Title of Invention

SYNERGISTIC COMBINATION OF ROFLUMILAST AND SALMETEROL

Abstract

A medicament comprising a PDE inhibitor, which is to be administered orally, from the PDE4 inhibitors group combined with a β2 adrenoceptor agonist in fixed or free combination, wherein the PDE inhibitor is roflumilast, a pharmacologically tolerable salt of roflumilast and/or the N-oxide of roflumilast and the fc adrenoceptor agonist is salmeterol or a pharmacologically tolerable salt thereof.

Full Text

Field of application of the invention PDE inhibitors which can be used as respiratory tract therapeutics in the sense of thte present invention are those compounds which slow the breakdown Of cyclic AMP (cAMP)^r cyclic GMP (cGMP) by inhibition of the phosphodiesterases, which can lead to a retetivje increase in the Intracellular concentration of cAMP or cGMP. The compounds preferred from the group of the abpvementioned £DE inhibitors iare arofylline, cipamfylline, D-4418, filaminast, ibudilast, lapratyfHne, ORG-2Q241, pidamttest, rolipram, SB-207499, tibenelast and V-11294A. The compounds particularly preferred jare BYK-33043 and in particular roflumilast. p2 adrenoceptor agonists which may particularly be mentioned are.those selectively acting substances which only have a slight cardiac action and therefore are also employee* in therapy, in particular in the oral therapy of respiratory tract disorders. p2 adrenoceptor agonists which may be mentioned are, for example: AR-C68397AA, broxaterol, CHM035, topical application in inhalatory form. For this, the p2 adrenoceptor agonist is preferably administered by inhalation in the form of an aerosol, the aerosol particles of solid, liquid or mixed composition having a diameter of 0.5 to 10 urn, advantageously of 2 to $ um. Aerosol generation can he carried out, for example, by pressure-driven jet atomizers)or ultrasonic atomizers, but advantageously by propellant*driven meterec aerosols for propeilant-free administration of micronized active compound* 1r#ftvWto\n&ot\ capsules. / The active compounds are dosed in an order of magnitude customary for the ^dividual de|e, it more likely Jjelng possible, on account of the Individual actiens, whiei are mutupy positively influencing and reinforcing, to reduce the respective d$$es on the combiijed administration of the active compounds compared with the norm. Custcmarity, thejpV adrenoceptor agonist (depending on potency) is administered in * dose o, for ewnile, 0.002 to 2.0 mg per day on administration by inhalation. i ' Depending on the inhaler system used, in addition to tha active expounds the administration forms additionally contain the required excipiema, such asi for «xkmie, propellents (e.g. Frigen in the case of metered aaro»oj*}» ai)|tose**ctH« suNtandis, emuisifiers, stabilizers, preservatives, flavorings, fillers (e.g. faetoa* in the dase of powfer inhalers) or, if appropriate, further active compounds. ' ■ '■.■■■.".■'".' . ■ ■ i For the purposes of inhalation, a large number of apparatus** are availajle wtth which aerosols of optimum particle size can be generated and adwWsfrfad, usinj an Inhaiatjon technique which is as right as possibie for the patient. In iMWitteh to the tie of adaptors (spacers, expanders) and pear-shaped containers (e.g. fttjiulwtor®, Voljroaticf)), ahd automatic devices emHting a puffer spray (Autohaier*), for «*§****# aeroaois in partetfai in the case of powder fnhalara, a number of technical solutions i*» asaftebte (eg. DtskhaJej®, Rotadisk*. Turbohaier® or the inhaler described in European Patent Application fp 0 505 321), using which an optimal administration of active in the case of the oral administration of the fc adrenoceptor agonists together with the P0E inhibitor, which is the preferred administration form, the p2 adrenoceptor agonist is administered in a daily dose of, for example, 0.05 to 60 mg. For the PDE inhibitors, it is possible in the case of oral administration to vary the doses - depending on the active compound - within a wide range, it being possible, as bounds, to start from a dose of 1 -2000 ug/kg of body weight. In the case of the administration of the preferred PDE inhibitor rofiumHast, the dose is in the range from 2 - 20 ug/kg of body Weight. The PDE inhibitors to be administered orally are formulated - if appropriate together with the fe adrenoceptor agonists - to give medicaments according to processes known per se and Pharmacology Model Late Inflammatory Airway Reaction in the Ovalbumin-servsitfee^kaJJfrnged Brown-Norwey feat Anti-Inflammatory activity of Roflurnilast, Pumafentrine (BYK-33043), and: Seimeterol was determined in ovalbumin (OVA)-8ensfti2ed and OVA-challenged Brown Norway rets. Sensitization was dona j by simultaneous injection of Bordetella pertussis suspension ip. and OVA/AHG suspension s.c. on eai 1; 14 and 21. 28 days after start of sensitization, conscious Brown-Norway rats were chaltengediby inhalation of the aerosolized OVA solution for 1 h (-20 ml/h). Non-ch«Henged. only sensitized animals were used as baseline control. Th6 drugs (thoroughly mixed witfc teetdee) or the placebo conjiol (lactose) Were administered intratracheal^ (i.t.) as dry powders 1 h before OVA-chtHenge. 4fh lajer. OVA-n-chjUehge «p Summary The PDE inhibitors Roflurnilast (PDE4 inhibitor) and Pumafentrine (PDE3>4 inhibitor) administered at doses of Q.3 pmol/kg and 3 umol/kg i.t., respectively, did not show any significant effects on cell infiltration and protein accumulation. The negative values obtained (trend: amplification of inflammation) fall Into the range of biological variably of the model and therefore, no significance must be attached to these data. We Claim: 1. A medicament comprising a PDE inhibitor, which is to be administered orally, from the PDE4 inhibitors group combined with a β2 adrenoceptor agonist in fixed or free combination, wherein the PDE inhibitor is roflumilast, a pharmacologically tolerable salt of roflumilast and/or the N-oxide of roflumilast and the fc adrenoceptor agonist is salmeterol or a pharmacologically tolerable salt thereof. 2. The medicament as claimed in claim 1, which is a fixed oral combination. 3. The medicament according to claim 3, wherein the respiratory tract disorder is bronchitis, obstructive bronchitis, allergic bronchitis, allergic asthma, bronchial asthma orCOPD. Dated this 18th day of January, 2002.

Documents:

in-pct-2002-00066-mum-cancelled pages(12-1-2007).pdf

in-pct-2002-00066-mum-claims(granted)-(12-1-2007).doc

in-pct-2002-00066-mum-claims(granted)-(12-1-2007).pdf

IN-PCT-2002-00066-MUM-CORRESPONDENCE(5-11-2008).pdf

in-pct-2002-00066-mum-correspondence(ipo)-(24-4-2007).pdf

in-pct-2002-00066-mum-correspondence1(20-9-2007).pdf

in-pct-2002-00066-mum-correspondence2(5-11-2008).pdf

in-pct-2002-00066-mum-form 1(12-1-2007).pdf

in-pct-2002-00066-mum-form 13(29-8-2007).pdf

in-pct-2002-00066-mum-form 13(5-11-2008).pdf

in-pct-2002-00066-mum-form 18(28-11-2005).pdf

in-pct-2002-00066-mum-form 2(granted)-(12-1-2007).doc

in-pct-2002-00066-mum-form 2(granted)-(12-1-2007).pdf

in-pct-2002-00066-mum-form 3(12-1-2007).pdf

in-pct-2002-00066-mum-form 3(18-1-2002).pdf

in-pct-2002-00066-mum-form 5(12-1-2007).pdf

in-pct-2002-00066-mum-form 5(18-1-2007).pdf

in-pct-2002-00066-mum-form-pct-isa-210(12-1-2007).pdf

IN-PCT-2002-00066-MUM-GENERAL POWER OF ATTORNEY(5-11-2008).pdf

in-pct-2002-00066-mum-power of attorney(14-8-2002).pdf