17-0.35 mg / kg, and then again using a dosage of 0.35-0.70 mg / kg. After each dosage, serial blood samples were taken at hour 0 before dosing, then at 0.25, 0.5, 1, 1 .5, 2, 3, 4, 6, 10, 24, and 32 hours after the dosage. The concentrations of buprenorphine in plasma (ng / mL) versus time were reported and presented graphically. The results are shown in figure 3.
These data show that the formulation described in Example 5 has a benefit, in the sense that buprenorphine is detected in the plasma shortly after transdermal dosing, which suggests that the analgesia will take place soon. Secondly, plasma levels are detected for as long as 32 hours after dosing, which suggests that the analgesia will be long lasting. Although certain currently preferred embodiments of the invention have been described herein, it will be apparent to those skilled in the art to those concerned by the invention that variations and modifications of the described embodiment can be made without departing from the spirit and scope of the invention. . Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law.
Claims (1)
- NOVELTY OF THE INVENTION CLAIMS 1 . A pharmaceutically acceptable composition, useful for the otic administration to an animal, comprising buprenorphine, a pharmaceutically acceptable carrier system comprising a solvent consisting of an aqueous phase and an organic phase, and at least one penetration enhancing agent. 2. - The pharmaceutically acceptable composition according to claim 1, further characterized in that the penetration enhancing agent includes lipophilic and / or hydrophilic components. 3. The pharmaceutically acceptable composition according to claim 2, further characterized in that the penetration enhancing agent is selected from the group consisting of esters of propylene glycol, menthol, alcohol, glycols, or water in an amount sufficient to improve the penetration of buprenorphine. 4. - The pharmaceutically acceptable composition according to claim 3, further characterized in that the glycol is propylene glycol monolaurate. 5. The pharmaceutically acceptable composition according to claim 3, further characterized by the alcohol is selected from the group consisting of ethanol, lauryl alcohol and lauryl alcohol esters. 6. - The pharmaceutically acceptable composition according to claim 5, further characterized in that the alcohol is an ester of lauryl alcohol. 7. - The pharmaceutically acceptable composition according to claim 1, further characterized in that the solvent is selected from the group consisting of 2-pyrrolidone, glyceryl formal, dimethylformamide, N-methyl-pyrrolidone, propylene glycol, polyethylene glycol, diethylisorbide, ethanol, isopropanol , 1,2-propanediol, glycerin, triethyl citrate, benzyl alcohol, dimethyl isosorbide and water. 8. - The pharmaceutically acceptable composition according to claim 7, further characterized in that the solvent is propylene glycol. 9. - The pharmaceutically acceptable composition according to claim 1, further characterized in that the composition has a pH range of about 3 to about 10. 10. The pharmaceutically acceptable composition according to claim 1, further characterized by additionally comprising a stabilizing agent. eleven . - The pharmaceutically acceptable composition according to claim 10, further characterized in that the agent The stabilizer is selected from the group consisting of BHT, BHA and monothioglycerol sodium. 12. - The pharmaceutically acceptable composition according to claim 1, further characterized in that it additionally comprises a preservative agent. 13. - The pharmaceutically acceptable composition according to claim 12, further characterized in that the preservative is selected from the group consisting of BHT, methyl p-hydroxybenzoate (methylparaben) and propyl p-hydroxybenzoate (propylparaben). 14. - The pharmaceutically acceptable composition according to claim 1, further characterized in that it additionally comprises a viscosity improving agent and / or an antioxidant agent. 15. - The pharmaceutically acceptable composition according to claim 14, further characterized in that the viscosity improving agent is selected from the group consisting of a polysaccharide gum, a water dispersible acid polymer, and / or a mixture thereof . 16. - The pharmaceutically acceptable composition according to claim 15, further characterized in that the viscosity improving agent is hydroxypropylcellulose. 17. - The pharmaceutically acceptable composition according to claim 14, further characterized in that the antioxidant agent is selected from the group consisting of BHT, BHA and monothioglycerol sodium. 18. - The pharmaceutically acceptable composition according to claim 1, further characterized in that it additionally comprises a non-opioid analgesic. 19. - The pharmaceutically acceptable composition according to claim 18, further characterized in that the non-opioid analgesic is selected from the group consisting of acemetacin, acetylsalicylic acid (aspirin), alminoprofen, benoxaprofen, bucilloxic acid, cofen, celecoxib, clidanac, deracoxib , diclofenac, diflunisal, dipirone, etodolac, fenoprofen, fentiazac, firocoxib, flobufen, flufenamic acid, flufenisal, flunixin, fluprofen, flurbiprofen, indoprofen, isoxicam, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, miroprofen, nabumetone, naproxen, niflumic acid, oxaprozin, oxepinac, phenylbutazone, piroxicam, pirprofen, pramoprofen, sudoxicam, sulindac, suprofen, tepoxaline, thiaprofenic acid, tiopinac, tolfenamic acid, tolmetin, trioxaprofen, zidometacin, zomepirac, and pharmaceutically acceptable salts thereof and mixtures thereof. 20. The use of a pharmaceutically acceptable composition as claimed in claim 1 in the manufacture of a drug useful for inducing analgesia in an animal, wherein the medicament is adapted to be administrable by otic route. twenty-one . The use of a pharmaceutically acceptable composition as claimed in claim 1 in the manufacture of a medicament useful for inducing a systemic analgesic effect in an animal, wherein the medicament is adapted to be administrable by otic route. 22. The use as claimed in claim 21, wherein the analgesic effect is at least about 8 hours. 23. - The use as claimed in claim 21, wherein at a dosage range of from about 0.05 to about 0.6 mg / kg a level of buprenorphine in the animal of one Cmax is achieved in a range of about 5 ng / ml to about 28 ng / ml and a Tmax in the range of about 0.5 hours to about 2 hours. 24. A pharmaceutically acceptable composition for transdermal administration to an animal comprising buprenorphine, a pharmaceutically acceptable carrier system comprising a solvent consisting of an aqueous phase and an organic phase, and at least one penetration enhancing agent. 25. - The pharmaceutically acceptable composition according to claim 24, further characterized in that the penetration enhancing agent includes lipophilic and / or hydrophilic components. 26. The pharmaceutically acceptable composition according to claim 25, further characterized in that the penetration enhancing agent is selected from the group consisting of esters of propylene glycol, menthol, alcohol, glycols and water in an amount sufficient to improve the penetration of buprenorphine . 27. The pharmaceutically acceptable composition according to claim 26, further characterized in that the glycol is propylene glycol monolaurate. 28. - The pharmaceutically acceptable composition according to claim 26, further characterized in that the alcohol is selected from the group consisting of ethanol, lauryl alcohol and lauryl alcohol esters. 29. - The pharmaceutically acceptable composition according to claim 26, further characterized in that the penetration enhancing agent is menthol. 30. - The pharmaceutically acceptable composition according to claim 24, further characterized in that the solvent is selected from the group consisting of 2-pyrrolidone, glyceryl formal, dimethylformamide, N-methyl-pyrrolidone, propylene glycol, polyethylene glycol, diethylosorbide, ethanol, isopropanol , 1,2-propanediol, glycerin, triethyl citrate, benzyl alcohol, dimethyl isosorbide and water. 31 - The pharmaceutically acceptable composition according to claim 30, further characterized in that the solvent is propylene glycol. 32. - The pharmaceutically acceptable composition according to claim 24, further characterized in that the composition has a pH in the range of about 3 to about 10. 33. The pharmaceutically acceptable composition according to claim 24, further characterized in that it comprises additionally a viscosity improving agent, a preservative and / or antioxidant agent. 34. - The pharmaceutically acceptable composition according to claim 33, further characterized in that the viscosity improving agent is selected from the group consisting of a polysaccharide gum, a water dispersible acid polymer, and / or a mixture thereof . 35. The pharmaceutically acceptable composition according to claim 34, further characterized in that the viscosity improving agent is hydroxypropylcellulose. 36. - The pharmaceutically acceptable composition according to claim 33, further characterized in that the preservative agent is selected from the group consisting of BHT, p- methyl hydroxybenzoate (methylparaben) and propyl p-hydroxybenzoate (propylparaben). 37. - The pharmaceutically acceptable composition according to claim 33, further characterized in that the antioxidant agent is selected from the group consisting of BHT, BHA and monothioglycerol sodium. 38. - The pharmaceutically acceptable composition according to claim 24, further characterized in that it additionally comprises a non-opioid analgesic. 39. - The pharmaceutically acceptable composition according to claim 38, further characterized in that the non-opioid analgesic is selected from the group consisting of acemetacin, acetylsalicylic acid (aspirin), alminoprofen, benoxaprofen, bucilloxic acid, carprofen, celecoxib, clidanac, deracoxib , diclofenac, diflunisal, dipirone, etodolac, fenoprofen, fentiazac, firocoxib, flobufen, flufenamic acid, flufenisal, flunixin, fluprofen, flurbiprofen, indoprofen, isoxicam, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, miroprofen, nabumetone, naproxen, niflumic acid, oxaprozin, oxepinac, phenylbutazone, piroxicam, pirprofen, pramoprofen, sudoxicam, sulindac, suprofen, tepoxaline, thiaprofenic acid, tiopinac, tolfenamic acid, tolmetin, trioxaprofen, zidometacin, zomepirac, and pharmaceutically acceptable salts thereof and mixtures thereof. 40. The use of a pharmaceutically acceptable composition as claimed in claim 24 in the manufacture of a medicament useful for inducing analgesia in an animal, wherein the medicament is adapted to be administrable transdermally. 41 The use of a pharmaceutically acceptable composition as claimed in claim 24 in the manufacture of a medicament useful for inducing a systemic analgesic effect in an animal, wherein the medicament is adapted to be administrable transdermally. 42. - The use as claimed in claim 41, wherein the analgesic effect is at least about 8 hours. 43. The use as claimed in claim 41, wherein at a dosage range of from about 0.17 to about 0.70 mg / kg a level of buprenorphine in the animal of a Cmax of about 3 to about 10 ng / ml is achieved. and a Tmax of about 30 minutes to about 4 hours.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US60/738,524 | 2005-11-21 |
Publications (1)
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MX2008006610A true MX2008006610A (en) | 2008-10-03 |
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