US 201500.94266A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2015/0094266 A1 Di Fulvio et al. (43) Pub. Date: Apr. 2, 2015 (54) XYLOGLUCAN AND PROTEIN (30) Foreign Application Priority Data COMPOSITIONS FOR THE TREATMENT OF INTESTINAL DISORDERS Jun. 11, 2013 (IT) .......................... MI2013A000.960 Apr. 15, 2014 (IT) .......................... MI2014AO00705 (71) Applicant: Novintethical Pharma, SA, Lugano Publication Classification (CH) (51) Int. Cl. (72) Inventors: Marco Di Fulvio, Soriano nel Cimino A61 K 38/39 (2006.01) (IT); Miguel Angel Alonso, Barcelona A61 K 38/16 (2006.01) (ES); Michele Giuseppe Di Schiena, 4. #% § Robecco sul Naviglio (IT) A61 K 45/06 (2006 oil (52) U.S. CI. (73) Assignee:- - Sºmee e Pharma, SA, Lugano CPC ...............(2013.01); A61K 38/39 A61K (2013.01); 45/06 (2013.01); A61K3I/716 A61 K (CH) 31/732 (2013.01); A61K 38/168 (2013.01) USPC ......................... 514/13.2; 514/17.2, 514/21.2 (21) Appl. No.: 14/566,546 (57) ABSTRACT Compositions include synergistic combinations of xyloglu cans and vegetable or animal proteins that are useful in the (22) Filed: Dec. 10, 2014 treatment of intestinal disorders or of disorders originating from the intestinal system and transferred to other systems, such as the genitourinary system. The compositions include Related U.S. Application Data xyloglucans or an extract containing xyloglucans, and one or more animal or vegetable proteins. Methods for the treatment (63) Continuation-in-part of application No. 14/092,365, or prevention of intestinal disorders are provided, including filed on Nov. 27, 2013. prevention of diarrhoea. Patent Application Publication Apr. 2, 2015 Sheet 1 of 2 US 2015/0094.266 A1 FIG. I. Patent Application Publication Apr. 2, 2015 Sheet 2 of 2 US 2015/0094.266 A1 *: p-0.001 from vehicle #: p-0.05 from CT CT FIG. 2 US 2015/0094.266 A1 Apr. 2, 2015 XYLOGLUCAN AND PROTEIN [0011] A composition for use in the prevention and treat COMPOSITIONS FOR THE TREATMENT OF ment of intestinal disorders or of disorders originating in the INTESTINAL DISORDERS intestinal system and transferred to other systems, is pro vided, said composition containing xyloglucans or extracts CROSS-REFERENCE TO RELATED containing xyloglucans, and at least one animal or vegetable APPLICATIONS protein. One preferred protein is gelatin. [0001] This is a continuation-in-part of co-pending U.S. [0012] A method for prevention or treatment of intestinal application Ser. No. 14/092,365, filed Nov. 27, 2013, which disorders or of disorders originating in the intestinal system claims priority to Italian Application No. MI2013A000960, and transferred to other systems, is provided, said method filed Jun. 11, 2013. The present application also claims pri comprising the steps of providing a composition comprising ority to Italian Application No. MI2014AO00705, filed Apr. xyloglucans or extracts containing xyloglucans, and at least 15, 2014. Each of the foregoing applications are hereby incor one animal or vegetable protein; and administering an effec porated by reference herein in their entirety. tive amount of the composition to a mammal in need thereof, said mammal having an intestinal disorder or a disorder origi FIELD OF THE INVENTION nating in the gastro-intestinal system and transferred to other systems. [0002] The invention refers to combinations that include [0013] In a further embodiment, a method for the preven synergistic combinations of xyloglucans and animal or veg tion of diarrhoea is provided, comprising the steps of pro etable proteins and to compositions for the treatment of intes viding a composition comprising xyloglucans or extracts tinal disorders, in particular diarrhoeal diseases of various containing xyloglucans, and a gelatin; and orally administer origin. ing an effective amount of the composition to a mammal in need thereof, whereby diarrhoea, or symptoms thereof, are BACKGROUND prevented. [0003] Diarrhoea is an often debilitating and dangerous symptom of many gastrointestinal disorders, especially in BRIEF DESCRIPTION OF THE DRAWINGS children and the elderly. Acute diarrhoea is primarily caused by intestinal infections, but may also be due to the use of [0014] FIG. 1 depicts the difference in water secretion in drugs, to radiation treatments and to other pathological con isolated intestinal jejunal loops 2 hrs after cholera toxin (CT) ditions (diverticulitis, poisoning by heavy metals, intestinal challenge in anesthetized rats, where either xyloglucan (XG) ischemia, allergies or intolerances). or a combination of xyloglucan (XG) and gelatin (P) were [0004] Acute diarrhoea due to infection is a serious prob orally administered 6 hrs before CT challenge. lem in developing countries as it is believed to cause the death [0015] FIG. 2 depicts the difference in water secretion in of at least 4 million children less than 5 years old annually. isolated intestinal jejunal loops 2 hrs after cholera toxin (CT) [0005] Chronic diarrhoea is most often caused by irritable challenge in anesthetized rats, where either gelatin (Gel) was bowel syndrome, coeliac disease, or inflammatory bowel dis orally administered 6 hrs before CT challenge, or a combina eases (e.g., Crohn’s disease, ulcerative colitis). tion of xyloglucan and gelatin (XG-Gel) was orally adminis [0006] In the light of the various etiologies, different thera tered 12 hrs before CT challenge. peutic options are available that are based on the administra tion of antibiotics/antibacterial agents, antispasmodic/anti DETAILED DESCRIPTION cholinergic agents, probiotics, and opioid receptor agonists. [0016] Surprisingly, it has now been found that combina Some of these treatments must however be used with great tions of xyloglucans with vegetable or animal proteins com caution as they do not act on the disease’s causal process. patible with oral administration in humans are particularly [0007] To overcome these negative effects, tannins com effective in the treatment and prevention of diarrhoea and plexed with animal proteins and gelatins, in particular with other infectious and/or inflammatory intestinal disorders. bovine gelatin, albumin, casein, and ovalbumin have long Xyloglucans are believed to have a film-forming effect on been proposed. intestinal mucosa that can decrease the permeability of the [0008] The use of such complexes in the treatment, for tight junctions of the intestinal mucosa and therefore impede example, of diarrhoea in its various forms is described in EP the entry of the pathogens responsible for acute intestinal 1764105, EP 2526939, EP 2361623 and US 20090062191. infections. The film-forming effect is not affected by pH Gelatin tannate has long been commercially available in cer changes. tain compositions or as a medical device for the treatment of [0017] In a principal embodiment the invention therefore acute diarrhoea. provides pharmaceutical compositions that have, as active [0009] Thus there arises the need for further therapeutic ingredients, xyloglucans or extracts that contain them incom treatments capable of replacing or being administered along bination with vegetable or animal proteins, in addition to side the ones available currently. suitable excipients, and other optional active ingredients. In an embodiment, the compositions are useful for the preven SUMMARY OF THE INVENTION tion and treatment of intestinal and genitourinary disorders. [0010] In one embodiment, the invention provides pharma [0018] Xyloglucans are molecules composed of a linear ceutical compositions comprising, as active ingredients, skeleton of fl-1,4-glucans with short lateral branches. These xyloglucans or xyloglucan-containing extracts and animal or branches can bind to one another (and other polar, hydrophilic vegetable proteins, combined with suitable excipients and molecules) due to xylose bonded to oxygen at the 6-position possibly with other active ingredients useful for the treatment of the sugar. These branched side chains may also contain of intestinal disorders, in particular diarrhoeal diseases. other sugars such as arabinose and fucose. US 2015/0094.266 A1 Apr. 2, 2015 [0019] Xyloglucans belong to the hemicellulose family ably between about 10 mg/dose and about 100 mg/dose. The associated with the cellulose within the cell wall of higher total daily dose of xyloglucan can be about 400 mg to about plants. A particularly rich source of xyloglucans is the seed of 800 mg. the tamarind (Tamarindus indica), a tropical tree native to [0029] The protein, in particular gelatin, may be adminis East Africa. tered orally at doses between about 10 mg/dose and about [0020) Extracts of tamarind seeds rich in xyloglucans are 3000 mg/dose, preferably between about 50 mg/dose and known and have been used in the medical field mainly as about 500 mg/dose. viscosifying agents in ophthalmic compositions or uses (U.S. [0030] The invention’s compositions are useful for the Pat. No. 6,056,950), mucoadhesive agents (WO2006/ treatment and prevention of intestinal disorders and in any 131262), tear substitutes (WO2009/044423), anti-infective case of disorders that originate in the intestinal system and are agents (WO2011/147767) and anti-inflammatory agents transferred to other systems, such as the genitourinary sys (WO2011/147768). tem. In fact, it is known that Gram-negative bacteria present [0021] The xyloglucans extracted from Tamarindus indica in the intestine, in particular Escherichia coli, can proliferate are commercially available, for example from Indena (Italy) in this organ