US 200601 10449A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0110449 A1 LOrber et al. (43) Pub. Date: May 25, 2006

(54) PHARMACEUTICAL COMPOSITION Publication Classification (76) Inventors: Richard R. Lorber, Scotch Plains, NJ (US); Heribert W. Staudinger, Union, (51) Int. Cl. NJ (US); Robert E. Ward, Summit, NJ A6II 3/473 (2006.01) (US) A6II 3L/24 (2006.01) Correspondence Address: A6IR 9/20 (2006.01) SCHERING-PLOUGH CORPORATION (52) U.S. Cl...... 424/464; 514/290: 514/540 PATENT DEPARTMENT (K-6-1, 1990) 2000 GALLOPNG HILL ROAD KENILWORTH, NJ 07033-0530 (US) (57) ABSTRACT (21) Appl. No.: 11/257,348

(22) Filed: Oct. 24, 2005 The present invention relates to formulations useful for Related U.S. Application Data treating respiratory disorders associated with the production of mucus glycoprotein, skin disorders, and allergic conjunc (60) Provisional application No. 60/622,507, filed on Oct. tivitis while substantially reducing adverse effects associ 27, 2004. Provisional application No. 60/621,783, ated with the administration of non-selective anti-cholin filed on Oct. 25, 2004. ergic agents and methods of use thereof. US 2006/01 10449 A1 May 25, 2006

PHARMACEUTICAL COMPOSITION example, Weinstein and Weinstein (U.S. Pat. No. 6,086,914) describe methods of treating allergic rhinitis using an anti CROSS REFERENCE TO RELATED agent with a limited capacity to pass across APPLICATION membranes, such as the blood-brain barrier, in combination with an antihistamine that is limited in both sedating and 0001. This application claims benefit of priority to U.S. anti-cholinergic properties. Such non-sedating formulations Patent Application 60/622,507, filed Oct. 27, 2004, the however, employ non-selective anti-cholinergic agents (e.g., entirety of which is incorporated by reference as if set forth methScopolamine , glycopyrrolate, and Sul fully herein. fate) that result in adverse effects including stimulation of the cardiovascular system (e.g., tachycardia). FIELD OF THE INVENTION 0007 Unlike previous therapies which employ non-se 0002 The present invention relates to formulations use lective anti-cholinergic agents that result in adverse effects ful for treating respiratory disorders associated with the including stimulation of the cardiovascular system (e.g., production of mucus glycoprotein, skin disorders, and aller tachycardia), there is a need for formulations useful for gic conjunctivitis while Substantially reducing adverse treating respiratory disorders associated with the production effects associated with the administration of non-selective and secretion of mucus glycoprotein while reducing adverse anti-cholinergic agents. In particular, the formulations effects (e.g., stimulation of the cardiovascular system) of include a selective muscarinic receptor Sub previous therapeutics. type M1 and/or M3 antagonist in combination with one or more pharmaceutically active agents. SUMMARY OF THE INVENTION

BACKGROUND OF THE INVENTION 0008. The present invention provides formulations useful for treating respiratory disorders associated with the pro 0003 Cholinergic receptors are divided into two major duction of mucus glycoprotein, skin disorders, and allergic classes: nicotinic acetylcholine receptors and muscarinic conjunctivitis while reducing adverse effects (e.g., stimula acetylcholine receptors based on their responsiveness to tion and/or depression of the central nervous system and/or and , respectively. Unlike nicotinic ace stimulation of the cardiovascular system). In particular, the tylcholine receptors which are ion channels, muscarinic present inventors believe that formulations that include a acetylcholine receptors belong to the Superfamily of G-pro selective muscarinic subtype M1 and/ tein coupled receptors that activate ionic channels through a or M3 antagonist in combination with one or more pharma second messenger cascade. Muscarinic acetylcholine recep ceutically active agents will reduce adverse effects (e.g., tors are further divided into subtypes M1-M5 characterized stimulation and/or depression of the central nervous system by their cellular actions, , and molecular biol and/or stimulation of the cardiovascular system) associated Ogy. with the use of non-selective acetylcholine receptor agents. In addition, the present inventors envisage that the present 0004. Likewise, anti-cholinergic agents are classified as formulations will permit a lower dose of one or more either anti-nicotinic acetylcholine agents or anti-muscarinic pharmaceutically active agents to be administered to achieve acetylcholine agents based on whether nicotinic acetylcho a therapeutic effect than would otherwise be required, line receptors or muscarinic acetylcholine receptors, respec thereby reducing adverse effects associated with the dosage tively, are targeted. Moreover, anti-muscarinic acetylcholine administered. Furthermore, in one embodiment, wherein the agents are further classified based on the Subtype of mus formulation comprises the selective muscarinic acetylcho carinic acetylcholine receptor (M1-M5) that is targeted. line receptor subtype M1 and M3 antagonist in 0005 Of the several subtypes of muscarinic acetylcho combination with the antihistamine desloratadine, the line receptor, subtypes M1 and M3 play important roles in present inventors believe that the combination will be stable the regulation of glandular secretion and vasomotor tone in despite desloratadine's known chemical reactivity and will human nasal mucosa Okayama et al., Am J Respir Cell Mol provide formulations with an improved degradation profile. Biol, 8(2):176-187 (1993); Mullol etal., J Appl Physiol, 73(5):2069-2073 (1992)). In particular, it has been sug 0009. The present invention also provides methods using gested that muscarinic acetylcholine receptor Subtype M3 these formulations for treating respiratory disorders associ has the predominant effect on mucus glycoprotein secretion ated with the production of mucus glycoprotein, skin disor from human nasal mucosa Mullol et al., J Appl Physiol, ders, and allergic conjunctivitis while reducing adverse 73(5):2069-2073 (1992)). In contrast, muscarinic acetylcho effects (e.g., stimulation and/or depression of the central line receptor Subtype M2 appears to have no effect on mucus nervous system and/or stimulation of the cardiovascular glycoprotein secretion Mullol et al., J Appl Physiol, system) of previous therapeutics. 73(5):2069-2073 (1992), but exclusively mediates the 0010. The present invention provides formulations com negative chronotropic effects on heart rate following vagal prising a selective muscarinic acetylcholine receptor Sub stimulation or administration of muscarinic Wess, type M1 and/or M3 antagonist in combination with one or Annu Rev Pharmacol Toxicol, 44:423-450 (2004). more pharmaceutically active agents. 0006 Numerous respiratory disorders are associated with 0011. In a preferred embodiment, the selective muscar the production and secretion of mucus glycoprotein (i.e., inic acetylcholine receptor subtype M1 and/or M3 antago high-molecular weight glycoconjugates released from Sub nist is , , , mucosal glands and epithelial goblet cells in the respiratory oxybutynin, desethyloxybutynin, , AQ-RA 741, tract). Previous therapies focused on using non-sedating , hexahydrosila-difenidol, p-flurohexahydro-sila formulations to treat such respiratory disorders. For difenidol (p-F-HHSiD)), 4-diphenylacetoxy-N-methylpip US 2006/01 10449 A1 May 25, 2006

eridine (4-DAMP) methiodide, or 4-DAMP methobromide, combination of one or more of these agents. More prefer or a pharmaceutically acceptable of any of these agents, ably, the antihistamine is desloratadine or a pharmaceuti or a combination of one or more of these agents. cally acceptable salt thereof. 0012. In one embodiment, the selective muscarinic ace 0015. In still yet another embodiment, one or more phar tylcholine receptor subtype M1 and/or M3 antagonist is a maceutically active agents is a decongestant. Preferably, the decongestant is a histamine H (e.g., selective muscarinic acetylcholine receptor subtype M1 thioperamide, impromidine, burimamide, clobempropit, antagonist. Preferably, the selective muscarinic acetylcho impentamine, mifetidine, S-Sopromidine, R-Sopromidine, line receptor Subtype M1 antagonist is glycopyrronium 3-(imidazol-4-yl)-propylguanidine (SKF-91.486), 3-(4- bromide, telenzepine, or pirenzepine, or a pharmaceutically chlorophenyl)methyl-5-2-(1 H-imidazol-4-yl)ethyl 12,3- acceptable salt of any of these agents, or a combination of oxadiazole (GR-175737), 4-(1-cyclohexylpentanoyl-4-pip one or more of these agents. More preferably, the selective eridyl) 1H-imidazole (GT-2016), 2-(2-4(5)-imidazolyl) muscarinic acetylcholine receptor Subtype M1 antagonist is ethylthio)-5-nitropyridine (UCL-1199), ), pirenzepine or a pharmaceutically acceptable salt thereof. levmetamfetamine, ephedrine, ephedrine hydrochloride, Preferably, the unit dosage form (single or divided dosage ephedrine Sulfate, naphazoline hydrochloride, oxymetazo form as is known to one of skill in the art) of pirenzepine is line hydrochloride, phenylephrine hydrochloride, propyl in the range of about 2.5 mg to about 250 mg. More hexedrine, Xylometazoline hydrochloride, phenylpropanola preferably, the unit dosage form of pirenzepine is in the mine, phenylephrine, or pseudoephedrine, or a range of about 100 mg to about 150 mg. Still more prefer pharmaceutically acceptable salt of any of these agents, or a ably, the unit dosage form of pirenzepine is about 50 mg combination of one or more of these agents. More prefer administered b.i.d or t.i.d. ably, the decongestant is phenylephrine or pseudoephedrine, 0013 In another embodiment, the selective muscarinic or a pharmaceutically acceptable salt of any of these agents. acetylcholine receptor subtype M1 and/or M3 antagonist is 0016. In yet other embodiments, one or more pharma a selective muscarinic acetylcholine receptor subtype M3 ceutically active agents is a corticosteroid; an expectorant; a antagonist. Preferably, the selective muscarinic acetylcho composition to relieve oropharyngeal discomfort; a P2Y line receptor subtype M3 antagonist is himbacine. AQ-RA receptor antagonist; a non-steroidal anti-inflammatory 741, darifenacin, hexahydrosila-difenidol, p-flurohexahy agent; a leukotriene antagonist; a Syk kinase inhibitor, or a dro-sila-difenidol (p-F-HHSiD)), 4-diphenylacetoxy-N-me 5-lipoxygenase inhibitor. thylpiperidine (4-DAMP) methiodide, or 4-DAMP metho bromide, or a pharmaceutically acceptable salt of any of 0017. In one preferred embodiment, the formulation these agents, or a combination of one or more of these comprises a therapeutically effective amount of darifenacin agents. More preferably, the selective muscarinic acetylcho or a pharmaceutically acceptable salt thereof in combination line receptor Subtype M3 antagonist is darifenacin or a with a therapeutically effective amount of desloratadine or a pharmaceutically acceptable salt thereof. pharmaceutically acceptable salt thereof. 0014. In another embodiment, the selective muscarinic 0018. In another preferred embodiment, the formulation acetylcholine receptor subtype M1 and/or M3 antagonist is comprises a therapeutically effective amount of oxybutynin a selective muscarinic acetylcholine receptor subtype M1 or a pharmaceutically acceptable salt thereof in combination and M3 antagonist. Preferably, the selective muscarinic with a therapeutically effective amount of desloratadine or a acetylcholine receptor subtype M1 and M3 antagonist is pharmaceutically acceptable salt thereof. oxybutynin, desethyloxybutynin, or a pharmaceutically 0019. In one embodiment, the pharmaceutically accept acceptable salt of any of these agents, or a combination of able salt of oxybutynin is prepared from a pharmaceutically one or more of these agents. More preferably, the selective acceptable acid addition salt selected from the group con muscarinic acetylcholine receptor subtype M1 and M3 sisting of acetic acid, benzenesulfonic acid, benzoic acid, antagonist is oxybutynin, desethyloxybutynin, or a pharma camphorsulfonic acid, citric acid, ethanesulfonic acid, ceutically acceptable salt of any of these agents. In one fumaric acid, gluconic acid, glutamic acid, hydrobromic embodiment, one or more pharmaceutically active agents is acid, hydrochloric acid, isethionic acid, lactic acid, maleic an antihistamine. Preferably, the antihistamine is , acid, malic acid, mandelic acid, methanesulfonic acid, mucic aZelastine, acrivastine, , cetirizine, chlor acid, nitric acid, pamoic acid, , phosphoric , , , carebastine, cyprohep acid, Succinic acid, Sulfuric acid, tartaric acid, and p-toluene tadine, , desloratadine, , dime Sulfonic acid. In a more preferred embodiment, the pharma thindene, ebastine, epinastine, efletirizine, feXofenadine, ceutically acceptable salt of oxybutynin is oxybutynin chlo hydroxy Zine, ketotifen, loratadine, levocabastine, levoceti ride. rizine, mizolastine, meduitazine, , noberastine, , norastemizole, picumast, pyrilamine, promethaZ 0020. In one embodiment, the therapeutically effective ine, tripelennamine, temelastine, trimeprazine, , amount of oxybutynin or a pharmaceutically acceptable salt thioperamide, impromidine, burimamide, clobenpropit, thereof is a unit dosage form (single or divided dosage form impentamine, mifetidine, S-Sopromidine, R-Sopromidine, as is known to one of skill in the art) in a range from about 3-(imidazol-4-yl)-propylguanidine (SKF-91.486), 3-(4- 0.1 mg to about 1 g administered q.d. Preferably, for chlorophenyl)methyl-5-2-(1 H-imidazol-4-yl)ethyl 12,3- administration orally, the therapeutically effective amount of oxadiazole (GR-175737), 4-(1-cyclohexylpentanoyl-4-pip oxybutynin or a pharmaceutically acceptable salt thereof is eridyl) 1H-imidazole (GT-2016), 2-(2-4(5)-imidazolyl) a unit dosage form in a range from about 1 mg to about 1 g ethylthio)-5-nitropyridine (UCL-1199), or clozapine, or a administered q.d., more preferably, in a range from about 25 pharmaceutically acceptable salt of any of these agents, or a mg to about 700 mg administered q.d. Preferably, for US 2006/01 10449 A1 May 25, 2006

administration by oral or intranasal inhalation, the therapeu oxybutynin, desethyloxybutynin, himbacine, AQ-RA 741, tically effective amount of oxybutynin or a pharmaceutically darifenacin, hexahydrosila-difenidol, p-flurohexahydro-sila acceptable salt thereof is a unit dosage form in a range from difenidol (p-F-HHSiD)), 4-diphenylacetoxy-N-methylpip about 0.1 mg to about 100 mg administered q.d. Yet more eridine (4-DAMP) methiodide, or 4-DAMP methobromide, preferably, the therapeutically effective amount of oxybuty or a pharmaceutically acceptable salt of any of these agents, nin or a pharmaceutically acceptable salt thereof is a unit or a combination of one or more of these agents. dosage form in a range from about 1.25 mg to about 30 mg administered q.d (e.g., about 1.25 mg, about 2.5 mg, about 0025. In one embodiment, the selective muscarinic ace 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg. tylcholine receptor subtype M1 and/or M3 antagonist is a about 30 mg administered q.d.). Still more preferably, the selective muscarinic acetylcholine receptor subtype M1 therapeutically effective amount of oxybutynin or a phar antagonist. Preferably, the selective muscarinic acetylcho maceutically acceptable salt thereof is a unit dosage form line receptor Subtype M1 antagonist is glycopyrronium which is about 1.25 mg, about 2.5 mg, about 3 mg, about 3.5 bromide, telenzepine, or pirenzepine, or a pharmaceutically mg, about 4 mg, about 4.5 mg, or about 5 mg administered acceptable salt of any of these agents, or a combination of b.i.d. t.i.d., or q.i.d. Yet still more preferably, the therapeu one or more of these agents. More preferably, the selective tically effective amount of oxybutynin or a pharmaceutically muscarinic acetylcholine receptor Subtype M1 antagonist is acceptable Salt thereof is a unit dosage form which is about pirenzepine or a pharmaceutically acceptable salt thereof. 2.5 mg or about 5 mg administered b.i.d. Preferably, the unit dosage form (single or divided dosage form as is known to one of skill in the art) of pirenzepine is 0021. In one embodiment, the therapeutically effective in the range of about 2.5 mg to about 250 mg. More amount of desloratadine or a pharmaceutically acceptable preferably, the unit dosage form of pirenzepine is in the salt thereof is a unit dosage form (single or divided dosage range of about 100 mg to about 150 mg. Still more prefer form as is known to one of skill in the art) in a range from ably, the unit dosage form of pirenzepine is about 50 mg about 1.25 mg to about 45 mg administered q.d. (e.g., about administered b.i.d or t.i.d. 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg. about 12 mg, about 14 mg, about 16 mg, about 18 mg, about 0026. In another embodiment, the selective muscarinic 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 acetylcholine receptor subtype M1 and/or M3 antagonist is mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, a selective muscarinic acetylcholine receptor subtype M3 about 38 mg, about 40 mg, about 42 mg, about 44 mg antagonist. Preferably, the selective muscarinic acetylcho administered q.d.). Preferably, the therapeutically effective line receptor subtype M3 antagonist is himbacine, AQ-RA amount of desloratadine or a pharmaceutically acceptable 741, darifenacin, hexahydrosila-difenidol, p-flurohexahy salt thereof is a unit dosage form in a range from about 1.25 dro-sila-difenidol (p-F-HHSiD)), 4-diphenylacetoxy-N-me mg to about 20 mg administered q.d. More preferably, the thylpiperidine (4-DAMP) methiodide, or 4-DAMP metho therapeutically effective amount of desloratadine or a phar bromide, or a pharmaceutically acceptable salt of any of maceutically acceptable salt thereof is a unit dosage form in these agents, or a combination of one or more of these a range from about 5 mg to about 10 mg administered q.d. agents. More preferably, the selective muscarinic acetylcho In one embodiment, the therapeutically effective amount of line receptor Subtype M3 antagonist is darifenacin or a desloratadine or a pharmaceutically acceptable salt thereof is pharmaceutically acceptable salt thereof. a unit dosage form which is about 1.25 mg, about 2.5 mg. 0027. In another embodiment, the selective muscarinic about 5.0 mg, about 7.5 mg, about 10.0 mg, about 12.5 mg. acetylcholine receptor subtype M1 and/or M3 antagonist is about 15 mg, 17.5 mg. or about 20.0 mg administered q.d. a selective muscarinic acetylcholine receptor subtype M1 0022. In one embodiment, the formulation comprising a and M3 antagonist. Preferably, the selective muscarinic therapeutically effective amount of darifenacin or oxybuty acetylcholine receptor subtype M1 and M3 antagonist is nin, or a pharmaceutically acceptable salt thereof in com oxybutynin, desethyloxybutynin, or a pharmaceutically bination with a therapeutically effective amount of deslora acceptable salt of any of these agents, or a combination of tadine or a pharmaceutically acceptable salt thereof further one or more of these agents. More preferably, the selective comprises one or more additional pharmaceutically active muscarinic acetylcholine receptor subtype M1 and M3 agents. Preferably, one or more additional pharmaceutically antagonist is oxybutynin, desethyloxybutynin, or a pharma active agents is another antihistamine; a decongestant; a ceutically acceptable salt of any of these agents. corticosteroid; an expectorant; a composition to relieve 0028. In yet another embodiment, one or more pharma oropharyngeal discomfort; a P2Y receptor antagonist; a ceutically active agents is an antihistamine. Preferably, the non-steroidal anti-inflammatory agent; a leukotriene antago antihistamine is azatadine, azelastine, acrivastine, bromphe nist; a Syk kinase inhibitor, or a 5-lipoxygenase inhibitor. niramine, cetirizine, chlorpheniramine, clemastine, cycliz 0023 The present invention also provides, methods for ine, carebastine, , carbinoxamine, deslorata treating a respiratory disorder associated with the production dine, doxylamine, dimethindene, ebastine, epinastine, of mucus glycoprotein in a patient Suffering therefrom efletirizine, fexofenadine, hydroxyzine, ketotifen, lorata comprising administering a therapeutically effective amount dine, levocabastine, levocetirizine, mizolastine, meduita of a selective muscarinic acetylcholine receptor subtype M1 Zine, mianserin, noberastine, meclizine, norastemizole, and/or M3 antagonist in combination with one or more picumast, pyrilamine, , tripelennamine, pharmaceutically active agents. temelastine, trimeprazine, triprolidine, thioperamide, impro midine, burimamide, clobenpropit, impentamine, mifeti 0024. In a preferred embodiment, the selective muscar dine, S-Sopromidine, R-Sopromidine, 3-(imidazol-4-yl)-pro inic acetylcholine receptor subtype M1 and/or M3 antago pylguanidine (SKF-91.486), 3-(4-chlorophenyl)methyl-5- nist is glycopyrronium bromide, telenzepine, pirenzepine, 2-(1H-imidazol-4-yl)ethyl) 1,2,3-oxadiazole (GR-175737), US 2006/01 10449 A1 May 25, 2006

4-(1-cyclohexylpentanoyl-4-piperidyl) 1H-imidazole (GT as is known to one of skill in the art) in a range from about 2016), 2-(2-4(5)-imidazolyl)ethylthio)-5-nitropyridine 0.1 mg to about 1 g administered q.d. Preferably, for (UCL-1199), or clozapine, or a pharmaceutically acceptable administration orally, the therapeutically effective amount of salt of any of these agents, or a combination of one or more oxybutynin or a pharmaceutically acceptable salt thereof is of these agents. More preferably, the antihistamine is deslo a unit dosage form in a range from about 1 mg to about 1 g ratadine or a pharmaceutically acceptable salt thereof. administered q.d., more preferably, in a range from about 25 mg to about 700 mg administered q.d. Preferably, for 0029. In still yet another embodiment, one or more phar administration by oral or intranasal inhalation, the therapeu maceutically active agents is a decongestant. Preferably, the tically effective amount of oxybutynin or a pharmaceutically decongestant is a histamine H receptor antagonist (e.g., acceptable salt thereof is a unit dosage form in a range from thioperamide, impromidine, burimamide, clobenpropit, about 0.1 mg to about 100 mg administered q.d. Yet more impentamine, mifetidine, S-Sopromidine, R-Sopromidine, preferably, the therapeutically effective amount of oxybuty 3-(imidazol-4-yl)-propylguanidine (SKF-91.486), 3-(4- nin or a pharmaceutically acceptable salt thereof is a unit chlorophenyl)methyl-5-2-(1H-imidazol-4-yl)ethyl 12,3- dosage form in a range from about 1.25 mg to about 30 mg oxadiazole (GR-175737), 4-(1-cyclohexylpentanoyl-4-pip administered q.d (e.g., about 1.25 mg, about 2.5 mg, about eridyl) 1H-imidazole (GT-2016), 2-(2-4(5)-imidazolyl) 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg. ethylthio)-5-nitropyridine (UCL-1199), clozapine), about 30 mg administered q.d.). Still more preferably, the levmetamfetamine, ephedrine, ephedrine hydrochloride, therapeutically effective amount of oxybutynin or a phar ephedrine Sulfate, naphazoline hydrochloride, oxymetazo maceutically acceptable salt thereof is a unit dosage form line hydrochloride, phenylephrine hydrochloride, propyl which is about 1.25 mg, about 2.5 mg, about 3 mg, about 3.5 hexedrine, Xylometazoline hydrochloride, phenylpropanola mg, about 4 mg, about 4.5 mg, or about 5 mg administered mine, phenylephrine, or pseudoephedrine, or a b.i.d. t.i.d., or q.i.d. Yet still more preferably, the therapeu pharmaceutically acceptable salt of any of these agents, or a tically effective amount of oxybutynin or a pharmaceutically combination of one or more of these agents. More prefer ably, the decongestant is phenylephrine or pseudoephedrine, acceptable salt thereof is a unit dosage form which is about or a pharmaceutically acceptable salt of any of these agents. 2.5 mg or about 5 mg administered b.i.d. 0035) In one embodiment, the therapeutically effective 0030. In yet other embodiments, one or more pharma amount of desloratadine or a pharmaceutically acceptable ceutically active agents is a corticosteroid; an expectorant; a salt thereof is a unit dosage form (single or divided dosage composition to relieve oropharyngeal discomfort; a P2Y form as is known to one of skill in the art) in a range from receptor antagonist; a non-steroidal anti-inflammatory about 1.25 mg to about 45 mg administered q.d. (e.g., about agent; a leukotriene antagonist; a Syk kinase inhibitor, or a 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg. 5-lipoxygenase inhibitor. about 12 mg, about 14 mg, about 16 mg, about 18 mg, about 0031. In one preferred embodiment, the method for treat 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 ing a respiratory disorder associated with the production of mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, mucus glycoprotein in a patient Suffering therefrom com about 38 mg, about 40 mg, about 42 mg, about 44 mg prises administering a therapeutically effective amount of administered q.d.). Preferably, the therapeutically effective darifenacin or a pharmaceutically acceptable salt thereof in amount of desloratadine or a pharmaceutically acceptable combination with a therapeutically effective amount of salt thereof is a unit dosage form in a range from about 1.25 desloratadine or a pharmaceutically acceptable salt thereof. mg to about 20 mg administered q.d. More preferably, the therapeutically effective amount of desloratadine or a phar 0032. In another preferred embodiment, the method for maceutically acceptable salt thereof is a unit dosage form in treating a respiratory disorder associated with the production a range from about 5 mg to about 10 mg administered q.d. of mucus glycoprotein in a patient Suffering therefrom In one embodiment, the therapeutically effective amount of comprises administering a therapeutically effective amount desloratadine or a pharmaceutically acceptable salt thereof is of oxybutynin or a pharmaceutically acceptable salt thereof a unit dosage form which is about 1.25 mg, about 2.5 mg. in combination with a therapeutically effective amount of about 5.0 mg, about 7.5 mg, about 10.0 mg, about 12.5 mg. desloratadine or a pharmaceutically acceptable salt thereof. about 15 mg, 17.5 mg. or about 20.0 mg administered q.d. 0033. In one embodiment, the pharmaceutically accept 0036). In one embodiment, the method comprising admin able salt of oxybutynin is prepared from a pharmaceutically istering a therapeutically effective amount of darifenacin or acceptable acid addition salt selected from the group con oxybutynin, or a pharmaceutically acceptable salt thereof in sisting of acetic acid, benzenesulfonic acid, benzoic acid, combination with a therapeutically effective amount of camphorsulfonic acid, citric acid, ethanesulfonic acid, desloratadine or a pharmaceutically acceptable salt thereof fumaric acid, gluconic acid, glutamic acid, hydrobromic further comprises administering one or more additional acid, hydrochloric acid, isethionic acid, lactic acid, maleic pharmaceutically active agents. Preferably, one or more acid, malic acid, mandelic acid, methanesulfonic acid, mucic additional pharmaceutically active agents is another antihis acid, nitric acid, pamoic acid, pantothenic acid, phosphoric tamine; a decongestant; a corticosteroid; an expectorant; a acid, Succinic acid, Sulfuric acid, tartaric acid, and p-toluene composition to relieve oropharyngeal discomfort; a P2Y Sulfonic acid. In a more preferred embodiment, the pharma receptor antagonist; a non-steroidal anti-inflammatory ceutically acceptable salt of oxybutynin is oxybutynin chlo agent; a leukotriene antagonist; a Syk kinase inhibitor, or a ride. 5-lipoxygenase inhibitor. 0034. In one embodiment, the therapeutically effective 0037. In addition, the present invention provides methods amount of oxybutynin or a pharmaceutically acceptable salt for treating a skin disorder in a patient Suffering therefrom thereof is a unit dosage form (single or divided dosage form comprising administering a therapeutically effective amount US 2006/01 10449 A1 May 25, 2006 of a selective muscarinic acetylcholine receptor subtype M1 picumast, pyrilamine, promethazine, tripelennamine, and/or M3 antagonist in combination with one or more temelastine, trimeprazine, triprolidine, thioperamide, impro pharmaceutically active agents. midine, burimamide, clobenpropit, impentamine, mifeti 0038. In a preferred embodiment, the selective muscar dine, S-Sopromidine, R-Sopromidine, 3-(imidazol-4-yl)-pro inic acetylcholine receptor subtype M1 and/or M3 antago pylguanidine (SKF-91.486), 3-(4-chlorophenyl)methyl-5- nist is glycopyrronium bromide, telenzepine, pirenzepine, 2-(1H-imidazol-4-yl)ethyl) 1,2,3-oxadiazole (GR-175737), oxybutynin, desethyloxybutynin, himbacine, AQ-RA 741, 4-(1-cyclohexylpentanoyl-4-piperidyl) 1H-imidazole (GT darifenacin, hexahydrosila-difenidol, p-flurohexahydro-sila 2016), 2-(2-4(5)-imidazolyl)ethylthio)-5-nitropyridine difenidol (p-F-HHSiD)), 4-diphenylacetoxy-N-methylpip (UCL-1199), or clozapine, or a pharmaceutically acceptable eridine (4-DAMP) methiodide, or 4-DAMP methobromide, salt of any of these agents, or a combination of one or more or a pharmaceutically acceptable salt of any of these agents, of these agents. More preferably, the antihistamine is deslo or a combination of one or more of these agents. ratadine or a pharmaceutically acceptable salt thereof. 0043. In still yet another embodiment, one or more phar 0039. In one embodiment, the selective muscarinic ace maceutically active agents is a decongestant. Preferably, the tylcholine receptor subtype M1 and/or M3 antagonist is a decongestant is a histamine H receptor antagonist (e.g., selective muscarinic acetylcholine receptor subtype M1 thioperamide, impromidine, burimamide, clobempropit, antagonist. Preferably, the selective muscarinic acetylcho impentamine, mifetidine, S-Sopromidine, R-Sopromidine, line receptor Subtype M1 antagonist is glycopyrronium 3-(imidazol-4-yl)-propylguanidine (SKF-91.486), 3-(4- bromide, telenzepine, or pirenzepine, or a pharmaceutically chlorophenyl)methyl-5-2-(1H-imidazol-4-yl)ethyl 12,3- acceptable salt of any of these agents, or a combination of oxadiazole (GR-175737), 4-(1-cyclohexylpentanoyl-4-pip one or more of these agents. More preferably, the selective eridyl) 1H-imidazole (GT-2016), 2-(2-4(5)-imidazolyl) muscarinic acetylcholine receptor Subtype M1 antagonist is ethylthio)-5-nitropyridine (UCL-1199), clozapine), pirenzepine or a pharmaceutically acceptable salt thereof. levmetamfetamine, ephedrine, ephedrine hydrochloride, Preferably, the unit dosage form (single or divided dosage ephedrine Sulfate, naphazoline hydrochloride, oxymetazo form as is known to one of skill in the art) of pirenzepine is line hydrochloride, phenylephrine hydrochloride, propyl in the range of about 2.5 mg to about 250 mg. More hexedrine, Xylometazoline hydrochloride, phenylpropanola preferably, the unit dosage form of pirenzepine is in the mine, phenylephrine, or pseudoephedrine, or a range of about 100 mg to about 150 mg. Still more prefer pharmaceutically acceptable salt of any of these agents, or a ably, the unit dosage form of pirenzepine is about 50 mg combination of one or more of these agents. More prefer administered b.i.d or t.i.d. ably, the decongestant is phenylephrine or pseudoephedrine, 0040. In another embodiment, the selective muscarinic or a pharmaceutically acceptable salt of any of these agents. acetylcholine receptor subtype M1 and/or M3 antagonist is a selective muscarinic acetylcholine receptor subtype M3 0044) In yet other embodiments, one or more pharma antagonist. Preferably, the selective muscarinic acetylcho ceutically active agents is a corticosteroid; an expectorant; a line receptor subtype M3 antagonist is himbacine. AQ-RA composition to relieve oropharyngeal discomfort; a P2Y 741, darifenacin, hexahydrosila-difenidol, p-flurohexahy receptor antagonist; a non-steroidal anti-inflammatory dro-sila-difenidol (p-F-HHSiD)), 4-diphenylacetoxy-N-me agent; a leukotriene antagonist; a Syk kinase inhibitor, or a thylpiperidine (4-DAMP) methiodide, or 4-DAMP metho 5-lipoxygenase inhibitor. bromide, or a pharmaceutically acceptable salt of any of 0045. In one preferred embodiment, the method for treat these agents, or a combination of one or more of these ing a skin disorder in a patient Suffering therefrom comprises agents. More preferably, the selective muscarinic acetylcho administering a therapeutically effective amount of darifena line receptor Subtype M3 antagonist is darifenacin or a cin or a pharmaceutically acceptable salt thereof in combi pharmaceutically acceptable salt thereof. nation with a therapeutically effective amount of deslorata dine or a pharmaceutically acceptable salt thereof. 0041. In another embodiment, the selective muscarinic acetylcholine receptor subtype M1 and/or M3 antagonist is 0046. In another preferred embodiment, the method for a selective muscarinic acetylcholine receptor subtype M1 treating a skin disorder in a patient Suffering therefrom and M3 antagonist. Preferably, the selective muscarinic comprises administering a therapeutically effective amount acetylcholine receptor subtype M1 and M3 antagonist is of oxybutynin or a pharmaceutically acceptable salt thereof oxybutynin, desethyloxybutynin, or a pharmaceutically in combination with a therapeutically effective amount of acceptable salt of any of these agents, or a combination of desloratadine or a pharmaceutically acceptable salt thereof. one or more of these agents. More preferably, the selective muscarinic acetylcholine receptor subtype M1 and M3 0047. In one embodiment, the pharmaceutically accept antagonist is oxybutynin, desethyloxybutynin, or a pharma able salt of oxybutynin is prepared from a pharmaceutically ceutically acceptable salt of any of these agents. acceptable acid addition salt selected from the group con sisting of acetic acid, benzenesulfonic acid, benzoic acid, 0042. In yet another embodiment, one or more pharma camphorsulfonic acid, citric acid, ethanesulfonic acid, ceutically active agents is an antihistamine. Preferably, the fumaric acid, gluconic acid, glutamic acid, hydrobromic antihistamine is azatadine, azelastine, acrivastine, bromphe acid, hydrochloric acid, isethionic acid, lactic acid, maleic niramine, cetirizine, chlorpheniramine, clemastine, cycliz acid, malic acid, mandelic acid, methanesulfonic acid, mucic ine, carebastine, cyproheptadine, carbinoxamine, deslorata acid, nitric acid, pamoic acid, pantothenic acid, phosphoric dine, doxylamine, dimethindene, ebastine, epinastine, acid, Succinic acid, Sulfuric acid, tartaric acid, and p-toluene efletirizine, fexofenadine, hydroxyzine, ketotifen, lorata Sulfonic acid. In a more preferred embodiment, the pharma dine, levocabastine, levocetirizine, mizolastine, meduita ceutically acceptable salt of oxybutynin is oxybutynin chlo Zine, mianserin, noberastine, meclizine, norastemizole, ride. US 2006/01 10449 A1 May 25, 2006

0.048. In one embodiment, the therapeutically effective 0051. In addition, the present invention provides methods amount of oxybutynin or a pharmaceutically acceptable salt for treating allergic conjunctivitis in a patient Suffering thereof is a unit dosage form (single or divided dosage form therefrom comprising administering a therapeutically effec as is known to one of skill in the art) in a range from about tive amount of a selective muscarinic acetylcholine receptor 0.1 mg to about 1 g administered q.d. Preferably, for subtype M1 and/or M3 antagonist in combination with one administration orally, the therapeutically effective amount of or more pharmaceutically active agents. oxybutynin or a pharmaceutically acceptable salt thereof is 0052. In a preferred embodiment, the selective muscar a unit dosage form in a range from about 1 mg to about 1 g inic acetylcholine receptor subtype M1 and/or M3 antago administered q.d., more preferably, in a range from about 25 nist is glycopyrronium bromide, telenzepine, pirenzepine, mg to about 700 mg administered q.d. Preferably, for oxybutynin, desethyloxybutynin, himbacine, AQ-RA 741, administration by oral or intranasal inhalation, the therapeu darifenacin, hexahydrosila-difenidol, p-flurohexahydro-sila tically effective amount of oxybutynin or a pharmaceutically difenidol (p-F-HHSiD)), 4-diphenylacetoxy-N-methylpip acceptable salt thereof is a unit dosage form in a range from eridine (4-DAMP) methiodide, or 4-DAMP methobromide, about 0.1 mg to about 100 mg administered q.d. Yet more or a pharmaceutically acceptable salt of any of these agents, preferably, the therapeutically effective amount of oxybuty or a combination of one or more of these agents. nin or a pharmaceutically acceptable salt thereof is a unit dosage form in a range from about 1.25 mg to about 30 mg 0053. In one embodiment, the selective muscarinic ace administered q.d (e.g., about 1.25 mg, about 2.5 mg, about tylcholine receptor subtype M1 and/or M3 antagonist is a 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg. selective muscarinic acetylcholine receptor subtype M1 about 30 mg administered q.d.). Still more preferably, the antagonist. Preferably, the selective muscarinic acetylcho therapeutically effective amount of oxybutynin or a phar line receptor Subtype M1 antagonist is glycopyrronium maceutically acceptable salt thereof is a unit dosage form bromide, telenzepine, or pirenzepine, or a pharmaceutically which is about 1.25 mg, about 2.5 mg, about 3 mg, about 3.5 acceptable salt of any of these agents, or a combination of mg, about 4 mg, about 4.5 mg, or about 5 mg administered one or more of these agents. More preferably, the selective b.i.d. t.i.d., or q.i.d. Yet still more preferably, the therapeu muscarinic acetylcholine receptor Subtype M1 antagonist is tically effective amount of oxybutynin or a pharmaceutically pirenzepine or a pharmaceutically acceptable salt thereof. acceptable Salt thereof is a unit dosage form which is about Preferably, the unit dosage form (single or divided dosage 2.5 mg or about 5 mg administered b.i.d. form as is known to one of skill in the art) of pirenzepine is in the range of about 2.5 mg to about 250 mg. More 0049. In one embodiment, the therapeutically effective preferably, the unit dosage form of pirenzepine is in the amount of desloratadine or a pharmaceutically acceptable range of about 100 mg to about 150 mg. Still more prefer salt thereof is a unit dosage form (single or divided dosage ably, the unit dosage form of pirenzepine is about 50 mg form as is known to one of skill in the art) in a range from administered b.i.d or t.i.d. about 1.25 mg to about 45 mg administered q.d. (e.g., about 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg. 0054. In another embodiment, the selective muscarinic about 12 mg, about 14 mg, about 16 mg, about 18 mg, about acetylcholine receptor subtype M1 and/or M3 antagonist is 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 a selective muscarinic acetylcholine receptor subtype M3 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, antagonist. Preferably, the selective muscarinic acetylcho about 38 mg, about 40 mg, about 42 mg, about 44 mg line receptor subtype M3 antagonist is himbacine. AQ-RA administered q.d.). Preferably, the therapeutically effective 741, darifenacin, hexahydrosila-difenidol, p-flurohexahy amount of desloratadine or a pharmaceutically acceptable dro-sila-difenidol (p-F-HHSiD)), 4-diphenylacetoxy-N-me salt thereof is a unit dosage form in a range from about 1.25 thylpiperidine (4-DAMP) methiodide, or 4-DAMP metho mg to about 20 mg administered q.d. More preferably, the bromide, or a pharmaceutically acceptable salt of any of therapeutically effective amount of desloratadine or a phar these agents, or a combination of one or more of these maceutically acceptable salt thereof is a unit dosage form in agents. More preferably, the selective muscarinic acetylcho a range from about 5 mg to about 10 mg administered q.d. line receptor Subtype M3 antagonist is darifenacin or a In one embodiment, the therapeutically effective amount of pharmaceutically acceptable salt thereof. desloratadine or a pharmaceutically acceptable salt thereof is 0055. In another embodiment, the selective muscarinic a unit dosage form which is about 1.25 mg, about 2.5 mg. acetylcholine receptor subtype M1 and/or M3 antagonist is about 5.0 mg, about 7.5 mg, about 10.0 mg, about 12.5 mg. a selective muscarinic acetylcholine receptor subtype M1 about 15 mg, 17.5 mg. or about 20.0 mg administered q.d. and M3 antagonist. Preferably, the selective muscarinic acetylcholine receptor subtype M1 and M3 antagonist is 0050. In one embodiment, the method comprising admin oxybutynin, desethyloxybutynin, or a pharmaceutically istering a therapeutically effective amount of darifenacin or acceptable salt of any of these agents, or a combination of oxybutynin, or a pharmaceutically acceptable salt thereof in one or more of these agents. More preferably, the selective combination with a therapeutically effective amount of muscarinic acetylcholine receptor subtype M1 and M3 desloratadine or a pharmaceutically acceptable salt thereof antagonist is oxybutynin, desethyloxybutynin, or a pharma further comprises administering one or more additional pharmaceutically active agents. Preferably, one or more ceutically acceptable salt of any of these agents. additional pharmaceutically active agents is another antihis 0056. In yet another embodiment, one or more pharma tamine; a decongestant; a corticosteroid; an expectorant; a ceutically active agents is an antihistamine. Preferably, the composition to relieve oropharyngeal discomfort; a P2Y antihistamine is azatadine, azelastine, acrivastine, bromphe receptor antagonist; a non-steroidal anti-inflammatory niramine, cetirizine, chlorpheniramine, clemastine, cycliz agent; a leukotriene antagonist; a Syk kinase inhibitor, or a ine, carebastine, cyproheptadine, carbinoxamine, deslorata 5-lipoxygenase inhibitor. dine, doxylamine, dimethindene, ebastine, epinastine, US 2006/01 10449 A1 May 25, 2006

efletirizine, fexofenadine, hydroxyzine, ketotifen, lorata acid, Succinic acid, Sulfuric acid, tartaric acid, and p-toluene dine, levocabastine, levocetirizine, mizolastine, meduita Sulfonic acid. In a more preferred embodiment, the pharma Zine, mianserin, noberastine, meclizine, norastemizole, ceutically acceptable salt of oxybutynin is oxybutynin chlo picumast, pyrilamine, promethazine, tripelennamine, ride. temelastine, trimeprazine, triprolidine, thioperamide, impro 0062. In one embodiment, the therapeutically effective midine, burimamide, clobenpropit, impentamine, mifeti amount of oxybutynin or a pharmaceutically acceptable salt dine, S-Sopromidine, R-Sopromidine, 3-(imidazol-4-yl)-pro thereof is a unit dosage form (single or divided dosage form pylguanidine (SKF-91.486), 3-(4-chlorophenyl)methyl-5- as is known to one of skill in the art) in a range from about 2-(1H-imidazol-4-yl)ethyl) 1,2,3-oxadiazole (GR-175737), 0.1 mg to about 1 g administered q.d. Preferably, for 4-(1-cyclohexylpentanoyl-4-piperidyl) 1H-imidazole (GT administration orally, the therapeutically effective amount of 2016), 2-(2-4(5)-imidazolyl)ethylthio)-5-nitropyridine oxybutynin or a pharmaceutically acceptable salt thereof is (UCL-1199), or clozapine, or a pharmaceutically acceptable a unit dosage form in a range from about 1 mg to about 1 g salt of any of these agents, or a combination of one or more administered q.d., more preferably, in a range from about 25 of these agents. More preferably, the antihistamine is deslo mg to about 700 mg administered q.d. Preferably, for ratadine or a pharmaceutically acceptable salt thereof. administration by oral or intranasal inhalation, the therapeu 0057. In still yet another embodiment, one or more phar tically effective amount of oxybutynin or a pharmaceutically maceutically active agents is a decongestant. Preferably, the acceptable salt thereof is a unit dosage form in a range from decongestant is a histamine H receptor antagonist (e.g., about 0.1 mg to about 100 mg administered q.d. Yet more thioperamide, impromidine, burimamide, clobenpropit, preferably, the therapeutically effective amount of oxybuty impentamine, mifetidine, S-Sopromidine, R-Sopromidine, nin or a pharmaceutically acceptable salt thereof is a unit 3-(imidazol-4-yl)-propylguanidine (SKF-91.486), 3-(4- dosage form in a range from about 1.25 mg to about 30 mg chlorophenyl)methyl-5-2-(1H-imidazol-4-yl)ethyl 12,3- administered q.d (e.g., about 1.25 mg, about 2.5 mg, about oxadiazole (GR-175737), 4-(1-cyclohexylpentanoyl-4-pip 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg. eridyl) 1H-imidazole (GT-2016), 2-(2-4(5)-imidazolyl) about 30 mg administered q.d.). Still more preferably, the ethylthio)-5-nitropyridine (UCL-1199), clozapine), therapeutically effective amount of oxybutynin or a phar levmetamfetamine, ephedrine, ephedrine hydrochloride, maceutically acceptable salt thereof is a unit dosage form ephedrine Sulfate, naphazoline hydrochloride, oxymetazo which is about 1.25 mg, about 2.5 mg, about 3 mg, about 3.5 line hydrochloride, phenylephrine hydrochloride, propyl mg, about 4 mg, about 4.5 mg, or about 5 mg administered hexedrine, Xylometazoline hydrochloride, phenylpropanola b.i.d. t.i.d., or q.i.d. Yet still more preferably, the therapeu mine, phenylephrine, or pseudoephedrine, or a tically effective amount of oxybutynin or a pharmaceutically pharmaceutically acceptable salt of any of these agents, or a acceptable salt thereof is a unit dosage form which is about combination of one or more of these agents. More prefer 2.5 mg or about 5 mg administered b.i.d. ably, the decongestant is phenylephrine or pseudoephedrine, 0063. In one embodiment, the therapeutically effective or a pharmaceutically acceptable salt of any of these agents. amount of desloratadine or a pharmaceutically acceptable 0.058. In yet other embodiments, one or more pharma salt thereof is a unit dosage form (single or divided dosage ceutically active agents is a corticosteroid; an expectorant; a form as is known to one of skill in the art) in a range from composition to relieve oropharyngeal discomfort; a P2Y about 1.25 mg to about 45 mg administered q.d. (e.g., about receptor antagonist; a non-steroidal anti-inflammatory 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg. agent; a leukotriene antagonist; a Syk kinase inhibitor, or a about 12 mg, about 14 mg, about 16 mg, about 18 mg, about 5-lipoxygenase inhibitor. 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, 0059. In one preferred embodiment, the method for treat about 38 mg, about 40 mg, about 42 mg, about 44 mg ing allergic conjunctivitis in a patient Suffering therefrom administered q.d.). Preferably, the therapeutically effective comprises administering a therapeutically effective amount amount of desloratadine or a pharmaceutically acceptable of darifenacin or a pharmaceutically acceptable salt thereof salt thereof is a unit dosage form in a range from about 1.25 in combination with a therapeutically effective amount of mg to about 20 mg administered q.d. More preferably, the desloratadine or a pharmaceutically acceptable salt thereof. therapeutically effective amount of desloratadine or a phar 0060. In another preferred embodiment, the method for maceutically acceptable salt thereof is a unit dosage form in treating allergic conjunctivitis in a patient Suffering there a range from about 5 mg to about 10 mg administered q.d. from comprises administering a therapeutically effective In one embodiment, the therapeutically effective amount of amount of oxybutynin or a pharmaceutically acceptable salt desloratadine or a pharmaceutically acceptable salt thereof is thereof in combination with a therapeutically effective a unit dosage form which is about 1.25 mg, about 2.5 mg. amount of desloratadine or a pharmaceutically acceptable about 5.0 mg, about 7.5 mg, about 10.0 mg, about 12.5 mg. salt thereof. about 15 mg, 17.5 mg. or about 20.0 mg administered q.d. 0061. In one embodiment, the pharmaceutically accept 0064. In one embodiment, the method comprising admin able salt of oxybutynin is prepared from a pharmaceutically istering a therapeutically effective amount of darifenacin or acceptable acid addition salt selected from the group con oxybutynin, or a pharmaceutically acceptable salt thereof in sisting of acetic acid, benzenesulfonic acid, benzoic acid, combination with a therapeutically effective amount of camphorsulfonic acid, citric acid, ethanesulfonic acid, desloratadine or a pharmaceutically acceptable salt thereof fumaric acid, gluconic acid, glutamic acid, hydrobromic further comprises administering one or more additional acid, hydrochloric acid, isethionic acid, lactic acid, maleic pharmaceutically active agents. Preferably, one or more acid, malic acid, mandelic acid, methanesulfonic acid, mucic additional pharmaceutically active agents is another antihis acid, nitric acid, pamoic acid, pantothenic acid, phosphoric tamine; a decongestant; a corticosteroid; an expectorant; a US 2006/01 10449 A1 May 25, 2006 composition to relieve oropharyngeal discomfort; a P2Y potency than muscarinic acetylcholine receptor Subtype M2. receptor antagonist; a non-steroidal anti-inflammatory In yet another embodiment, the agent inhibits cell signaling agent; a leukotriene antagonist; a Syk kinase inhibitor, or a from muscarinic acetylcholine receptor subtype M1 and/or 5-lipoxygenase inhibitor. M3 with about 10-fold greater potency than muscarinic 0065. In a particular embodiment, the compositions of acetylcholine receptor subtype M2. the present invention are useful for the treatment or allevia 0071. As used herein, the phrase “therapeutically effec tion of symptoms of anterior rhinitis. tive amount” with respect to a selective muscarinic acetyl receptor subtype M1 and/or M3 antagonist means a DETAILED DESCRIPTION OF THE therapeutic benefit in the treatment or management of the INVENTION referenced disorder (e.g., a respiratory disorder associated with the production of mucus glycoprotein, a skin disorder, 0.066 As used herein, the following terms shall have the or allergic conjunctivitis). definitions set forth below. 0072. As used herein, the phrase “therapeutically effec 0067. As used herein, the phrase “respiratory disorder tive amount” with respect to one or more pharmaceutically associated with the production of mucus glycoprotein’ active agents means a therapeutic benefit in the treatment or includes respiratory disorders that would be improved by management of the referenced disorder (e.g., a respiratory inhibition of nasal Secretion and the pathway triggering disorder associated with the production of mucus glycopro nasal Secretion. For example, allergic rhinitis, non-allergic tein, a skin disorder, or allergic conjunctivitis). rhinitis (e.g., vasomotor rhinitis and non-allergic rhinitis 0073. As used herein, the phrase “pharmaceutically eosinophilia syndrome (NARES)), infectious rhinitis (e.g., active agent” refers to an antihistamine, a decongestant, a symptoms associated with the common cold), sinusitits (i.e., corticosteroid, an expectorant, a composition to relieve an inflammation, or Swelling, of the mucous membranes that oropharyngeal discomfort, a P2Y receptor antagonist, a line the sinus cavities), and post-nasal drip (i.e., wherein non-steroidal anti-inflammatory agent, a leukotriene antago drainage from the nose and sinuses drips down the back of nist, a Syk kinase inhibitor, or a 5-lipoxygenase inhibitor. the throat). In addition, respiratory disorders associated with 0074 As used herein the phrase “pharmaceutically the production of mucus glycoprotein include conditions acceptable salt” refers to a non-toxic salt prepared from that are triggered or exacerbated by nasal secretion. For pharmaceutically acceptable acids or bases (including inor example, respiratory congestion, cough, and allergic airway ganic acids or bases, or organic acids or bases). Examples of disease manifested by symptoms including wheezing, chest Such inorganic acids are hydrochloric, hydrobromic, tightness, cough, and dyspnea. hydroiodic, Sulfuric, and phosphoric. Appropriate organic 0068. As used herein, the phrase “skin disorder includes acids may be selected, for example, from aliphatic, aromatic, the skin reactions of urticaria and angioedema. These skin carboxylic and Sulfonic classes of organic acids, examples of disorders may be triggered by exposure to certain foods, which are formic, acetic, propionic, succinic, glycolic, glu medications, or virus infections. Urticarira (commonly curonic, maleic, furoic, glutamic, benzoic, anthranilic, Sali referred to as hives or welts) are red, itchy, raised areas of cylic, phenylacetic, mandelic, embonic (pamoic), methane the skin of varying shapes and sizes. Urticarira are the result Sulfonic, ethanesulfonic, pantothenic, benzenesulfonic, of release of histamine and other compounds from mast cells Stearic, Sulfanilic, algenic, and galacturonic. Examples of that cause serum to leak from local blood vessels and Such inorganic bases include metallic salts made from alu thereby cause Swelling in the skin. Angioedema is a form of minum, calcium, lithium, , , , tissue Swelling similar to urticaria, but involving deeper skin and . Appropriate organic bases may be selected, for tissues (i.e., "deep hives') and generally lasting longer than example, from N,N-dibenzylethylenediamine, chlorop rocaine, choline, diethanolamine, ethylenediamine, meglu urticaria. maine (N-methylgulcaine), lysine, and procaine. Examples 0069. As used herein, the phrase “allergic conjunctivitis' of Suitable pharmaceutically acceptable acid addition salts refers to an irritation by an allergen of the clear, thin for oxybutynin include acetic, benzenesulfonic (besylate), membrane called the conjunctiva that covers the eyeball and benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, the inside of the eyelids. Symptoms may include swollen gluconic, glutamic, hydrobromic, hydrochloric, isethionic, eyes, itchy/burning eyes, tearing, and ocular redness. Some lactic, maleic, malic, mandelic, methanesulfonic, mucic, common allergens include pollen from trees, grass and nitric, pamoic, pantothenic, phosphoric, Succinic, Sulfuric, ragweed, animal skin and secretions such as Saliva, per tartaric, and p-toluene Sulfonic. The hydrochloride has par fumes and cosmetics, skin medicines, air pollution and ticular utility. Smoke. 0075. As used herein, the phrase “medicinal agent' 0070. As used herein, the phrase “selective muscarinic includes a Substance that is a selective muscarinic acetyl acetylcholine receptor subtype M1 and/or M3 antagonist' choline receptor subtype M1 and/or M3 antagonist, and/or a means an agent that inhibits cell signaling from muscarinic pharmaceutically active agent. acetylcholine receptor subtype M1 and/or M3 with greater 0076. As used herein the phrase “dosage form” refers to potency than muscarinic acetylcholine receptor Subtype M2. a composition comprising at least one medicinal agent and In one embodiment, the agent inhibits cell signaling from a carrier formulated into a delivery system (i.e., tablet, muscarinic acetylcholine receptor subtype M1 and/or M3 capsule, oral gel, orally consumable films, orally disinte with about 5-fold greater potency than muscarinic acetyl grating tablet (e.g., Reditabs(R), syrup, nasal spray, powders choline receptor subtype M2. In another embodiment, the for constitution or Suspension, powder (sprinkles) that is put agent inhibits cell signaling from muscarinic acetylcholine onto foods) in association with at least one inactive ingre receptor subtype M1 and/or M3 with about 7.5-fold greater dient. US 2006/01 10449 A1 May 25, 2006

0077. As used herein the term “capsule” refers to a Such as alginic acid, sodium alginate, and ammonium cal special container or enclosure made of methyl cellulose, cium alginate; cellulosic materials such as methylcellulose, polyvinyl alcohols, or denatured gelatins or starch for hold Sodium carboxymethylcellulose, and hydroxypropylmethyl ing or containing a composition comprising a formulation of cellulose; polyvinylpyrrolidinone; and inorganics Such as the present invention and a carrier. Hard shell capsules are magnesium aluminum silicate. The amount of binder in the typically made of blends of relatively high gel strength bone composition can range from about 2% to about 20% by and pork skin gelatins. The capsule itself may contain Small weight of the composition, more preferably from about 3% amounts of dyes, opaquing agents, plasticizers, and preser to about 10% by weight, even more preferably from about vatives. 3% to about 6% by weight. 0078. As used herein the term “tablet” refers to a com 0085. As used herein the term “lubricant” refers to a pressed or molded Solid dosage form containing a compo substance added to the dosage form to enable the tablet, sition comprising a formulation of the present invention and granules, etc. after it has been compressed, to release from a carrier with suitable diluents. The tablet can be prepared by the mold or die by reducing friction or wear. Suitable compression of mixtures or granulations obtained by wet lubricants include metallic Stearates such as magnesium granulation, dry granulation or by compaction. Stearate, calcium Stearate or potassium Stearate; Stearic acid; high waxes; and water soluble lubricants such 0079. As used herein the phrase “oral gel” refers to a as Sodium chloride, Sodium benzoate, Sodium acetate, composition comprising a formulation of the present inven Sodium oleate, polyethylene glycols, and d1-leucine. Lubri tion and a carrier dispersed or solubilized in a hydrophilic cants are usually added at the very last step before com semi-solid matrix. pression, since they must be present on the Surfaces of the 0080. As used herein the phrase “orally consumable film' granules and in between them and the parts of the tablet refers to a composition comprising a formulation of the press. The amount of lubricant in the composition can range present invention and an edible film carrier. from about 0.2% to about 5% by weight of the composition, 0081. As used herein the phrase “powders for constitu preferably from about 0.5% to about 2%, more preferably tion” refers to powder blends containing a composition from about 0.3% to about 1.5% by weight. comprising a formulation of the present invention and a 0086 As used herein the term "glidant’ refers to a carrier with suitable diluents which can be suspended in Substance that prevents caking and improves the flow char water or juices. acteristics of granulations, so that flow is Smooth and 0082) As used herein the term "diluent” refers to a uniform. Suitable glidants include silicon dioxide and talc. Substance that usually makes up the major portion of the The amount of glidant in the composition can range from composition or dosage form. Suitable diluents include Sug about 0.1% to about 5% by weight of the composition, arS Such as lactose, Sucrose, mannitol, and Sorbitol; starches preferably from about 0.5% to about 2% by weight. derived from , corn , and ; and celluloses 0087 As used herein the phrase “coloring agent” refers to Such as microcrystalline cellulose. The amount of diluent in a Substance that provides coloration to the composition or the composition can range from about 10% to about 90% by the dosage form. Such substances can include food grade weight of the total composition, preferably from about 25% dyes and food grade dyes adsorbed onto a Suitable adsorbent to about 75%, more preferably from about 30% to about Such as clay or aluminum oxide. The amount of the coloring 60% by weight, even more preferably from about 12% to agent can vary from about 0.1% to about 5% by weight of about 60%. the composition, preferably from about 0.1% to about 1%. 0083. As used herein the term “disintegrant” refers to a 0088 As used herein the term “” refers to Substance added to the dosage form to help it break apart the rate and extent to which the medicinal agent is absorbed (disintegrate) and release the medicinal agent(s). Suitable into the systemic circulation from an administered dosage disintegrants include starches; “cold water soluble” modi form as compared to a standard or control, as well as to fied Starches such as sodium carboxymethyl starch; natural topical bioavailability. and synthetic gums such as locust bean, karaya, guar, tragacanth, and agar, cellulose derivatives such as methyl 0089. One preferred selective muscarinic acetylcholine cellulose and sodium carboxymethylcellulose; microcrystal receptor subtype M1 and M3 antagonist is oxybutynin or a line celluloses and cross-linked microcrystalline celluloses pharmaceutically acceptable salt thereof (e.g., Oxybutynin Such as Sodium croScarmellose; alginates Such as alginic chloride). A racemic mixture of oxybutynin chloride is acid and sodium alginate; clays such as bentonites; and available under the trademark Ditropan R) and Ditropan XLR effervescent mixtures. The amount of disintegrant in the by Ortho-McNeil Pharmaceutical, Inc., Raritan, N.J. A race composition can range from about 2% to about 15% by mic mixture of R- and S-enantiomers of oxybutynin or a weight of the composition, more preferably from about 4% pharmaceutically acceptable salt thereof may be used in the formulations and methods of the present invention. Alter to about 10% by weight. natively, the R-enantiomer or the S-enantiomer, Substan 0084 As used herein the term “binder” refers to a sub tially free of the S-enantiomer or the R-enantiomer, respec stance that binds or “glues' powders together and makes tively, may be used in the formulations and methods of the them cohesive by forming granules, thus serving as the present invention. Use of the S-enantiomer of oxybutynin “adhesive' in the dosage form. Binders add cohesive for the treatment of asthma is disclosed in U.S. Pat. No. strength already available in the diluent or bulking agent. 6.294.582. Likewise, the selective muscarinic acetylcholine Suitable binders include Sugars such as Sucrose; starches receptor subtype M1 and M3 antagonist may be a derivative derived from wheat, corn rice, and potato; natural gums such of oxybutynin (e.g., desethyloxybutynin), or a pharmaceu as acacia, gelatin, and tragacanth; derivatives of seaweed tically acceptable salt thereof. A racemic mixture of R- and US 2006/01 10449 A1 May 25, 2006

S-enantiomers of desethyloxybutynin may be used in the form as is known to one of skill in the art) of the present formulations and methods of the present invention. Alter composition can range from about 1 mg to 40 mg, also from natively, the R-enantiomer or the S-enantiomer of desethy about 2.5 mg to about 10 mg (e.g., about 5 mg). The levo loxybutynin, substantially free of the S-enantiomer or the isomer of cetirizine may also be combined with a selective R-enantiomer, respectively, may be used in the formulations muscarinic acetylcholine receptor subtype M1 and/or M3 and methods of the present invention. Quaternary ammo antagonist in the formulations of the present invention. U.S. nium derivatives of oxybutynin and methods of their use for Pat. No. 6,319,927 discloses a method of using levocetiriz the treatment of asthma, chronic obstructive pulmonary ine as a sleep aid. disease, allergic rhinitis, or infectious rhinitis are disclosed 0094. In addition, other antihistamines useful for formu in WO O4/O39763. lations of the present invention include azatadine, azelastine, 0090 The present invention also provides an antihista acrivastine, brompheniramine, chlorpheniramine, clemas mine in combination with a selective muscarinic acetylcho tine, cyclizine, carebastine, cyproheptadine, carbinoxamine, line receptor subtype M1 and/or M3 antagonist. One pre doxylamine, dimethindene, ebastine, epinastine, efletirizine, ferred antihistamine for use with a selective muscarinic hydroxy Zine, ketotifen, levocabastine, mizolastine, meduita acetylcholine receptor subtype M1 and/or M3 antagonist is Zine, mianserin, noberastine, meclizine, norastemizole, desloratadine, available under the trademark ClarineXOR) by picumast, pyrilamine, promethazine, tripelennamine, Schering Corporation, Kenilworth, N.J. This compound is temelastine, trimeprazine, and triprolidineastemizole. Pref described in Quercia et al., Hosp Formul, 28:137-53 (1993), erably, the amount of norastemizole which can be employed in U.S. Pat. 4,659,716, and in WO 96/20708. The use of in a unit dosage form (single or divided dosage form as is desloratadine for the treatment of congestion is disclosed in known to one of skill in the art) of the present composition U.S. Pat. No. 6,432,972. Desloratadine is an antagonist of is about 10 mg or more. the H histamine receptor . The H receptors are those 0095 The present invention provides a decongestant in that mediate the response antagonized by conventional anti combination with a selective muscarinic acetylcholine histamines. H receptors are present, for example, in the receptor subtype M1 and/or M3 antagonist. Preferably, the ileum, the skin, and the bronchial Smooth muscle of man and decongestant is an oral or nasal decongestant. Examples of other mammals. The amount of desloratadine which can be nasal decongestants useful in the present invention include employed in a unit dosage form (single or divided dosage the sympathomimetic nasal decongestants. Such nasal form as is known to one of skill in the art) of the present decongestants approved for use in the United States include compositions can range from about 1.25 mg to about 45 mg. levmetamfetamine (also known as 1-desoxyephedrine), also from about 1.25 mg to about 20 mg, also from about 5 ephedrine, ephedrine hydrochloride, ephedrine Sulfate, nap to about 10 mg. Preferably, the dosage amount is 1.25 mg. hazoline hydrochloride, oxymetazoline hydrochloride, phe 2.5 mg, 5.0 mg, 10.0 mg. or 20.0 mg. More preferably, the nylephrine hydrochloride, propylhexedrine, and Xylometa dosage amount is 5.0 mg. Zoline hydrochloride. Oral decongestants for use in the 0.091 Another antihistamine for use with a selective present invention include phenylpropanolamine, phenyleph muscarinic acetylcholine receptor subtype M1 and/or M3 rine, and pseudoephedrine. Pseudoephedrine as well as antagonist is loratadine, available under the trademark Clar pharmaceutically acceptable acid additional salts (e.g., those itinR) from Schering Corporation, Kenilworth, N.J. Lorata of HCl or H2SO4), is a sympathomimetic drug recognized by dine, described in U.S. Pat. No. 4,282,233, is a potent those skilled in the art as a safe therapeutic agent effective tricyclic and antihistaminic drug of slow release, with a for treating nasal congestion and is commonly administered selective antagonist of peripheric H receptors activity. orally and concomitantly with an antihistamine for treatment of nasal congestion associated with allergic rhinitis. The use 0092 Another antihistamine for use with a selective of pseudoephedrine as a nasal decongestant in the present muscarinic acetylcholine receptor subtype M1 and/or M3 invention is preferred in amounts of about 120 mg pseu antagonist is fexofenadine, available under the trademark doephedrine sulfate dosed one to 4 times daily. However, Allegra R) from Aventis, Strasbourg, France. Fexofenadine is lesser amounts of pseudoephedrine Sulfate may be used in described in U.S. Pat. No. 5,578,610. Preferably, the phar combination with a selective muscarinic acetylcholine maceutically acceptable salt is fexofenadine hydrochloride. receptor subtype M1 and/or M3 antagonist. The amount of fexofenadine which can be employed in a unit dosage form (single or divided dosage form as is known 0096. The present invention also provides a corticoster to one of skill in the art) of the present composition can oid in combination with a selective muscarinic acetylcholine range from about 30 mg to 200 mg, also from about 30 mg receptor subtype M1 and/or M3 antagonist. Corticosteroids to about 180 mg, (e.g., about 30 mg, about 60 mg, about 120 for use in the present invention include dexamethasone, mg, about 180 mg). butoxicort, rofileponide, budesonide, deflazacort, ciclesonide, fluticasone, beclomethasone, loteprednol, 0093. Another antihistamine for use with a selective mometasone, betametaSone, or triamcinolone. For instance, muscarinic acetylcholine receptor subtype M1 and/or M3 when the corticosteroid is fluticasone, it may be adminis antagonist is cetirizine, available under the trademark tered at the dose of 2 sprays of 50 ug of fluticasone ZYRTEC(R) from Pfizer Inc., New York, N.Y. Cetirizine propionate each in each nostril once daily. Alternatively, it hydrochloride is a racemic compound with an empirical may be administered at a dose of fluticasone is 1 spray of 50 formula of CHCINO2HC1. Cetirizine hydrochloride is ug of fluticasone propionate each in each nostril once daily. a white, crystalline powder that is water-soluble. U.S. Pat. When the corticosteroid is triamcinolone, it may be admin No. 6,258,814 discloses cetirizine as well as the use of istered at a dose of triamcinolone is 220 ug per day as two cetirizine as a sleep aid. The amount of cetirizine which can sprays in each nostril once daily. Alternatively, it may be be employed in a unit dosage form (single or divided dosage administered at a dose of 110 ug per day as one spray in each US 2006/01 10449 A1 May 25, 2006

nostril once daily. When the corticosteroid is budesonide, acetylcholine receptor subtype M1 and/or M3 antagonist. the administered dose of budesonide may be 64 ug per day Diquafosol tetrasodium is a P2Y receptor that administered as one spray per nostril of 32 ug once daily. activates receptors on the ocular surface and inner lining of the eyelid to stimulate the release of water, salt, mucin, and 0097. A particularly preferred steroid is mometasone —the key components of natural tears. Mucin is made furoate. Mometasone furoate is a corticosteroid approved for in specialized cells and acts to lubricate surfaces. Lipids in topical dermatologic use to treat inflammatory and/or pru the eye are oily substances that form the outer-most layer of ritic manifestations of corticosteroid-responsive dermatoses. the tear film and are responsible for the prevention of excess The compound may be prepared in accordance with the tear fluid evaporation. In preclinical testing, diduafosol procedures disclosed in U.S. Pat. Nos. 4,472.393, 4,731,447, reportedly increased the Secretions of natural tear compo 4,873,335, and 6,127,353, all of which are hereby incorpo nents. Dicquafosol is available from Inspire Pharmaceuticals, rated by reference in their entirety. Mometasone furoate is a Inc., Durham, NC. P2Y receptor agonists are a new class of topically active steroid which is not readily bioavailable. It compounds being developed for the treatment of a variety of is commercially available as a spray for intra-nasal admin conditions, including chronic bronchitis and cystic fibrosis. istration under the name of NasoneXR). Use of mometasone Other mucolytic agents may include N-acetylcysteine and furoate for the treatment of airway passages and lung endogenous ligand compound UTP. These compositions diseases is disclosed in U.S. Pat. Nos. 6,677.323, 6,677,322, may be administered either orally or nasally as set forth 6,365,581, 6,187,765, 6,068,832, 6,057,307, 5,889,015, below in amounts that are known to one of skill in the art. 5,837,699, and 5,474,759, all of which are incorporated by reference in their entirety. For the treatment of allergic, 0101 The present invention also provides a non-steroidal non-allergic rhinitis and/or inflammatory disorders of the anti-inflammatory (NSAIDs) agent in combination with a upper or lower airway passages, the Substantially non selective muscarinic acetylcholine receptor subtype M1 and/ systematically bioavailable amount of mometasone furoate or M3 antagonist. Suitable NSAID’s include acetylsalicylic which may be administered as an aqueous Suspension or dry acid, acetaminophen, indomethacin, diclofenac, piroxicam, powder is in the range of about 10 ug/day to about 5000 tenoxicam, ibuprofen, naproxen, ketoprofen, nabumetone, ug/day, about 10 g/day to about 4000 ug/day, about 10 ketorolac, azapropaZone, mefenamic acid, tolfenamic acid, ug/day to about 2000 ug/day, about 25 ug/day to about 1000 Sulindac, diflunisal, tiaprofenic acid, podophyllotoxin ug/day, about 25 ug/day to about 400 ug/day, about 25 derivatives, acemetacin, aceclofenac, droxicam, oxaprozin, ug/day to about 200 g/day, about 25 ug/day to about 100 floctafenine, phenylbutaZone, proglumetacin, flurbiprofen, g/day, or about 25 g/day to about 50 g/day in single or tolimetin, and fenbufen. These compositions may be admin divided doses. istered either orally or nasally as set forth below in amounts that are known to one of skill in the art. 0098. The present invention also provides an expectorant 0102) The present invention also provides a leukotriene in combination with a selective muscarinic acetylcholine antagonist in combination with a selective muscarinic ace receptor subtype M1 and/or M3 antagonist. Ambroxol is a tylcholine receptor subtype M1 and/or M3 antagonist. Suit bromhexine metabolite, chemically identified as trans-4(2- able leukotriene D antagonists include zileuton, doce amino-3,5-dibromobenzil, amine) ciclohexane hydrochlo benone, piripost, ICI-D2318, MK-591, MK-886, sodium ride, which has been widely used during more than two 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethynyl)phenyl) decades as an expectorant agent or stimulating pulmonary -3-(2-(2-hydroxy-2-propyl)phenyl)thio)methyl)cyclo surfactant factor. The compound is described in U.S. Pat. propane-acetate; 1 -(((1(R)-(3-(2-(2,3-dichlorothieno3.2-b No. 3,536,712. Guaiafenesin is an expectorant, whose tech pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-meth nical name is 3-(2-methoxyphenoxy)-1,2-propanediol. The ylethyl)phenyl)propyl)thio)-methyl)cyclopropaneacetic compound is described in U.S. Pat. No. 4.390,732. Terpin hydrate is an expectorant, whose technical name is 4-hy acid, praniukast, Zafirlukast, and montelukast. These com droxy-C, C, 4-trimethylcyclohexane-methanol. Potassium positions may be administered either orally or nasally as set guaicolsulfonate is an expectorant, whose technical name is forth below in amounts that are known to one of skill in the 3-hydroxy-4-methoxybenzenesulfonic acid mix with mono art. potassium 4-hydroxy-3-methoxybenzenesulfonate. These 0103 Montelukast is a leukotriene Dantagonist capable combinations may be administered orally as set forth below. of antagonizing the receptors for the cysteinyl leukotrienes and is described in EP 0 480 717. A preferred pharmaceu 0099. The present invention also provides a composition tically acceptable salt of montelukast is the monosodium to relieve oropharyngeal discomfort in combination with a salt, also known as montelukast sodium. The amount of selective muscarinic acetylcholine receptor subtype M1 and/ montelukast which can be employed in a unit dosage form or M3 antagonist. Compositions to relieve oropharyngeal (single or divided dosage form as is known to one of skill in discomfort, Such as Sore throat, cold or canker Sores, painful the art) of the present invention can range from about 1 mg gums, and other conditions include topical anesthetics Such to 100 mg, also from about 5 mg to about 20 mg, preferably as phenol, hexylresorcinol, salicyl , benzyl alcohol, about 10 mg. dyclonine, dibucaine, benzocaine, buticaine, cetylpyri dinium chloride, diperidon, clove oil, menthol, camphor, 0.104) The compound 1-(((R)-(3-(2-(6,7-difluoro-2- eugenol, and others. Similarly, drugs that may be incorpo quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phe rated for application to the skin for relieving discomfort nyl)thio)methylcyclopropaneacetic acid is a leukotriene include lidocaine, benzocaine, tetracaine, dibucaine, antagonist described in WO 97/28797 and U.S. Pat. No. pramoxine, , benzyl alcohol, and others. 5,270,324. A pharmaceutically acceptable salt of this com pound is the Sodium salt, also known as Sodium 1-(((R)-(3- 0100. The present invention also provides a P2Y recep (2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hy tor agonist in combination with a selective muscarinic droxy-2-propyl) phenyl)thio)-methylcyclopropaneacetate. US 2006/01 10449 A1 May 25, 2006

0105 The compound 1-(((1(R)-3(3-(2-(2,3-dichlo formulation may contain a selective muscarinic acetylcho rothieno 3.2-bipyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1- line receptor subtype M1 and/or M3 antagonist in combi hydroxy-1-methylethyl)phenyl)propyl)-thio)methyl)cyclo nation with desloratadine and/or pseudoephedrine for the propaneacetic acid is a leukotriene antagonist described in treatment of the referenced disorder (e.g., a respiratory WO 97/28797 and U.S. Pat. No. 5,472.964. A pharmaceu disorder associated with the production of mucus glycopro tically acceptable Salt of this compound is the Sodium salt, tein, a skin disorder, or allergic conjunctivitis). also known as sodium 1-(((1(R)-3(3-(2-(2,3-dichlorothieno 3.2-bpyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy 0.112. The formulations of the present invention may be 1-methylethyl)phenyl)propyl)-thio)methyl)cyclopropaneac administered in specific, measured amounts in the form an etate. aerosol (Solution and/or Suspension). The aerosol may be delivered using devices found useful for providing measured 0106 Pranlukast is a leukotriene antagonist described in Substantially non-systematically bioavailable amounts of WO97/28797 and EPO 173516. The technical name for this aerosolized pharmaceutical compositions thereof for deliv compound is N-4-oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopy ery to the oral airway passages and lungs by oral inhalation ran-8-yl)-p-(4-phenylbutoxy)benzamide. The amount of or intranasally by inhalation. Such devices include pressur praniukast which can be employed in a unit dosage form ized metered-dose inhalers (“MDI) which deliver aero (single or divided dosage form as is known to one of skill in Solized particles Suspended in chlorofluorocarbon propel the art) can range from about 100 mg to about 700 mg. lants (e.g., CFC-11, CFC-12), or the non preferably from about 112 mg to about 675 mg; also from chlorofluorocarbons or alternate propellants (e.g., the about 225 mg to about 450 mg; also from about 225 mg to fluorocarbons, HFC-134A or HFC-227) with or without about 300 mg. Surfactants and Suitable bridging agents. 0107 Zafirlukast is a leukotriene antagonist described in 0113. The formulations of the present invention may be WO97/28797 and EPO 1995.43. The technical name for this also administered in specific, measured amounts in the form compound is cyclopentyl-3-2-methoxy-4-(o-tolylsulfonyl of an aqueous Suspension by use of a pump spray bottle. )carbamoyl benzyl-1-methylindole-5-carbamate. Such pump spray bottles include the pump spray bottle used 0108. The compound 2-2-(4-tert-butyl-2-thiazolyl)-5- to deliver NASONEX(R) Nasal Spray as well as the pump benzofuranyloxymethylphenyl)acetic acid is a leukotriene spray bottle disclosed in the Schering Corporation Industrial antagonist and/or inhibitor whose method for preparation is Design Deposit DM/026304, registered by the Hague Union described in U.S. Pat. No. 5.296.495 and Japanese Patent JP on Jun. 1, 1993 (each are available from Schering Corpo 08325265 A. An alternative name for this compound is ration). 2-2-4-(1,1-dimethylethyl)-2-thiazolyl-5-benzofuranyl 0114. The formulations of the present invention may also oxymethyl-benzeneacetic acid. The code number for this be administered via a Dry Powder Inhaler. Such inhalers compound is FK011 or FR150011. The compound has a include Schering's Twisthaler, Diskhaler (Allen & Han molecular formula of CHNOS and molecular weight of burys), Accuhaler (Allen & Hanburys), Diskus (Glaxo), 421.52. Spiros (Dura), Easyhaler (Orion), Cyclohaler (Pharmache 0109 The present invention also provides a syk kinase mie), Cyclovent (Pharmachemie), Rotahaler (Glaxo), Spin inhibitor in combination with a selective muscarinic acetyl haler (Fisons), FlowCaps(Hovione), Turbospin (PH&T), choline receptor subtype M1 and/or M3 antagonist. Syk Turbohaler (Astra), EZ Breath (Norton Healthcare/IVAX), kinase inhibitors include R112, available from Rigel Phar MIAT-HALER (Miat), Pulvinal (Chiesi), Ultrahaler (Fisons/ maceuticals, Inc. A recent study reportedly showed a greater Rhone Poulenc Rorer), MAG-Haler (GGU), Prohaler than 20% relative improvement for R112 over placebo (an (Valois), Taifun (Leiras), JAGO DPI (JAGO), and M. L. absolute difference of 9% over placebo) and up to 38% Laboratories DPI (ML Laboratories). improvement for R112 from baseline measurements (prior 0115 For oral dosage form preparations, a pharmaceuti to drug initiation). In particular, symptoms most closely cally acceptable carrier (which includes diluents, excipients, associated with chronic nasal congestion (e.g., stufly nose) or carrier materials) is also present in the formulation. The were reportedly improved with R112 over placebo. carrier is suitably selected with respect to the intended form 0110. The present invention also provides a 5-lipoxyge of administration, i.e., oral tablets, capsules (either solid nase inhibitor in combination with a selective muscarinic filled, semi-solid filled, or liquid filled), powders for con acetylcholine receptor subtype M1 and/or M3 antagonist. stitution, oral gels, orally consumable films, elixirs, syrups, 5-lipoxygenase inhibitors include any agent, or compound Suspensions, and the like, and consistent with conventional that inhibits, restrains, retards or otherwise interacts with the pharmaceutical practices. For example, for oral administra enzymatic action of 5-lipoxygenase, such as, but not limited tion in the form of tablets or capsules, the medicinal agent to, zileuton, docebenone, piripost, and the like. In addition, may be combined with any oral non-toxic pharmaceutically 5-lipoxygenase inhibitors include any agent or compound acceptable inert carrier, Such as lactose, starch, Sucrose, that inhibits, retrains, retards or otherwise interacts with the cellulose, magnesium Stearate, dicalcium phosphate, cal action or activity of 5-lipoxygenase activating protein, Such cium Sulfate, mannitol, ethyl alcohol (liquid forms), and the like. Moreover, when desired or needed, suitable binders, as, but not limited to MK-591 and MK-886. lubricants, disintegrants, disinfectants and coloring agents 0111. As will be evident to one of skill in the art, the may also be incorporated in the mixture. Suitable binders formulations of the present invention may contain a selec include starch, gelatin, natural Sugars, corn Sweeteners, tive muscarinic acetylcholine receptor subtype M1 and/or natural and synthetic gums such as acacia, Sodium alginate, M3 antagonist in combination with one or more pharma carboxymethylcellulose, polyethylene glycol, and waxes. ceutically active agents as set forth herein. For instance, the Suitable lubricants include boric acid, sodium benzoate, US 2006/01 10449 A1 May 25, 2006

sodium acetate, sodium chloride, and the like. Suitable symptoms. Efficacy endpoints studies may include Total disintegrants include starch, methylcellulose, guar gum, and Symptom Score, Total Nasal Symptom Score, Total Non the like. Suitable disinfectants include benzalkonium chlo nasal Symptom Score, Individual Symptom Scores, and ride and the like. Sweetening and flavoring agents and Health Quality of Life (HQOL) analysis in efficacy trials. preservatives may also be included where appropriate. The compositions of the present invention may be tested for 0116. Additionally, the formulations of the present inven reducing the total symptom scores (the Sum of individual tion may be formulated in sustained release form to provide scores for rhinorrhea, post-nasal drip, Sneezing, congestion/ the rate controlled release of any one or more of the stuffiness, nasal itching, itchy/burning eyes, tearing, ocular components or medicinal agents to optimize the therapeutic redness, and itchy ears/palate). An important efficacy end effects. Suitable dosage forms for sustained release include point that may be analyzed in the studies is the AM NOW layered tablets (e.g., containing layers of varying disinte total symptom score. This parameter measures the total gration rates or controlled release polymeric matrices symptom relief by the patient after 24 hours before taking impregnated with the medicinal agents) that are shaped in the next day dose. tablet form or capsules containing Such impregnated or 0123 The compositions of the present invention may be encapsulated porous polymeric matrices. particularly useful for the treatment and prevention of the 0117 Conventional methods for preparing tablets are nasal (stuffiness/congestion, rhinorrhea, post-nasal drip, known. Such methods include dry methods such as direct nasal itching, Sneezing) and non-nasal (itchy/burning eyes, compression and compression of granulation produced by tearing/watery eyes, redness of the eyes, itching of the compaction, wet methods, or other special procedures. ears/palate) symptoms of seasonal and perennial allergic rhinitis, including nasal congestion, in patients in need of 0118 For ophthalmic compositions, the compositions of Such treating and/or preventing. the present invention may take various forms. For example, they may be an aqueous gel or liquid, or an ointment. In a EXAMPLE preferred embodiment, the composition is a water-in-oil emulsion with the active ingredients in the aqueous droplets 0.124. This is a Phase II, randomized, double-blind, pla Suspended in a lotion or flowable ointment base comprising, cebo controlled, double-dummy, multicenter, dose-ranging e.g., petrolatum, oil, and the like. Additional emol study of desloratadine (DL) in subjects at least 18 years of lient ingredients such as isopropyl myristate may also be age with Seasonal Allergic Rhinitis (SAR) and Post-Nasal added. Such a lotion or ointment covers the conjunctiva and Drip. Subjects were randomized to one of 5 treatment arms: cornea with a thin film that both carries active ingredients DL 2.5 mg BID, Oxybutynin (Oxy) 5 mg BID, DL 2.5 and provides for prolonged drainage through the naso mg--Oxy 2.5 mg given concurrently BID, DL 2.5 mg +Oxy lacrimal ducts. The film also provides a barrier to evapora 5 mg given concurrently BID, or placebo in a 1:1:1:1:1 ratio. tive loss of water from the corneal stroma. The total target enrollment was 500 subjects with 100 per 0119) The selective muscarinic acetylcholine receptor arm. The study consisted of a 7-day Treatment Phase. subtype M1 and/or M3 antagonist and one or more phar 0.125 The primary efficacy variable was the change from maceutically active agents administered in the method of baseline in the average AM/PM PRIOR post nasal drip score treating the referenced disorder (e.g., a respiratory disorder over the Treatment Phase of 7 days. The analysis was based associated with the production of mucus glycoprotein, a skin on a main effect analysis of variance (ANOVA), which disorder, or allergic conjunctivitis) may be administered extracted Sources of variation due to treatment and center. concurrently or sequentially (i.e., by the sequential admin The primary objective is to estimate the effect of DL 2.5 istration of the ingredients in a suitable order). mg--OXy 5 mg in reducing post nasal drip compared to DL 0120) The formulations disclosed herein may be either alone and placebo. Pairwise treatment comparisons were sedating or non-sedating. In one embodiment, the formula examined using the 95% confidence intervals of the treat tions disclosed herein are sedating. In an alternative embodi ment differences at an unadjusted 2-sided alpha-level of ment, the formulations disclosed herein are non-sedating or O.05. mildly sedating. 0.126 The order of examination was as follows: DL 2.5 0121 For disorders of the lower airways, the severity in mg+Oxy 5 mg BID vs. DL and DL 2.5 mg--Oxy 5 mg BID a patient can be quantified by objective pulmonary function vs. placebo, followed by DL 2.5 mg--Oxy 2.5 mg BID vs. tests, including a measurement of the patients forced expi DL and DL 2.5 mg+Oxy 2.5 mg BID vs. placebo. ratory volume in 1 second (FEV). When this result is about 0127. After the examination of post nasal drip, the key 65 to 79 percent of the predicted value (determined using a secondary efficacy variable, anterior rhinorrhea, was exam formula that takes into account the patients age and size), ined in the same manner. the airway obstruction is considered to be mild. For an FEV. value about 50 to 64 percent of predicted, the airway 0128. A preliminary assessment of the consistency of obstruction is classified as moderate; if the value is less than results across centers for the primary efficacy variable was 50 percent of predicted, the airway obstruction is considered made using an ANOVA model that extracted sources of to be severe; and if the value is less than 30 percent the variation due to treatment, center, and treatment-by-center airway obstruction is considered to be very severe. This test interaction. To be included in this analysis, centers must utilizes relatively simple and inexpensive equipment, and have had at least two Subjects in each treatment group with therefore is widely used for diagnosis, and to monitor the post nasal drip evaluations. progression lung and airway disorders during treatment. 0129. There were 540 subjects randomized into the study. 0122) For disorders of the upper airways, there are also Of those, 106 subjects were in the DL 2.5 mg BID group: objective parameters for measuring an improvement in 108, 108, 111 and 107 were in the Oxy 5 mg BID, DL 2.5 US 2006/01 10449 A1 May 25, 2006 mg+Oxy 2.5 mg BID, DL 2.5 mg--Oxy 5 mg BID and 0.136 The Oxy 5 mg BID treatment demonstrated a -0.49 placebo groups, respectively. The table below provides a least squares mean decrease from baseline which was less Summary of the numbers of Subjects in the analysis Subsets. than the placebo response. 0.137 The key secondary efficacy variable, anterior rhi norrhea, was also examined. The combination of DL 2.5 DL DL 2.5 Oxy 5 DL2.5/ 2.5/Oxy mg+Oxy 5 mg demonstrated a treatment difference of 0.19 Subjects BID mg bID Oxy 2.5 bid 5 bid Placebo Total points vs. placebo and 0.16 points vs. DL alone. The lower dose combination of DL 2.5 mg--Oxy 2.5 mg BID demon Randomized 106 108 108 111 107 S4O strated a 0.14 point advantage over placebo, and a 0.11 point Efficacy 999 97 1OO 105 101 502 advantage over DL alone. However, the differences between placebo and the individual components DL and Oxy alone Of the 540 randomized subjects, 384 (71.11%) were female, were only 0.03 and 0.04, respectively. 156 (28.89%) were male: 421 (77.96%) were Caucasian, 0.138. The results for the total symptom score excluding 119 (22.04%) were non-Caucasian. Subjects age ranged post nasal drip, demonstrated a treatment difference of 0.71 from 18 to 76 years. point between DL alone and placebo. This is similar to the 0130. There were 38 subjects excluded from the efficacy results from previous studies of DL in subjects with SAR, evaluable subset. A majority of these subjects were excluded confirming the activity of DL in this study. due to insufficient efficacy data. Determination of evaluabil ity was perfomed prior to unblinding the database. Though 0.139. The percentage of subjects reporting any treatment the treatment duration specified in the protocol was 7 days, emergent adverse events was 22.78% (123/540 subjects) about 70% of subjects also completed their diary on the AM overall. Of these, 17 subjects (16.0%) were in the DL 2.5 mg of Day 8 since the final office visit was scheduled on that group, 33 (30.6%), 22 (20.4%), 36 (32.4%) and 15 (14.0%) day. Therefore, the AM Day 8 data were included in the subjects were in the Oxy 5 mg BID, DL 2.5 mg--Oxy 2.5 mg calculation of the one-week average. BID, DL 2.5 mg--Oxy 5 mg BID, and placebo groups respectively. Dry mouth was the most common adverse 0131 Overall, only 14 (2.6%) subjects discontinued from event, reported by 49 (9.07%) subjects across the 5 treat the treatment phase. Most of them occurred in the Oxy 5 mg ment groups. There were 15 subjects reporting dry mouth in BID group (5.56%), while the other four treatment groups (DL 2.5 mg, DL 2.5 mg--Oxy 2.5 mg, DL 2.5 mg--OXy 5 mg. the Oxy 5 mg BID group (13.9%), and 19 subjects reporting and placebo) had a discontinuation rate of 1.89%, 0.93%, the events in the DL 2.5 mg--Oxy 5 mg group (17.1%). The 1.80% and 2.80% respectively. Discontinuation due to lower dose combination of DL 2.5 mg--Oxy 2.5 mg BID adverse events (6, 1.11%) was the most common reason for group had 8 subjects (7.4%) reporting dry mouth. These discontinuation across the treatment groups. rates are higher than that of DL alone with 4 subjects (3.8%) and placebo with 3 subjects (2.8%). 0132) The primary efficacy variable was the change from baseline in the average AM/PM PRIOR post nasal drip score 0140) Except for dry mouth, similar adverse event pro over the Treatment Phase of 7 days. files were noted across the five treatments. 0133. The Baseline post nasal drip scores were compa 0.141. The differences between DL 2.5 mg+Oxy 5 mg rable across the treatment groups, ranging from 2.60 in the BID and placebo or DL alone in the treatment of post nasal DL 2.5 mg+Oxy 2.5 mg BID treatment to 2.66 in placebo. drip were 0.06 and 0.05, respectively, and did not approach The least square mean changes were -0.68(-24.8%), -0.49 the target difference of 0.24 points. Even though the lower (-17.8%), -0.60(-22.2%)-0.63 (-23.8%), and -0.57 limits of the 95% confidence intervals (-0.21 and -0.20) did (-20.7%), in the DL 2.5 mg BID, Oxy 5 mg BID, DL 2.5 allow for the possibility of approaching the target treatment mg+Oxy 2.5 mg BID, DL 2.5 mg--Oxy 5 mg BID and difference, the probability of observing such differences placebo respectively. (0.06 and 0.05) are low if the true treatment difference was O.17. 0134) The treatment difference between DL 2.5 mg--Oxy 5 mg BID and DL alone was 0.05 point in favor of DL alone. 0.142 However, for anterior rhinorrhea, the key second In addition, the difference between this combination and ary endpoint, the differences between DL 2.5 mg+Oxy 5 mg placebo is 0.06 points and represents only 4 of the target BID and placebo or DL alone were near or above the least difference (0.24 points) specified in the protocol. The 95% significant difference of 0.17 points. The incidence rates of confidence interval for the difference between DL 2.5 dry mouth in the three Oxy-containing treatment groups mg+Oxy 5 mg BID and DL alone was between -0.21 and were greater than that of DL alone or placebo, consistent 0.10. A confirmatory analysis based on the evaluable sub with the adverse event profile of Oxybutynin. jects was consistent with the primary results based on all randomized subjects. 0.143. The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, vari 0135 There was evidence of a slight treatment-by-center ous modifications of the invention in addition to those interaction (p=0.13) in a full-model analysis of variance, described herein will become apparent to those skilled in the indicating that the above results might vary across centers. art from the foregoing description. Such modifications are After further exploration, evidence of this interaction can be intended to fall within the scope of the appended claims. attributed to the Oxy 5 mg BID and placebo treatment Various publications are cited herein, the disclosures of groups. which are incorporated by reference in their entireties. US 2006/01 10449 A1 May 25, 2006

What is claimed: 14. The formulation of claim 1 wherein the therapeuti 1. A formulation comprising a therapeutically effective cally effective amount of desloratadine or a pharmaceuti amount of oxybutynin or a pharmaceutically acceptable salt cally acceptable Salt thereof is a unit dosage form in a range thereof in combination with a therapeutically effective from about 1.25 mg to about 20 mg administered q.d. amount of desloratadine or a pharmaceutically acceptable 15. The formulation of claim 1 wherein the therapeuti salt thereof. cally effective amount of desloratadine or a pharmaceuti 2. The formulation of claim 1 wherein the pharmaceuti cally acceptable Salt thereof is a unit dosage form in a range cally acceptable salt of oxybutynin is prepared from a from about 5 mg to about 10 mg administered q.d. pharmaceutically acceptable acid addition salt selected from 16. The formulation of claim 1 wherein the therapeuti the group consisting of acetic acid, benzenesulfonic acid, cally effective amount of desloratadine or a pharmaceuti benzoic acid, camphorsulfonic acid, citric acid, ethane cally acceptable salt thereof is a unit dosage form which is Sulfonic acid, fumaric acid, gluconic acid, glutamic acid, about 1.25 mg, about 2.5 mg, about 5.0 mg, about 7.5 mg. hydrobromic acid, hydrochloric acid, isethionic acid, lactic about 10.0 mg, about 12.5 mg, about 15 mg, 17.5 mg, or acid, maleic acid, malic acid, mandelic acid, methane about 20.0 mg administered q.d. Sulfonic acid, mucic acid, nitric acid, pamoic acid, pan 17. The formulation of claim 1 wherein the therapeuti tothenic acid, phosphoric acid. Succinic acid, Sulfuric acid, cally effective amount of desloratadine or a pharmaceuti tartaric acid, and p-toluene Sulfonic acid. cally acceptable salt thereof is a unit dosage form which is 3. The formulation of claim 1 wherein the pharmaceuti about 1.25 mg administered q.d. cally acceptable salt of oxybutynin is oxybutynin chloride. 18. The formulation of claim 1 wherein the therapeuti 4. The formulation of claim 1 wherein the therapeutically cally effective amount of desloratadine or a pharmaceuti effective amount of oxybutynin or a pharmaceutically cally acceptable salt thereof is a unit dosage form which is acceptable salt thereof is a unit dosage form in a range from about 2.5 mg administered q.d. about 0.1 mg to about 1 g administered q.d. 19. The formulation of claim 1 wherein the therapeuti 5. The formulation of claim 1 wherein the therapeutically cally effective amount of desloratadine or a pharmaceuti effective amount of oxybutynin or a pharmaceutically cally acceptable salt thereof is a unit dosage form which is acceptable salt thereof is a unit dosage form in a range from about 5.0 mg administered q.d. about 1 mg to about 1 g administered q.d. 20. The formulation of claim 1 wherein the therapeuti 6. The formulation of claim 1 wherein the therapeutically cally effective amount of desloratadine or a pharmaceuti effective amount of oxybutynin or a pharmaceutically cally acceptable salt thereof is a unit dosage form which is acceptable salt thereof is a unit dosage form in a range from about 10.0 mg administered q.d. about 25 mg to about 700 mg administered q.d. 21. The formulation of claim 1 wherein the therapeuti 7. The formulation of claim 1 wherein the therapeutically cally effective amount of desloratadine or a pharmaceuti effective amount of oxybutynin or a pharmaceutically cally acceptable salt thereof is a unit dosage form which is acceptable salt thereof is a unit dosage form in a range from about 20.0 mg administered q.d. about 0.1 mg to about 100 mg administered q.d. 22. The formulation of claim 1 further comprising one or 8. The formulation of claim 1 wherein the therapeutically more additional pharmaceutically active agents. effective amount of oxybutynin or a pharmaceutically 23. The formulation of claim 22 wherein one or more acceptable salt thereof is a unit dosage form in a range from additional pharmaceutically active agents is another antihis about 1.25 mg to about 30 mg administered q.d. tamine. 9. The formulation of claim 1 wherein the therapeutically 24. The formulation of claim 22 wherein one or more effective amount of oxybutynin or a pharmaceutically additional pharmaceutically active agents is a decongestant. acceptable Salt thereof is a unit dosage form which is about 25. The formulation of claim 22 wherein one or more 1.25 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 additional pharmaceutically active agents is a corticosteroid. mg, about 20 mg, about 25 mg, or about 30 mg administered 26. The formulation of claim 22 wherein one or more q.d. additional pharmaceutically active agents is an expectorant. 10. The formulation of claim 1 wherein the therapeuti 27. The formulation of claim 22 wherein one or more cally effective amount of oxybutynin or a pharmaceutically additional pharmaceutically active agents is a composition acceptable Salt thereof is a unit dosage form which is about to relieve oropharyngeal discomfort. 1.25 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 28. The formulation of claim 22 wherein one or more mg, about 4.5 mg, or about 5 mg and which is administered additional pharmaceutically active agents is a P2Y receptor b.i.d. t.i.d., or q.i.d. antagonist. 11. The formulation of claim 1 wherein the therapeutically 29. The formulation of claim 22 wherein one or more effective amount of oxybutynin or a pharmaceutically additional pharmaceutically active agents is a non-steroidal acceptable Salt thereof is a unit dosage form which is about anti-inflammatory agent. 2.5 mg and which is administered b.i.d. 30. The formulation of claim 22 wherein one or more 12. The formulation of claim 1 wherein the therapeuti additional pharmaceutically active agents is a leukotriene cally effective amount of oxybutynin or a pharmaceutically antagonist. acceptable Salt thereof is a unit dosage form which is about 31. The formulation of claim 22 wherein one or more 5 mg and which is administered b.i.d. additional pharmaceutically active agents is a Syk kinase 13. The formulation of claim 1 wherein the therapeuti inhibitor. cally effective amount of desloratadine or a pharmaceuti 32. The formulation of claim 22 wherein one or more cally acceptable Salt thereof is a unit dosage form in a range additional pharmaceutically active agents is a 5-lipoxyge from about 1.25 mg to about 45 mg administered q.d. nase inhibitor. US 2006/01 10449 A1 May 25, 2006

33. A method for treating a respiratory disorder associated 46. The method of claim 33 wherein the therapeutically with the production of mucus glycoprotein in a patient effective amount of desloratadine or a pharmaceutically Suffering therefrom comprising administering a therapeuti acceptable salt thereof is a unit dosage form in a range from cally effective amount of oxybutynin or a pharmaceutically about 1.25 mg to about 20 mg administered q.d. acceptable salt thereof in combination with a therapeutically 47. The method of claim 33 wherein the therapeutically effective amount of desloratadine or a pharmaceutically effective amount of desloratadine or a pharmaceutically acceptable salt thereof. acceptable salt thereof is a unit dosage form in a range from 34. The method of claim 33 wherein the pharmaceutically about 5 mg to about 10 mg administered q.d. acceptable salt of oxybutynin is prepared from a pharma 48. The method of claim 33 wherein the therapeutically ceutically acceptable acid addition salt selected from the effective amount of desloratadine or a pharmaceutically group consisting of acetic acid, benzenesulfonic acid, ben acceptable salt thereof is a unit dosage form which is about Zoic acid, camphorsulfonic acid, citric acid, ethanesulfonic 1.25 mg, about 2.5 mg, about 5.0 mg, about 7.5 mg, about acid, fumaric acid, gluconic acid, glutamic acid, hydrobro 10.0 mg, about 12.5 mg, about 15 mg, 17.5 mg, or about mic acid, hydrochloric acid, isethionic acid, lactic acid, 20.0 mg administered q.d. maleic acid, malic acid, mandelic acid, methanesulfonic 49. The method of claim 33 wherein the therapeutically acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, effective amount of desloratadine or a pharmaceutically phosphoric acid, Succinic acid, Sulfuric acid, tartaric acid, acceptable salt thereof is a unit dosage form which is about and p-toluene Sulfonic acid. 1.25 mg administered q.d. 35. The method of claim 33 wherein the pharmaceutically 50. The method of claim 33 wherein the therapeutically acceptable salt of oxybutynin is oxybutynin chloride. effective amount of desloratadine or a pharmaceutically 36. The method of claim 33 wherein the therapeutically acceptable salt thereof is a unit dosage form which is about effective amount of oxybutynin or a pharmaceutically 2.5 mg administered q.d. acceptable salt thereof is a unit dosage form in a range from 51. The method of claim 33 wherein the therapeutically about 0.1 mg to about 1 g administered q.d. effective amount of desloratadine or a pharmaceutically 37. The method of claim 33 wherein the therapeutically acceptable salt thereof is a unit dosage form which is about effective amount of oxybutynin or a pharmaceutically 5.0 mg administered q.d. acceptable salt thereof is a unit dosage form in a range from 52. The method of claim 33 wherein the therapeutically effective amount of desloratadine or a pharmaceutically about 1 mg to about 1 g administered q.d. acceptable salt thereof is a unit dosage form which is about 38. The method of claim 33 wherein the therapeutically 10.0 mg administered q.d. effective amount of oxybutynin or a pharmaceutically 53. The method of claim 33 wherein the therapeutically acceptable salt thereof is a unit dosage form in a range from effective amount of desloratadine or a pharmaceutically about 25 mg to about 700 mg administered q.d. acceptable salt thereof is a unit dosage form which is about 39. The method of claim 33 wherein the therapeutically 20.0 mg administered q.d. effective amount of oxybutynin or a pharmaceutically 54. The method of claim 33 further comprising adminis acceptable salt thereof is a unit dosage form in a range from tering one or more additional pharmaceutically active about 0.1 mg to about 100 mg administered q.d. agents. 40. The method of claim 33 wherein the therapeutically 55. The method of claim 54 wherein one or more addi effective amount of oxybutynin or a pharmaceutically tional pharmaceutically active agents is another antihista acceptable salt thereof is a unit dosage form in a range from mine. about 1.25 mg to about 30 mg administered q.d. 56. The method of claim 54 wherein one or more addi 41. The method of claim 33 wherein the therapeutically tional pharmaceutically active agents is a decongestant. effective amount of oxybutynin or a pharmaceutically 57. The method of claim 54 wherein one or more addi acceptable Salt thereof is a unit dosage form which is about tional pharmaceutically active agents is a corticosteroid. 1.25 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 58. The method of claim 54 wherein one or more addi mg, about 4.5 mg. or about 5 mg administered q.d. tional pharmaceutically active agents is an expectorant. 42. The method of claim 33 wherein the therapeutically 59. The method of claim 54 wherein one or more addi effective amount of oxybutynin or a pharmaceutically tional pharmaceutically active agents is a composition to acceptable Salt thereof is a unit dosage form which is about relieve oropharyngeal discomfort. 1.25 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 60. The method of claim 54 wherein one or more addi mg, about 4.5 mg, or about 5 mg and which is administered tional pharmaceutically active agents is a P2Y receptor b.i.d. t.i.d., or q.i.d. antagonist. 43. The method of claim 33 wherein the therapeutically 61. The method of claim 54 wherein one or more addi effective amount of oxybutynin or a pharmaceutically tional pharmaceutically active agents is a non-steroidal acceptable Salt thereof is a unit dosage form which is about anti-inflammatory agent. 2.5 mg and which is administered b.i.d. 62. The method of claim 54 wherein one or more addi 44. The method of claim 33 wherein the therapeutically tional pharmaceutically active agents is a leukotriene effective amount of oxybutynin or a pharmaceutically antagonist. acceptable Salt thereof is a unit dosage form which is about 63. The method of claim 54 wherein one or more addi 5 mg and which is administered b.i.e. tional pharmaceutically active agents is a Syk kinase inhibi 45. The method of claim 33 wherein the therapeutically tOr. effective amount of desloratadine or a pharmaceutically 64. The method of claim 54 wherein one or more addi acceptable salt thereof is a unit dosage form in a range from tional pharmaceutically active agents is a 5-lipoxygenase about 1.25 mg to about 45 mg administered q.d. inhibitor. US 2006/01 10449 A1 May 25, 2006

65. A method for treating a skin disorder in a patient 71. The formulation of claim 68 wherein one or more Suffering therefrom comprising administering a therapeuti additional pharmaceutically active agents is a corticosteroid. cally effective amount of oxybutynin or a pharmaceutically 72. The formulation of claim 68 wherein one or more acceptable salt thereof in combination with a therapeutically additional pharmaceutically active agents is an expectorant. effective amount of desloratadine or a pharmaceutically 73. The formulation of claim 68 wherein one or more acceptable salt thereof. additional pharmaceutically active agents is a composition 66. A method for treating allergic conjunctivitis in a to relieve oropharyngeal discomfort. patient Suffering therefrom comprising administering a 74. The formulation of claim 68 wherein one or more therapeutically effective amount of oxybutynin or a phar additional pharmaceutically active agents is a P2Y receptor maceutically acceptable salt thereof in combination with a antagonist. therapeutically effective amount of desloratadine or a phar 75. The formulation of claim 68 wherein one or more maceutically acceptable salt thereof. additional pharmaceutically active agents is a non-steroidal 67. A formulation for the treatment of anterior rhinorrhea anti-inflammatory agent. comprising a therapeutically effective amount of oxybutynin 76. The formulation of claim 68 wherein one or more or a pharmaceutically acceptable salt thereof in combination additional pharmaceutically active agents is a leukotriene with a therapeutically effective amount of desloratadine or a antagonist. pharmaceutically acceptable salt thereof. 77. The formulation of claim 68 wherein one or more 68. The formulation of claim 67 further comprising a additional pharmaceutically active agents is a Syk kinase second pharmaceutically active agent. inhibitor. 69. The formulation of claim 68 wherein one or more 78. The formulation of claim 68 wherein one or more additional pharmaceutically active agents is another antihis additional pharmaceutically active agents is a 5-lipoxyge tamine. nase inhibitor. 70. The formulation of claim 68 wherein one or more additional pharmaceutically active agents is a decongestant.