MXPA02001830A - Combinacion sinergica de inhibidores de pde y agonista de beta 2 adrenoceptor. - Google Patents
Combinacion sinergica de inhibidores de pde y agonista de beta 2 adrenoceptor.Info
- Publication number
- MXPA02001830A MXPA02001830A MXPA02001830A MXPA02001830A MXPA02001830A MX PA02001830 A MXPA02001830 A MX PA02001830A MX PA02001830 A MXPA02001830 A MX PA02001830A MX PA02001830 A MXPA02001830 A MX PA02001830A MX PA02001830 A MXPA02001830 A MX PA02001830A
- Authority
- MX
- Mexico
- Prior art keywords
- medicament
- salt
- adrenoceptor agonist
- pde inhibitor
- acid
- Prior art date
Links
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- 238000011260 co-administration Methods 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
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- 239000000839 emulsion Substances 0.000 description 1
- 229960001022 fenoterol Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
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- 235000019634 flavors Nutrition 0.000 description 1
- 229960002848 formoterol Drugs 0.000 description 1
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229960000708 hexoprenaline Drugs 0.000 description 1
- OXLZNBCNGJWPRV-UHFFFAOYSA-N hexoprenaline Chemical compound C=1C=C(O)C(O)=CC=1C(O)CNCCCCCCNCC(O)C1=CC=C(O)C(O)=C1 OXLZNBCNGJWPRV-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- YXOKBHUPEBNZOG-UHFFFAOYSA-N hydron;4-hydroxy-7-[2-[2-[3-(2-phenylethoxy)propylsulfonyl]ethylamino]ethyl]-3h-1,3-benzothiazol-2-one;chloride Chemical compound Cl.C1=2SC(=O)NC=2C(O)=CC=C1CCNCCS(=O)(=O)CCCOCCC1=CC=CC=C1 YXOKBHUPEBNZOG-UHFFFAOYSA-N 0.000 description 1
- SYCWERNQGSKYAG-QVRIGTRMSA-N hydron;8-hydroxy-5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-methoxyphenyl)propan-2-yl]amino]ethyl]-1h-quinolin-2-one;chloride Chemical compound Cl.C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C2=C1C=CC(=O)N2 SYCWERNQGSKYAG-QVRIGTRMSA-N 0.000 description 1
- TWTMQRXNAZGSCE-UHFFFAOYSA-N hydron;[6-(methylamino)-1-(2-methylpropanoyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl] 2-methylpropanoate;chloride Chemical compound Cl.C1=CC(OC(=O)C(C)C)=C(OC(=O)C(C)C)C2=C1CC(NC)CC2 TWTMQRXNAZGSCE-UHFFFAOYSA-N 0.000 description 1
- 229950002451 ibuterol Drugs 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229960001317 isoprenaline Drugs 0.000 description 1
- 229950008204 levosalbutamol Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- JSJCTEKTBOKRST-UHFFFAOYSA-N mabuterol Chemical compound CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(C(F)(F)F)=C1 JSJCTEKTBOKRST-UHFFFAOYSA-N 0.000 description 1
- 229950004407 mabuterol Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229950001737 meluadrine Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- XUDYTJVYZTVYGI-INIZCTEOSA-N methyl (2R)-2-(3,4-dimethoxyphenyl)-3-(3-oxo-1H-isoindol-2-yl)propanoate Chemical compound COC(=O)[C@@H](CN1Cc2ccccc2C1=O)c1ccc(OC)c(OC)c1 XUDYTJVYZTVYGI-INIZCTEOSA-N 0.000 description 1
- YTFBNFMILWHYAP-UWJYYQICSA-N methyl (3s,4s)-3-acetyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidine-1-carboxylate Chemical compound CC(=O)[C@]1(C)CN(C(=O)OC)C[C@H]1C1=CC=C(OC)C(OC2CCCC2)=C1 YTFBNFMILWHYAP-UWJYYQICSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- DVWBMWJOYIFITF-UHFFFAOYSA-N n'-hydroxy-5,6-dimethoxy-1-benzothiophene-2-carboximidamide;hydrochloride Chemical compound Cl.C1=C(OC)C(OC)=CC2=C1SC(C(\N)=N\O)=C2 DVWBMWJOYIFITF-UHFFFAOYSA-N 0.000 description 1
- DPHDSIQHVGSITN-UHFFFAOYSA-N n-(3,5-dichloropyridin-4-yl)-2-[1-[(4-fluorophenyl)methyl]-5-hydroxyindol-3-yl]-2-oxoacetamide Chemical compound C1=C(C(=O)C(=O)NC=2C(=CN=CC=2Cl)Cl)C2=CC(O)=CC=C2N1CC1=CC=C(F)C=C1 DPHDSIQHVGSITN-UHFFFAOYSA-N 0.000 description 1
- HHRNQOGXBRYCHF-UHFFFAOYSA-N n-[2-hydroxy-5-[1-hydroxy-2-(propan-2-ylamino)ethyl]phenyl]methanesulfonamide Chemical compound CC(C)NCC(O)C1=CC=C(O)C(NS(C)(=O)=O)=C1 HHRNQOGXBRYCHF-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229960001476 pentoxifylline Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000002570 phosphodiesterase III inhibitor Substances 0.000 description 1
- 229960005414 pirbuterol Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 150000007519 polyprotic acids Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229960002288 procaterol Drugs 0.000 description 1
- FKNXQNWAXFXVNW-BLLLJJGKSA-N procaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)[C@@H](NC(C)C)CC FKNXQNWAXFXVNW-BLLLJJGKSA-N 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229960001457 rimiterol Drugs 0.000 description 1
- IYMMESGOJVNCKV-SKDRFNHKSA-N rimiterol Chemical compound C([C@@H]1[C@@H](O)C=2C=C(O)C(O)=CC=2)CCCN1 IYMMESGOJVNCKV-SKDRFNHKSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 229950010289 soterenol Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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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
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
La invencion se refiere a la administracion combinada de inhibidores de PDE y agonistas de ?2 adrenoceptor para el tratamiento de desordenes del tracto respiratorio.
Description
COMBINACIÓN SINERGICA DE INHIBIDORES DE PDE Y AGONISTA DE BETA 2 ADRENOCEPTOR
Campo de aplicación de la invención La invención se refiere a la combinación de ciertos compuestos activos conocidos para fines terapéuticos. Las substancias usadas en la combinación de acuerdo con la invención son conocidos compuestos de la clase de inhibidores de PDE y compuestos activos de la clase de agonistas de ß2 adrenoceptor. Su uso combinado en el sentido de acuerdo con la invención para fines terapéuticos todavía no ha sido descrito en la técnica anterior
Descripción de la invención El objetivo de la presente invención es hacer disponibles agentes terapéuticos de tracto respiratorio, los cuales satisfagan las siguientes condiciones: - Buena acción anti-inflamatoria Bronco-relajación y dilatación notables Buena disponibilidad oral, al menos con respecto al inhibidor de PDE - Menores efectos laterales - Buena conveniencia para terapia de largo plazo Influencia favorable sobre hiper-reactividad bronquial.
Se ha encontrado ahora que el uso combinado de un inhibidor de PDE, el cual puede ser usado como el agente terapéutico de tracto
t-.-t_- M : ? .fc-t- - I I , respiratorio y de un agonista de ß2 adrenoceptor, satisface de manera sobresaliente las condiciones antes mencionadas. Los inhibidores de PDE que pueden ser usados como agentes terapéuticos de tracto respiratorio en el sentido de la presente invención, son esos compuestos que retardan la descomposición de AMP cíclica (cAMP) o GMP cíclica (cGMP) mediante inhibición de las fosfodiesterasas,
, lo cual puede conducir a un incremento relativo en la concentración intracelular de cAMP o cGMP. Los posibles inhibidores de PDE dentro del significado de la presente invención son principalmente aquellas substancias que serán consideradas parte de la clase de inhibidor de PDE4 y aquellas substancias que pueden ser designadas como tipos mixtos de inhibidores de PDE3/4. A manera de ejemplo, esos inhibidores de PDE pueden ser mencionados, los cuales son descritos o reclamados en las siguientes solicitudes de patentes y patentes: DE 1545687, DE 2028869, DE 2123328, DE 2315801, DE 2402908, DE 2413935, DE 3900233, EP 0103497, EP 0139464, EP 0158380, EP 0163965, EP 0335386, EP 0389282, EP 0428302, EP 0435811, EP 0459505, EP 0470805, EP 0490823, EP 0506194, EP 0511865, EP 0527117, EP 0557016, EP 0626939, EP 0664289, EP 0671389, EP 0685474, EP 0685475, EP 0685479, EP 0736532, EP 0738715, EP 0748805, EP 0763534, EP 0816357, EP 0819688, EP 0819689, EP 0832886, EP 0834508, EP 0848000, JP 92234389, JP 94329652, JP 95010875, JP 98072415, JP 98147585, US 5703098, US 5739144, WO 9117991, WO 9200968, WO 921961, WO 9307146, WO 9315044, WO 9315045, WO 9318024, WO 9319068, WO
9319720, WO 9319747, WO 9319749, WO 9319751 , WO 9325517 WO
9402465, WO 9412461, WO 9420455, WO 9422852, , WO 9427947 WO
9501338, WO 9501980, WO 9503794, WO 9504045, , WO 9504046 WO
9505386, WO 9508534, WO 9509623, WO 9509624, , WO 9509627 WO 9509836, WO 9514667, WO 9514680, WO 9514681 , WO 9517392 WO
9517399, WO 9519362, WO 9520578, WO 9522520, , WO 9524381 WO
9527692, WO 9535281, WO 9535283, WO 8424174, , WO 9600218 WO
9601825, WO 9606843, WO 9611690, WO 9611917, , WO 9612720 WO
9631486, WO 9631487, WO 9631487, WO 9635683, , WO 9636595 WO 9636596, WO 9636611, WO 9636625, WO 9636638, , WO 9638150 WO
9639408, WO 9640636, WO 9703967, WO 9704779, , WO 9705105 WO
9708143, WO 9709345, WO 9712895, WO 9718208, , WO 9719078 WO
9720833, WO 9722585, WO 9722586, WO 9723457, , WO 9723460 WO
9723461, WO 9724117, WO 9724355, WO 9725312, , WO 9728131 WO 9730999, WO 9731000, WO 9732853, WO 9735854, , WO 9736905 WO
9743288, WO 9744036, WO 9744322, WO 9747604, , WO 9748697 WO
9804534, WO 9805327, WO 9806692, WO 9806704, , WO 9807715 WO
9808828, WO 9808830, WO 9808841, WO 9808844, WO 9809946 wo
9809961, WO 9811113, WO 9814448, WO 9818796, WO 9821208 WO 9822453, WO 9845268, WO 9855481, WO 9856756, WO 9905111 WO
9905112, WO 9505113, WO 9906404 y WO 9918095 Se enfatizará que esos inhibidores de PDE, los cuales son reclamados en las solicitudes de patente o patentes EP 0393500, EP 0510562, WP 0553174, WO 9501338,
WO 9603399, WO 9636625, WO 9636626, WO 9735854, WO 9821208, WO 9831674, WO 9840382, WO 9855481, WO 9905111, WO 9905112, WO
aá.-i -_-_ - -?- >tl_ -.a..-,--, i • "—-—» -'-*---.- ----i-- -t__-. .--,--4. &..1. _._.__ 99051 13, WO 9931071 y WO 9931090. Se prefieren aquí substancias que tengan buena disponibilidad oral. Inhibidores de PDE ejemplares se muestran en las siguientes páginas con la ayuda de sus fórmulas:
-t .. ?.j-.fej---. ___. ,__-___-----. --_-. .------a- _ __--_-_-.--. _ . ----- .. .. -k-t-i ._. J a
__._- -...--fe-.'.,.,..... _ ÍL á ^-k
t-i-jii I.J...--..1.I. :. .i,--..-.. .- -,--. .. --_,.„».. «•_
jifa, til. Ir lf M"- -- -*»— - — - - . *¿.;_fc.i _U
>*>*.* Í^ W
l-l.-.A i-?-t- .. ?..-.to.?- -i. - , ___--. - - -._ ---._-.-,---_-----^-----i__-^--_, _-___.-------_--- _-_-fe_á--Í
-i-A-----. ---_.. a..--.-- - . -,--_-__--- _.--._ -* -. fe t- „ - -...---fe. _.. -.-_. ---^-_--. -_-_--, ._*.-.,. -- . J-fc- . t ... J.J
BYK-33043 (Pumafentrin)
*í s-»¡^. -¡¡Ma
_-_-- _- - a--¿--A-?_-Í_.--_. --i---. . - .--_.--_----. ¿---i. i. -i .
Roflumilast
-A^_Í ¿..-X.i,_.__:.....i >i'ift.--i|?T.---._^-...--_.-_,-. . • ; -í-i-í--
Ningún átomo de hidrógeno es indicado en las fórmulas anteriores -O está de acuerdo con -OH, -N es NH2. Los grupos metilo, por ejemplo, en los átomos de oxígeno, están indicados por líneas. Los inhibidores de PDE a ser enfatizados, los cuales son seleccionados de los compuestos antes mencionados y los cuales pueden ser mencionados, son los compuestos activos de arofílina, atizoram, AWD- 12-281, BYA-19-8004, benafentrina, BYK-33043, CC-3052, CDP-840, Cl- 1918, cipanfilina, CP-220629, CP-293121, D-22888, D-4396, D-4418, denbufilína, filaminast, GW-3600, ibudilast, KF-17625, KS-506-G, laprafilina, NA-0226A, NA-23063A, ORG-20241, ORG-30029, PDB-093, pentoxifilina, piclamilast, roflumilast, rolipram, RPR-117658, RPR-122818, RPR-132294, RPR-132703, RS-17597, RS-25344-999, SB-207499, SB- 210667, SB-211572, SB-211600, SB-212066, SB-212179, SDZ-ISQ-844,
SDZ-MNS-949, SKF-107806, SQ-20006, T-2585, T-440, tibenelast, tolafentrina, UCB-29646, V-11294A, YM-58997, YM-976 y zardaverina. Los compuestos preferidos del grupo de los inhibidores de PDE antes mencionados son arofilina, cipanfilina-D4418, fila inast, ibudilast, laprafilina, ORG-20241, piclamilast, rolipram, SB-207499, tibenelast y V- 11294A. Los compuestos particularmente preferidos son BYK-33043 y en particular, roflumilast. Los agonistas de ß2 adrenoceptor los cuales pueden ser particularmente mencionados, son aquellas substancias que actúan selectivamente, las cuales solo tienen una ligera acción cardiaca y por lo tanto, también son empleadas en terapia, en particular en la terapia oral de desórdenes del tracto respiratorio. Los agonistas de ß2 adrenoceptor, los cuáles pueden ser mencionados son, por ejemplo: AR-C68397AA, broxaterol, CHF-1035, HOKU-81, ibuterol, KUL-1248, soterenol, meluadrina, TA-2005, tiaramida, salbutamol, levosalbutamol, tulobuterol, terbutalina, carbuterol, pirbuterol, reproterol, clenbuterol, fenoterol, hexoprenalina, orciprenalina, isoprenalina, formoterol, salmeterol, rimiterol, procaterol, bambuterol, bitolterol y mabuterol. Los agonistas de ß2 adrenoceptor fácilmente disponibles de manera oral, tales como clenbuterol, orciprenalina, salbutamol, terbutalina, tulobuterol, bambuterol y reproterol son preferidos. Se prefieren particularmente los así llamados agonistas de ß2 adrenoceptor de acción larga, tal como salmeterol. Los inhibidores de PDE y los agonistas de ß2 adrenoceptor pueden estar presentes como tales o en forma unida químicamente. Se entiende por la presente que los compuestos activos mencionados también pueden
íá/¡?.Í¿&-J!&Sáb?&i1&-* **""» '.-- .»,.-_---,> '^^ .^A,HÍ ,--_.--,__ A___. ,í í? estar presentes, por ejemplo, en la forma de sus sales farmacológicamente tolerables y/o como solvatos (por ejemplo, hidratos), y/o en la forma de sus N-óxidos, etc. Las sales farmacológicamente tolerables adecuadas aquí, son en particular, sales de adición de ácido solubles en agua e insolubles en agua, con ácidos tales como, por ejemplo, ácido clorhídrico, ácido bromhídrico, ácido fosfórico, ácido nítrico, ácido sulfúrico, ácido acético, ácido cítrico, ácido D-glucónico, ácido benzoico, ácido 2-(4- hidroxibenzoil)-benzoico, ácido butírico, ácido sulfosalicílico, ácido maleico, ácido láurico, ácido málico, ácido fumárico, ácido succínico, ácido oxálico, ácido tartárico, ácido embónico, ácido esteárico, ácido toluenosulfónico, ácido metanosulfónico o ácido 1-hidroxi-2-naftoico, siendo empleados los ácidos en la preparación de sales - dependiendo de si es un ácido mono- o polibásico y dependiendo de la sal deseada - en una proporción cuantitativa equimolar o una que difiera de ella Adicionalmente, los compuestos activos mencionados también pueden estar presentes como enantiómeros puros o como mezclas de enantiómeros en cualquier proporción de mezclado. Los desórdenes del tracto respiratorio, los cuales pueden ser mencionados son, en particular, desórdenes bronquiales inducidos por alérgenos e inflamación (bronquitis, bronquitis obstructiva, bronquitis espástica, bronquitis alérgica, asma alérgica, asma bronquial, COPD), los cuales pueden ser tratados mediante la combinación de acuerdo con la invención, también en el sentido de una terapia de largo plazo (si se desea con ajuste apropiado de la dosis de los componentes individuales para las
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necesidades en el momento, por ejemplo, necesidades sujetas a variaciones relacionadas con las estaciones). Se entenderá "uso combinado" o "combinación" dentro del significado de la presente invención como el significado de que los componentes individuales pueden ser administrados de manera simultánea (en la forma de un medicamento de combinación), más o menos simultáneamente (a partir de unidades de empaque separadas) o en sucesión (directamente en sucesión o de manera alternativa en un intervalo relativamente largo) en una manera que es conocida per se y acostumbrada. Dentro del significado de la presente invención, "uso" es entendido preferiblemente como que significa la administración oral de ambos compuestos activos. Si solo se administra oralmente el inhibidor de PDE, "uso" con respecto al agonista de ß2 adrenoceptor es entendido en particular, como que significa la aplicación tópica en forma inhalada. Para esto, el agonista de ß2 adrenoceptor es administrado, preferiblemente, mediante inhalación en la forma de un aerosol, las partículas de aerosol de composición sólida, líquida o mixta teniendo un diámetro de 0.5 a 10 µm, ventajosamente de 2 a 6 µm. La generación de aerosol puede ser realizada, por ejemplo, mediante atomizadores de chorro impulsados por presión o atomizadores ultrasónicos, pero ventajosamente mediante aerosoles medidos impulsados por propulsor o administración libre de propulsor de compuestos activos micronizados a partir de cápsulas de inhalación. Los compuestos activos son dosificados en un orden de magnitud acostumbrado para la dosis individual, siendo más probable, a causa de
ís*fí..--. -^fc* l.--__?_.i_j-L-_.------. ---•-. jd8jj_..-._-M__, , »_, .-. -.-.~--.-_-_----,iW- - •_-__-_---__-_ __ „_ ______ ._ __¿f íj __~ las acciones individuales, las cuales influencian y refuerzan mutuamente de manera positiva, para reducir las dosis respectivas en la administración combinada de los compuestos activos comparados con la norma. De manera acostumbrada, el agonista de ß2 adrenoceptor (dependiendo de la potencia) es administrado en una dosis de, por ejemplo, 0002 a 2.0 mg por día sobre administración por inhalación. Dependiendo del sistema inhalador usado, además de los compuestos activos, las formas de administración contienen adicionalmente los excipientes requeridos, tales como, por ejemplo, propulsores (por ejemplo, Fpgen en el caso de aerosoles medidos), substancias de superficie activa, emulsificantes, estabilizantes, conservadores, saborizantes, rellenos (por ejemplo, lactosa en el caso de inhaladores de polvo) o, si es apropiado, compuestos activos adicionales.
Para los fines de inhalación, un gran número de aparatos está disponible, con los cuales los aerosoles de tamaño de partícula óptimo pueden generarse y administrarse, usando una técnica de inhalación la cual es tan correcta como sea posible para el paciente. Además del uso de adaptadores (separadores, expansores) y recipientes enfor a de pera (por ejemplo, Nebulator®, Volumatic®) y dispositivos automáticos que emiten una atomización de bocanada (Autohaler®), para aerosoles medidos, en particular en el caso de inhaladores de polvo, una variedad de soluciones técnicas está disponible (por ejemplo, Diskhaler®, Rotadisk®, Turbohaler® o el inhalador descrito en la solicitud de patente europea EP 0 505 321), y usando éstas puede lograrse una óptima administración del compuesto activo.
En el caso de la administración oral de los agonistas de ß2 adrenoceptor junto con el inhibidor de PDE, el cual es la forma de administración preferida, el agonista de ß2 adrenoceptor es administrado en una dosis diaria de, por ejemplo, 0.05 a 60 mg. Para los inhibidores de PDE, es posible en el caso de la administración oral, variar las dosis -dependiendo del compuesto activo - dentro de un amplio rango, siendo posible, como límites, para iniciar a partir de una dosis de 1 - 2000 µg/kg de peso corporal. En el caso de la administración del inhibidor de PDE preferido, roflumilast, la dosis está en el rango desde 2 - 20 µg/kg de peso corporal. Los inhibidores de PDE a ser administrados oralmente son formulados - si es apropiado junto con los agonistas de ß2 adrenoceptor -para dar medicamentos de acuerdo con los procesos conocidos per se y familiares para la persona experta en la técnica. Los compuestos farmacológicamente activos son empleados como medicamentos, de preferencia en combinación con excipientes farmacéuticos o vehículos adecuados, en la forma de tabletas, tabletas recubiertas, cápsulas, emulsiones, suspensiones o soluciones, estando el contenido de compuesto activo ventajosamente entre 0.1 y 95% y, mediante la elección apropiada de los excipientes y vehículos, siendo posible lograr una forma de administración farmacéutica diseñada de manera precisa para el o los compuestos activos y/o el inicio de acción deseado (por ejemplo, una forma de liberación sostenida o una forma entérica). En particular, vale la pena mencionar dentro del significado de la administración oral combinada de ambos compuestos activos de acuerdo con la invención, las formas de
..*-**-*».---i-fe-t-ite-. _-_- t_L_-_ j--fa_-..b---.- administración oral, por ejemplo, tabletas o cápsulas, en las cuales una parte del agonista de ß2 adrenoceptor y el inhibidor de PDE está presente en forma de liberación no sostenida y una parte adicional, de preferencia mayor, del agonista de ß2 adrenoceptor está presente en la forma de liberación sostenida. La persona experta en la técnica es familiar con base en a su conocimiento con cuáles excipientes o vehículos son adecuados para las formulaciones farmacéuticas deseadas. Además de solventes, agentes formadores de gel, excipientes de tabletas y otros portadores de compuestos activos, es posible usar, por ejemplo, antioxidantes, dispersantes, emulsificantes, antiespumantes, correctores de sabor, conservadores, solubilizantes, colorantes o promotores de permeación y agentes formadores de complejos (por ejemplo, ciclodextrinas). Farmacología Modelo Reacción inflamatoria tardía en vías respiratorias en la rata Brown-Norway sensibilizada/retada con ovalbúmina La actividad anti-inflamatoria de roflumilast, pumafentrin (BY-33043) y Salmeterol fue determinada en ratas Brown Norway sensibilizadas con ovalbúmina (OVA) y retadas con OVA. La sensibilización se hizo mediante inyección simultánea de suspensión i.p de Bordetella pertussis y suspensión de OVA/AHG s.c. en el día 1, 14 y 28. 28 días después del inicio de la sensibilización, se retaron ratas Brown-Norway conscientes mediante inhalación de la solución de OVA en aerosol durante 1 h (-20 ml/h). Se usaron animales no retados, solo sensibilizados, como control
ii---a-t-.-U.jtj de línea de base Los medicamentos (profundamente mezclados con lactosa) o el control de placebo (lactosa) fueron administrados de manera intratraqueal (i.t.) como polvos secos 1 h antes del reto con OVA 48 h después, los animales retados con OVA o no retados fueron anestesiados y se les realizó un lavado bronqueoalveolar (BAL) usando 3x4 ml de amortiguador BAL por animal. Se determinaron el número de células totales y eosinófilos en el fluido BAL y la concentración de proteína en el fluido BAL libre de células. Los cambios relativos inducidos por medicamento fueron calculados y analizados estadísticamente por la prueba de Jonckheere Terpstra.
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Resultados
Síntesis Los inhibdores de PDE Roflumilast (inhibidor de PDE4) y Pumafentrin (inhibidor de PDE3>4) administrados a dosis de 0.3 µmol/kg y 3 µmol/kg i.t., respectivamente, no muestran algún efecto significativo
sobre la infiltración celular y acumulación de proteínas. Los valores negativos obtenidos (tendencia: amplificación de la inflamación) caen en el rango de variabilidad biológica del modelo y por lo tanto, no se debe atribuir significancia a estos datos. En contraste, el agonista de receptor ß adrenérgico de larga acción Salmeterol administrado a una dosis de 3 µmol/kg i.t. exhibió efectos inhibidores sobre el influjo de eosinófilos y células totales hacia el espacio alveolar y niveles de proteína en el fluido BAL. Sin embargo, los datos fracasaron en alcanzar significancia. La co-administración del inhibidor de PDE Roflumilast o Pumafentrin con Salmeterol, resultó en efectos sinérqicos comparados con la administración de cada compuesto solo, es decir, ambos inhibidores de PDE combinados con el ß2 agonista mostraron inhibición significativa de eosinófilos y reducción de la concentración de proteína en el fluido BAL. La combinación del inhibidor PDE3/4 Pumafentrin y Salmeterol fue más eficaz en todos los parámetros medidos (la diferencia no fue significativa), y adicionalmente, mostró un efecto significativo sobre la inhibición de influjo de células totales hacia el espacio alveolar.
Claims (12)
1. Un medicamento que comprende un inhibidor de PDE, el cual va a ser administrado oralmente, a partir del grupo de inhibidores PDE4 o PDE3/4 combinado con un agonista ß2 adrenoceptor en combinación fija o libre.
2. El medicamento como se reclama en la reivindicación 1, el cual es una combinación oral fija.
3. El medicamento como se reclama en la reivindicación 1 o 2 para usarse en el tratamiento terapéutico de desórdenes del tracto respiratorio.
4. El medicamento como se reclama en la reivindicación 1 o 2, en donde el inhibidor de PDE es un compuesto seleccionado del grupo que consiste de arofilina, cipamfilina, D-4418, filaminast, ibudilast, lapraf il ina , ORG-20241, piclamilast, rolipram, SB-207499, tibenalst y V-11294A o una sal de los mismos.
5. El medicamento como se reclama en la reivindicación 1 o 2, en donde el inhibidor de PDE es roflumilast, su sal y/o su N-óxido.
6. El medicamento como se reclama en la reivindicación 1 o 2, en donde el inhibidor de PDE es BYK-33043, su sal y/o su N-óxido.
7. El medicamento como se reclama en la reivindicación 1 o 2, en donde el inhibidor de PDE es roflumilast, su sal y/o su N-óxido y el agonista de ß2 adrenoceptor es salmeterol o una sal del mismo.
8. El medicamento como se reclama en la reivindicación 1 o 2, en donde el inhibidor de Pde es BYK-33043, su sal y/o su N-óxido y el agonista de ß2 adrenoceptor es salmeterol o una sal del mismo.
9. El medicamento como se reclama en la reivindicación 1 o 2, en donde el agonista de ß2 adrenoceptor es clenbuterol, orciprenalina, salbutamol, terbutalina, tulobuterol, bambuterol o reproterol o una sal de los mismos.
10. El medicamento como se reclama en la reivindicación 1 o 2, en donde el inhibidor de PDE es arofilina, cipamfilina, D-4418, filaminast, ibudilast, laprafilina, ORG-20241, piclamilast, rolipram, SB-207499, tibenelast o V-11294A o una sal de los mismos, y el agonista de ß2 adrenoceptor es clenbuterol, orciprenalina, salbutamol, terbutalina, tulobuterol, bambuterol o reproterol o una sal de los mismos.
11. El medicamento como se reclama en la reivindicación 1 o 2, en donde el inhibidor de PDE es roflumilast o BYK-33043, sus sales y/o sus N-óxidos y el agonista de ß2 adrenoceptor es clenbuterol, orciprenalina, terbutalina, tulobuterol, bambuterol o reproterol o una sal de los mismos.
12. El uso de un inhibidor de PDE, el cual va a ser administrado oralmente, a partir del grupo de inhibidores de PDE4- o PDE3/4 en el uso combinado con un agonista de ß2 adrenoceptor en el tratamiento terapéutico de desórdenes de tracto respiratorio. -A-fc-4-l- -fa-t,**--- ¿^^.«^jJ^^^^^^J^W^fc^^AgKto^^-^^^^^^**^^!^^*
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2000
- 2000-08-11 SI SI200030862T patent/SI1212089T1/sl unknown
- 2000-08-11 PL PL356252A patent/PL200923B1/pl unknown
- 2000-08-11 PT PT00954625T patent/PT1212089E/pt unknown
- 2000-08-11 DK DK00954625T patent/DK1212089T3/da active
- 2000-08-11 JP JP2001518088A patent/JP5038568B2/ja not_active Expired - Fee Related
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- 2000-08-11 CA CA2715683A patent/CA2715683A1/en not_active Abandoned
- 2000-08-11 TR TR2002/01317T patent/TR200201317T2/xx unknown
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- 2000-08-11 AT AT06110822T patent/ATE447952T1/de not_active IP Right Cessation
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