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(12) Patent Application Publication (10) Pub. No.: US 2006/0110449 A1 Lorber Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2006/0110449 A1 Lorber Et Al 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 cholinergic agent with a limited capacity to pass across lipid 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 nitrate, glycopyrrolate, and atropine 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 acetylcholine 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 nicotine and muscarine, 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 acetylcholine receptor 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, pharmacology, 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 oxybutynin 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 agonists 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 glycopyrronium bromide, telenzepine, pirenzepine, mucosal glands and epithelial goblet cells in the respiratory oxybutynin, desethyloxybutynin, himbacine, AQ-RA 741, tract). Previous therapies focused on using non-sedating darifenacin, 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 salt 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 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-(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), 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,
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