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WO 2014/067008 Al 8 May 2014 (08.05.2014) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/067008 Al 8 May 2014 (08.05.2014) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/536 (2006.01) A61P 1/10 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/365 (2006.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/CA20 13/050829 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 3 1 October 2013 (3 1.10.201 3) TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 13/664,762 31 October 20 12 (3 1.10.20 12) US UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventors; and EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicants : LAMB, G. Blair [CA/CA]; 6432 Chelsea MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Road., Kilbride, Ontario L7P 0M9 (CA). FAIRLEY, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Grant, D. [CA/CA]; 2815 Radisson Ave., Windsor, KM, ML, MR, NE, SN, TD, TG). Ontario N9E 1Y2 (CA). Declarations under Rule 4.17 : (74) Agents: TANDAN, Susan et al; Gowling Lafleur Hender — as to the identity of the inventor (Rule 4.1 7(Ϊ)) son LLP, One Main Street West, Hamilton, Ontario L8P 4Z5 (CA). — of inventorship (Rule 4.17(iv)) (81) Designated States (unless otherwise indicated, for every Published: kind of national protection available): AE, AG, AL, AM, — with international search report (Art. 21(3)) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 0 o0 o o (54) Title: THERAPY FOR CONSTIPATION (57) Abstract: The current application relates to the use of lipase inhibitors for treating acute, sub-acute, or chronic constipation res - ulting from opiod administration, dehydration, lazy bowel, paralytic bowel, menstruation, bowel resection, and bedridden. Preferred lipase inhibor is selected from orlistat, cetilistat, saponins, cioscin, escins, cyclocanosides, polyphenols, terpenes, and pancreatic lipase inhibitors. The lipase inhibitor can be administered topically, ΓΜ , Γ , SC, or mucosally. THERAPY FOR CONSTIPATION FIELD OF THE INVENTION [001] The present invention relates to methods and compositions for the treatment of bowel disorders, especially constipation associated with the administration of painkillers. BACKGROUND OF THE INVENTION [002] Constipation is a frequent side effect of many conditions and medications. For example, opioids may lead to constipation since these agents decrease peristaltic activity in the gastrointestinal (Gl) tract. Because of the mechanisms involved in opioid- induced constipation, some treatments that may be applicable for common, functional constipation are inappropriate for ambulatory-care patients prescribed opioid analgesics. Also in these patients, the distress of constipation may add to the discomfort already present from pain, and they might decrease or discontinue the opioid to avoid constipation. Therefore motivating such patients to comply with their opioid therapy also requires an approach for managing constipation [003] Constipation is broadly defined as the passage of hard, dry stools less frequently than the patient's usual bowel-habit pattern. [004] Constipation resulting from opioid use is the most common component of a more general condition called opioid-induced bowel dysfunction, OBD. Signs and symptoms of OBD include dry hard stools, straining during evacuation, incomplete evacuation, bloating, abdominal distension, and retention of the contents of the bowel. [005] Bulk-forming laxatives are typically not appropriate in opioid-induced constipation because peristalsis is inhibited in these patients so stool softener and bowel stimulants are often used. Some patients may take mild over-the-counter bulk laxatives and fail to mention this to their physician. This can result in painful, colic-like symptoms. [006] Attempts have been made to solve the problem of opioid induced constipation. For example, U.S. patent no. 6982283 discloses a method for treating drug-induced constipation that comprises administering an effective amount of 15-keto-prostaglaindin compound to a subject suffering from drug-induced constipation or a subject having a strong possibility of suffering from it. U.S. patent no. 8278323 describes certain quinolizidine and octahydropyridopyrazine compounds, pharmaceutical compositions, and methods of their use as opioid receptor antagonists for the treatment of opioid induced constipation. The use of an opioid antagonist effectively reduces the amount of physiologically available opioid. However, the dose that leads to constipation is approximately four-fold less than the dose required for an analgesic response. SUMMARY OF THE INVENTION [007] In one aspect of the invention, there is provided a method of treating acute, sub acute or chronic constipation in a patient having a condition requiring such treatment, comprising the administration of a lipase inhibitor. [008] J n one preferred embodiment the lipase inhibitor is selected from the group consisting of: orlistat, atl-962 (cetalstat) and gt389-255. [009] In another preferred embodiment, the lipase is naturally and comprise saponins, platycodin saponins, scabio saponins, sessiloside and chiisanoside, chikusetsusaponins, dioscin and derivatives, escins, teasaponins, cyclocariosides, polyphenoics, oolong tea polyphenols, polyphenol rich extracts including grape seed extract, nelumbo nucifera extract, salacia reticulata hot water extract, peanut shell extract, mangifera indica leaf and steam bark extracts, ct-ii extracts, terpenes including carnosic acid, crocin and crocetin and pancreatic lipase inhibitors from microbial sources such as lipstatin. [0010] In another embodiment the condition is selected from the group consisting of opiod administration, dehydration, lazy bowel, paralytic bowel, menstruation related constipation, bowel resection and being bedridden. [001 1] In a further embodiment the lipase inhibtor is administered topicalll, IM, IV, SC, or mucosally. [0012] In yet another embodiment the preferred lipase inhibitor is orlistat or cetalstat [0013] In another aspect the invention is a method for treating chronic pain comprising administering a pain medication in combination with a lipase inhibitor. [0014] In another aspect of the invention there is provided a composition for the treatment of chronic constipation comprising 30 to 150 mg of a lipase inhibitor. [0015] In a preferred embodiment the composition is formulated for oral administration. [0016] In another embodiment the composition is in the form of a tablet, lozenge, pill, troche, capsule, soft-gel capsule, sachet or other combining vehicle, elixir, powder, including lyophilised powder, solution, granule, suspension, emulsion, syrup or tincture. Slow-release, or delayed-release, forms may also be prepared, for example in the form of coated particles, multi-layer tablets or microgranules.. [0017] In another embodiment the composition is provided in a compliance-enhancing blister pack DETAILED DESCRIPION [0018] The present invention provides a novel method of treatment for constipation. This novel type of treatment has a much improved therapeutic result for those who are suffering chronic constipation related to the use of opiates, other pain-killers, antidepressants and other situations such as paralysis, infection, cancer, radiation therapy and dehydration. [0019] Lipase inhibitors are typically used for aiding weight loss. The active ingredient in some of the prescription products such as Xenical and Alii is orlistat. Other lipase inhibitors that function in the same way are herbal or are naturally sourced. [0020] Lipase inhibitors block the action of the two compounds found in the digestive juices of the stomach and small intestine. These enzymes are known to break down the fat molecules that are in our diet. Without the action of these compounds, the molecules of fat are too large to be digested by our stomach and then to enter our bloodstream. Lipase inhibitors essentially keep the fat molecule intact and undigested thus instead of becoming part of the body, the fat is excreted as waste through the bowels. [0021] One of the known side effects of lipase inhibitors like Xenical is that the patient may experience loose bowels including episodes of diarrhea. This is of course a negative side effect for those persons who are taking the medication for weight-loss. [0022] For those persons facing a problem of chronic constipation, the use of lipase inhibitors offers a new treatment alternative. The lipase inhibitors that block the production of pancreatic and gastric enzymes that break down fat provided to treat chronic constipation is a novel use for these compounds. [0023] The present invention provides a novel approach to the provision of such antigens and immunogens by inactivation of purified RS virus. [0024] According to the present invention synthetic, chemical or naturally
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