US 20080038336A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0038336A1 Esquea et al. (43) Pub. Date: Feb. 14, 2008 (54) SOLID PHARMACEUTICAL COMPOSITION Publication Classification CONTAINING ACOMBINATION OF AN INTESTINAL MOTILITY REGULATING (51) Int. Cl. AGENT AND AN ANTFLATULENT A69/20 (2006.01) A6II 3/695 (2006.01) (76) Inventors: Marta Luz Torres Esquea, Barranquilla (CO); Raul Bello (52) U.S. Cl. .......................................... 424/464; 514/63 Vergara, Barranquilla (CO) (57) ABSTRACT Correspondence Address: This invention relates to a solid pharmaceutical composition Isaac A. Angres that include a regulating agent of digestive and/or intestinal Suite 301, 2001 Jefferson Davis Highway motility which has an agonist effect on peripheral u, 6 and Arlington, VA 22202 Kopiate receptors; and an antiflatulent for the treatment and regulation of intestinal motility and flatulence in mammals. (21) Appl. No.: 11/527,501 More in particularly, the pharmaceutical composition (22) Filed: Sep. 27, 2006 includes: (a) at least a regulating agent of intestinal motility Such as trimebutine; (b) at least an antiflatulent such as (30) Foreign Application Priority Data simethicone; (c) at least a flowability promoter; (d) one or more lubricant; (e) at least an extender/diluent; (f) at least a Aug. 10, 2006 (CO) ................................... O6-078456 disintegrant; and, (g) at least a binder. US 2008/0038336 A1 Feb. 14, 2008 SOLID PHARMACEUTICAL COMPOSITION on the location and severity of the abnormalities. Heartburn CONTAINING A COMBINATION OF AN and constipation are common symptoms of motility disor INTESTINAL MOTILITY REGULATING ders. Other frequent complaints include: chronic Vomiting, AGENT AND AN ANTIFLATULENT nausea, cramping, bloating, abdominal distention and diar rhea after eating. 0007. The most common motility disturbance is a 0001. This application claims priority from Colombian troublesome but relatively benign condition called “irritable Patent Application No. 06-078456 filed Aug. 10, 2006, bowel syndrome’ (IBS). It accounts for 50 percent of all which is hereby incorporated in its entirety by reference patients who see a GI specialist. herein. 0008. The primary function of the gastrointestinal tract is to absorb ingested nutrients. This is achieved when transit FIELD OF THE INVENTION along the esophagus and gastrointestinal tract is at a rate which facilitates optimal digestion and absorption of water 0002 The present invention relates to compositions and and electrolytes. Abnormal patterns in gastrointestinal motill methods for treating and/or preventing lower gastrointesti ity result in number of disorders ranging from diffuse nal (GI) disorders in mammalian patients, more particularly esophageal spasm (an esophageal obstructive disorder by for alleviating and/or preventing the lower GI symptoms dysphagia), achalasia (an obstructive disorder in which the associated with such disorders. The present invention further lower esophageal sphincter fails to relax adequately result relates to methods for preventing and/or treating functional ing in dysphagia) and pain due to functional bowel disorders bowel disorders and more particularly the invention con such as irritable bowel syndrome (IBS), non-ulcer dyspep cerns the use of trimebutine 2-dimethylamino-2-phenylbu sia, and idiopathic constipation. tyl 3,4,5-trimethoxybenzoate hydrogen maleate. Stereoiso 0009 Gastrointestinal distress presents itself as discom mers of trimebutine and metabolites thereof, in combination fort associated with an intestinal disorder by symptoms of with simethicone for preventing and/or treating functional diarrhea and flatulence or gas. Diarrhea is the abnormally bowel disorders. frequent passage of watery stool. Diarrhea may have a variety of causes including bacteria or viral induced diar BACKGROUND OF THE INVENTION rhea. Travelers diarrhea, for example, is also believed to be 0003 Healthy digestion requires coordinated movements of microbial origin. Diarrhea may also be a side effect of of the stomach and intestines to mix food with digestive drug administration, particularly antibiotics. Diarrhea may enzymes, to stir the nutrients so they approach the intestinal be induced by food intolerance which is caused by allergy or wall for absorption into the body, and to propel the intestinal the ingestion of foods that are excessively fatty, spicy, or contents through the digestive tract. The movement of the contain a high degree of fermentable carbohydrate, rough walls of the gastrointestinal (GI) tract and their contents is age or a large number of seeds. Food intolerance may also called gastrointestinal motility. Gastrointestinal motility is be brought on by a preformed toxin in the food thus causing controlled by the nerves and muscles within the gastrointes food poisoning. Other conditions and diseases can also tinal tract. cause diarrhea, and diarrhea may only be one of many 0004. The normal patterns of the nerves and muscles are symptoms associated with a major illness. influenced every day by many factors. Sleeping and waking 0010 Diarrhea is thus a symptom of an intestinal disorder changes motility, as does exercise. Emotional distress can or other bodily function and symptomatic relief can be also have profound effects on gastrointestinal motility. Even accomplished by the use of various prescription and non the food that you eat releases substances into the blood prescription products. The active ingredients in these prod which influence motility. Nerve connections between the ucts include trimebutine, loperamide, attapulgite, bismuth brain and the GI tract send messages in both directions. subsalicylate, diphenoxylate HCl, polycarbophil, calcium These modify not only GI motility, but also perceptions from polycarbophil and mixtures thereof. the gut. 0011 Flatulence or intestinal gas is another intestinal 0005 Motility disorders occur when the nerves in the disorder which contributes to gastrointestinal distress. Such gastrointestinal tract are missing, immature, or damaged by gas exists as trapped gas bubbles which manifest itself by infections or toxins. Disorders can also occur when the feelings of pain, bloating and cramping in the abdominal nerves are adversely influenced by chemical Substances aca. from inside the body (such as the chemicals released during 0012 While various products exist for treating diarrhea an inflammation caused by Crohn's disease), or outside the and gas simultaneously, no product has heretofore been body (Such as opiates given for pain). In this case, the nerves proposed for treating the combination of the symptoms of and muscles of the GI tract do not function in a strong or both diarrhea and gas which contains trimebutine in com coordinated fashion. Motility disorders may also occur when bination with simethicone. the GI muscles are diseased—either from a genetic defect 0013 Trimebutine belongs to the class of medications (such as some forms of muscular dystrophy) or an acquired called spasmolytics and it is a noncompetitive spasmolytic. disorder (such as progressive systemic sclerosis and amy Trimebutine is a prokinetic agent that acts directly on the loidosis). In this case, the coordinated contractions produced Smooth muscle of the GI tract and it is known to regulate by the GI muscles are too weak to move the intestinal abnormal intestinal activity. It is used to treat irritable bowel COntentS. syndrome (spastic colon). This condition is caused by over 0006 Symptoms soon arise when there are abnormalities active movements of the bowels. Trimebutine works by in the strength or coordination of contractions. Sometimes slowing down the movements of the bowel. The actions of the symptoms are accompanied by evidence of growth trimebutine 3,4,5-trimethoxybenzoic acid 2-(dimethy failure or tissue damage. The symptoms may vary depending lamino)-2-phenylbutylester on the gastrointestinal tract are US 2008/0038336 A1 Feb. 14, 2008 mediated via (i) an agonist effect on peripheral L. 8 and K dissolution of the antidiarrheals, antiperistaltic and hista opiate receptors and (ii) release of gastrointestinal peptides mine H2 antagonist occurs in an adverse manner. such as motilin and modulation of the release of other peptides, including vasoactive intestinal peptide, gastrin and OBJECTS OF THE INVENTION glucagon. Trimebutine accelerates gastric emptying, induces 0017. It is therefore a primary object of the present premature phase III of the migrating motor complex in the invention to provide a composition for the treatment of intestine and modulates the contractile activity of the colon. gastrointestinal distress. Recently, trimebutine has also been shown to decrease 0018. Another object of the invention is to provide a reflexes induced by distension of the gut lumen in animals pharmaceutical composition for treating gastrointestinal dis and it may therefore modulate visceral sensitivity. Clinically, tress, containing an effective amount of an antidiarrheal trimebutine has proved to be effective in the treatment of compound combined with an antiflatulent effective amount both acute and chronic abdominal pain in patients with of simethicone. 0019. A still further object of the invention is to provide functional bowel disorders, especially irritable bowel syn a pharmaceutical composition comprising: (a) an effective drome, at doses ranging from 300 to 600 mg/day. It is also amount of an intestinal motility regulating agent which has effective in children presenting with