Methods and Materials for Treating Pancreatic Diseases and Disorders - Patent application

Abstract

This document relates to methods and materials for treating pancreatitis (e.g., chronic pancreatitis) in a mammal (e.g., a human). For example, methods of using one or more lipase inhibitors to treat a mammal suffering from or at risk of developing pancreatitis (e.g., chronic pancreatitis) are provided.

Description

[Technical field]

[0001] Priority claim This application claims the benefit of U.S. Provisional Application Serial No. 63 / 325,680, filed March 31, 2022, the entire contents of which are incorporated herein by reference.

[0002] Technical Field This document relates to methods and materials for treating pancreatic diseases, disorders, and conditions in mammals (e.g., humans). For example, this document provides methods and materials for using one or more lipase inhibitors to treat a mammal having, or at risk of developing, one or more pancreatic diseases, disorders, and / or conditions. [Background technology]

[0003] New cases of chronic pancreatitis occur in approximately 8 per 100,000 people annually, with the disease currently affecting approximately 50 per 100,000 people in the United States (Muniraj et al., Disease-a-Month.DM (2014) 60: 530-50). Globally, pancreatitis caused 123,000 deaths in 2013, up from 83,000 in 1990 (GBD 2013 Mortality and Causes of Death, Collaborators Lancet (2014) 385: 117-71).

[0004] Postoperative pancreatic fistula occurs in 10-20% of patients after pancreatic surgery and is a significant cause of morbidity. There is no cure for postoperative pancreatic fistula. Summary of the Invention [Problem to be solved by the invention]

[0005] Provided herein are methods and materials for treating pancreatic diseases, disorders, and conditions in a mammal (e.g., a human). For example, provided herein are methods and materials for administering one or more lipase inhibitors to a mammal (e.g., a human) to treat a mammal having or at risk for developing a pancreatic disease, disorder, or condition. [Means for solving the problem]

[0006] As described herein, lipase inhibitors can be effective for treating pancreatic diseases and disorders (e.g., pancreatic diseases and disorders associated with adhesions and / or fibrosis). In some embodiments, one or more lipase inhibitors can be used to reduce or slow the progression of pancreatitis (e.g., chronic pancreatitis), pancreatic cancer, and / or postoperative pancreatic fistula in a mammal (e.g., human). In some embodiments, one or more lipase inhibitors can be used to reduce the risk of developing pancreatitis (e.g., chronic pancreatitis), pancreatic cancer, and / or postoperative pancreatic fistula in a mammal (e.g., human). For example, as demonstrated herein, one or more lipase inhibitors can be used to reduce adhesions in the pancreas (e.g., adhesions between pancreatic apical cells and / or endothelial cells) and / or adhesions in the peritoneal cavity, and / or to reduce fibrosis in the pancreas and tissues surrounding the pancreas and / or in the peritoneal cavity.

[0007] In general, one aspect of the present disclosure features a method for reducing adhesions in the pancreas and / or abdominal cavity of a mammal. The method can consist of, consist essentially of, or consist of administering a lipase inhibitor to a mammal in need thereof. The mammal can have chronic pancreatitis, pancreatic cancer, or a post-operative pancreatic fistula. The mammal can be a human. The inhibitor can be compound 767 or a pharma- ceutically acceptable salt thereof. The inhibitor can have the following structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0008] In another aspect, this document features a method for reducing pancreatic and / or intraperitoneal fibrosis in a mammal. The method can consist of, consist essentially of, or consist of administering a lipase inhibitor to a mammal in need thereof. The mammal can have chronic pancreatitis, pancreatic cancer, or a post-operative pancreatic fistula. The mammal can be a human. The inhibitor can be compound 767 or a pharma- ceutically acceptable salt thereof. The inhibitor can have the following structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0009] In another aspect, this document features a method for reducing inflammation in the pancreas and / or intraperitoneal cavity of a mammal. The method can consist of, consist essentially of, or consist of administering a lipase inhibitor to a mammal in need thereof. The mammal can have chronic pancreatitis, pancreatic cancer, or a post-operative pancreatic fistula. The mammal can be a human. The inhibitor can be compound 767 or a pharma- ceutically acceptable salt thereof. The inhibitor can have the following structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0010] In another aspect, this document features the use of a composition comprising a lipase inhibitor to reduce adhesions and / or fibrosis in the pancreas and / or abdominal cavity of a mammal. The mammal can be a human. The inhibitor can be compound 767 or a pharma- ceutically acceptable salt thereof. The inhibitor can have the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0011] In another aspect, this document features a lipase inhibitor for use as a medicament for reducing adhesions and / or fibrosis in the pancreas and / or abdominal cavity of a mammal. The mammal can be a human. The inhibitor can be compound 767 or a pharma- ceutically acceptable salt thereof. The inhibitor can have the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0012] In another aspect, this document features a lipase inhibitor for use in reducing adhesions and / or fibrosis in the pancreas and / or peritoneal cavity of a mammal. The mammal can be a human. The inhibitor can be compound 767 or a pharma- ceutically acceptable salt thereof. The inhibitor can have the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Although the present invention can be practiced using methods and materials similar or equivalent to those described herein, suitable methods and materials are described below. All publications, patent applications, patents, and other documents described herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0014] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will become apparent from the description and drawings, and from the claims. [Brief description of the drawings]

[0015] [Figure 1]Figure 1, panels A-C, show representative images of the peritoneal cavity of a control mouse (Figure 1, panel A) and a mouse treated with glyceryl trilinoleate (GTL; Figure 1, panels B and C). Mice treated with GTL had nodules and strands (arrows).

[0016] [Diagram 2] Figure 2, panels A and B, are representative images of the pancreas duodenum and spleen excised en bloc from a control mouse (Figure 2, panel A) and a mouse treated with GTL (Figure 2, panel B). In the GTL-treated mouse, nodules and strands (arrows) were observed in the interorgan plane.

[0017] [Diagram 3] Figure 3 includes representative images of morphological evaluation of the spleen of mice administered GTL. Staining shows an extensive fibrotic appearance in the area between the pancreas and the spleen.

[0018] [Figure 4] Figure 4, panels A–C, contain representative images of nodules from mice treated with GTL stained with HE (Figure 4, panel A), von Kossa stain (Figure 4, panel B), or Sirius red (Figure 4, panel C). In mice administered GTL, fibrils surround partially hydrolyzed lipids.

[0019] [Diagram 5] Panels A-B of Figure 5 contain representative images of nodules from GTL-treated mice stained with von Kossa stain (Panel A of Figure 5) or Masson's trichrome stain (Panel B of Figure 5). In GTL-treated mice, fibrosis surrounds partially hydrolyzed lipids.

[0020] [Figure 6]Panels A-B of Figure 6 contain representative images of the abdominal cavity (upper panels) and surrounding pancreatic (lower panels) organs of mice treated with GTL alone (Panel A of Figure 6) and with both GTL and 767 (Panel B of Figure 6). Nodules were clearly observed in the GTL-treated group (Figure 6, Panel A, arrows). Mice treated with both GTL and 767 had no significant nodules in the abdominal cavity or near the pancreas.

[0021] [Figure 7] Figure 7, Panels A-B, are graphs showing the unsaturated fatty acid (UFA) composition of the postoperative pancreatic harvest. The black dots represent the early harvest. Figure 7, Panel B, shows the time course of change in non-esterified fatty acid (NEFA) composition and concentration in micromolar (μM) in the harvest after pancreatic surgery. The black dots represent the highest concentration of NEFA. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Detailed Description of the Invention The present disclosure provides methods and materials for treating pancreatic diseases, disorders, and conditions. For example, the present disclosure provides methods and materials for administering one or more lipase inhibitors to a mammal (e.g., a human) having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions to treat the mammal. In some embodiments, one or more lipase inhibitors can be used to reduce or slow the progression of pancreatitis (e.g., chronic pancreatitis), pancreatic cancer, and / or postoperative pancreatic fistula. For example, one or more lipase inhibitors can be administered to a mammal having pancreatitis (e.g., chronic pancreatitis), pancreatic cancer, and / or postoperative pancreatic fistula to reduce or slow the progression of pancreatitis (e.g., chronic pancreatitis), pancreatic cancer, and / or postoperative pancreatic fistula. In some cases, one or more lipase inhibitors can be used to reduce the risk of developing pancreatitis (e.g., chronic pancreatitis), pancreatic cancer, and / or postoperative pancreatic fistula. For example, one or more lipase inhibitors can be administered to a mammal at risk of developing pancreatitis to reduce the risk of developing pancreatitis (e.g., chronic pancreatitis), pancreatic cancer, and / or post-operative pancreatic fistula.

[0023] The methods provided herein can be used to treat any suitable pancreatic disease, disorder, or condition. Examples of pancreatic diseases, disorders, and conditions that can be treated as described herein include, but are not limited to, pancreatitis, pancreatic cancer, postoperative pancreatic fistula, and cystic lesions of the pancreas. In some embodiments, the pancreatic disease, disorder, or condition is not acute pancreatitis. When treating pancreatitis as described herein, the pancreatitis can be chronic pancreatitis. Chronic pancreatitis can result from heavy alcohol use and / or develop from acute pancreatitis. When treating pancreatic cancer as described herein, the pancreatic cancer can be any stage of pancreatic cancer. When treating pancreatic cancer as described herein, in some cases, the pancreatic cancer can include fibrotic stroma.

[0024] In some cases, one or more (e.g., one, two, three, four, or more) lipase inhibitors can be used to reduce the severity of one or more symptoms of pancreatitis (e.g., chronic pancreatitis). For example, one or more lipase inhibitors can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having or at risk of developing pancreatitis, such as chronic pancreatitis) to reduce the severity of one or more symptoms of pancreatitis. Examples of symptoms of pancreatitis (e.g., chronic pancreatitis) include, but are not limited to, epigastric pain, abdominal pain that feels worse after eating, weight loss without effort, and steatorrhea. In some embodiments, the methods and materials described herein can be effective in reducing the severity of one or more symptoms of pancreatitis (e.g., chronic pancreatitis) in a mammal having pancreatitis (e.g., chronic pancreatitis) by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more.

[0025] In some cases, one or more (e.g., one, two, three, four, or more) lipase inhibitors can be used to reduce or eliminate inflammation in the pancreas and / or peritoneal cavity of a mammal (e.g., a human). For example, one or more lipase inhibitors can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions) to reduce or eliminate inflammation in the pancreas and / or peritoneal cavity of the mammal. In some embodiments, the methods and materials described herein can be effective to reduce inflammation in the pancreas and / or peritoneal cavity of a mammal having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.

[0026] In some cases, one or more (e.g., one, two, three, four or more) lipase inhibitors can be used to reduce or slow the progression of pancreatitis. For example, one or more lipase inhibitors can be administered to a mammal in need thereof (e.g., a human with pancreatitis, such as chronic pancreatitis) to reduce or slow the progression of pancreatitis in the mammal. In some embodiments, the methods and materials described herein can be effective to reduce or slow the progression of pancreatitis in a mammal with pancreatitis (e.g., chronic pancreatitis) by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95 or more. In some embodiments, the methods and materials described herein may be effective to reduce or slow the progression of pancreatitis in a mammal with pancreatitis (e.g., chronic pancreatitis), for example, by at least 6 months (e.g., about 6 months, about 8 months, about 10 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 4 years, about 5 years, or more).

[0027] In some cases, one or more (e.g., one, two, three, four, or more) lipase inhibitors can be used to delay or prevent the onset of pancreatitis. For example, one or more lipase inhibitors can be administered to a mammal (e.g., a human) in need thereof (e.g., a human at risk of developing pancreatitis, such as chronic pancreatitis) to delay or prevent the onset of pancreatitis in the mammal. In some embodiments, the methods and materials described herein can be effective to delay the onset of pancreatitis in a mammal at risk of developing pancreatitis (e.g., chronic pancreatitis) by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more. In some embodiments, the methods and materials described herein can be effective to delay the onset of pancreatitis in a mammal at risk of developing pancreatitis (e.g., chronic pancreatitis), for example, by at least 6 months (e.g., about 6 months, about 8 months, about 10 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 4 years, about 5 years, or more).

[0028] In some cases, one or more (e.g., one, two, three, four, or more) lipase inhibitors can be used to reduce or eliminate adhesions in the pancreas (e.g., adhesions between pancreatic apical cells and / or endothelial cells) and / or adhesions in the peritoneal cavity. For example, one or more lipase inhibitors can be administered to a mammal in need thereof (e.g., a human having one or more pancreatic diseases, disorders, and / or conditions) to reduce or eliminate adhesions in the pancreas (e.g., adhesions between pancreatic apical cells and / or endothelial cells) and / or adhesions in the peritoneal cavity of the mammal. In some embodiments, the methods and materials described herein can be effective to reduce adhesions in the pancreas (e.g., adhesions between pancreatic apical cells and / or endothelial cells) and / or adhesions in the peritoneal cavity of a mammal having one or more pancreatic diseases, disorders, and / or conditions by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.

[0029] In some cases, one or more (e.g., one, two, three, four, or more) lipase inhibitors can be used to delay or prevent the development of adhesions in the pancreas (e.g., adhesions between pancreatic apical cells and / or endothelial cells) and / or adhesions in the peritoneal cavity. For example, one or more lipase inhibitors can be administered to a mammal (e.g., a human) in need thereof (e.g., a human at risk of developing one or more pancreatic diseases, disorders, and / or conditions) to delay or prevent the development of adhesions in the pancreas (e.g., adhesions between pancreatic apical cells and / or endothelial cells) and / or adhesions in the peritoneal cavity of the mammal. In some embodiments, the methods and materials described herein can be effective to delay the onset of adhesions in the pancreas (e.g., adhesions between pancreatic apical cells and / or endothelial cells) and / or peritoneal cavity of a mammal at risk for developing one or more pancreatic diseases, disorders, and / or conditions, for example, by 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In some embodiments, the methods and materials described herein can be effective to delay the onset of adhesions in the pancreas (e.g., adhesions between pancreatic apical cells and / or endothelial cells) and / or peritoneal cavity of a mammal at risk for developing one or more pancreatic diseases, disorders, and / or conditions, for example, by at least 6 months (e.g., about 6 months, about 8 months, about 10 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 4 years, about 5 years, or more).

[0030] In some cases, one or more (e.g., one, two, three, four, or more) lipase inhibitors can be used to reduce or eliminate fibrosis in the pancreas and / or peritoneal cavity. For example, one or more lipase inhibitors can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having one or more pancreatic diseases, disorders, and / or conditions) to reduce or eliminate fibrosis in the pancreas and / or peritoneal cavity of the mammal. In some embodiments, the methods and materials described herein can be effective to reduce fibrosis in the pancreas and / or peritoneal cavity of a mammal having one or more pancreatic diseases, disorders, and / or conditions by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.

[0031] In some cases, one or more (e.g., one, two, three, four, or more) lipase inhibitors can be used to delay or prevent the onset of fibrosis in the pancreas and / or peritoneal cavity. For example, one or more lipase inhibitors can be administered to a mammal (e.g., a human) in need thereof (e.g., a human at risk of developing one or more pancreatic diseases, disorders, and / or conditions) to delay or prevent the onset of fibrosis in the pancreas and / or peritoneal cavity of the mammal. In some embodiments, the methods and materials described herein can be effective to delay the onset of fibrosis in the pancreas and / or peritoneal cavity of a mammal at risk of developing one or more pancreatic diseases, disorders, and / or conditions by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In some embodiments, the methods and materials described herein may be effective to delay the onset of fibrosis in the pancreas and / or abdominal cavity of a mammal at risk for developing one or more pancreatic diseases, disorders, and / or conditions, for at least 6 months (e.g., about 6 months, about 8 months, about 10 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 4 years, about 5 years, or more).

[0032] In some cases, one or more (e.g., one, two, three, four, or more) lipase inhibitors can be used to improve the survival of a mammal. For example, one or more lipase inhibitors can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having one or more pancreatic diseases, disorders, and / or conditions) to improve the survival of the mammal. In some embodiments, the methods and materials described herein can be effective to improve the survival of a mammal having one or more pancreatic diseases, disorders, and / or conditions by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In some embodiments, the methods and materials described herein can be effective to improve the survival of a mammal having one or more pancreatic diseases, disorders, and / or conditions by, for example, at least 6 months (e.g., about 6 months, about 8 months, about 10 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 4 years, about 5 years, or more).

[0033] Any type of mammal having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions can be treated as described herein. Examples of mammals having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions and that can be treated as described herein include, but are not limited to, humans and non-human primates such as monkeys, dogs, cats, horses, cows, pigs, sheep, rabbits, mice, and rats.

[0034] In some embodiments, the methods described herein can include identifying a mammal (e.g., a human) as having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions. Any suitable method can be used to identify a mammal as having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions. For example, abdominal ultrasound, computed tomography (CT) scan, and / or blood tests (e.g., for increased amylase and / or lipase, such as levels above about 3 times the upper limit of normal) can be used to identify a human or other mammal as having or at risk of developing pancreatitis (e.g., chronic pancreatitis). For example, imaging tests (e.g., CT) scans, magnetic resonance imaging (MRI) scans, positron emission tomography (PET) scans, endoscopic ultrasound (EUS), pancreatic tissue biopsies, and / or blood tests (e.g., for pancreatic tumor markers such as CA19-9) can be used to identify a human or other mammal as having or at risk of developing pancreatic cancer. For example, amylase levels (e.g., serum amylase levels) and / or imaging tests (e.g., contrast-enhanced CT and endoscopic retrograde cholangiopancreatography (ERCP)) can be used to identify whether a human or other mammal has or is at risk for developing one or more pancreatic fistulas.

[0035] A mammal (e.g., a human) having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions can be administered or instructed to self-administer any one or more (e.g., one, two, three, four, or more) lipase inhibitors. The lipase inhibitor can inhibit any suitable lipase (e.g., pancreatic lipase). For example, the lipase inhibitor can inhibit pancreatic lipase (PL) polypeptide and / or pancreatic lipase-related protein 2 polypeptide (PLRP2). In some cases, the lipase inhibitor can reduce or eliminate the ability of a lipase to hydrolyze one or more lipids. The lipase inhibitor that can be used as described herein can inhibit any suitable lipase that can hydrolyze one or more lipids. In some embodiments, lipase inhibitors that can be used to treat a mammal (e.g., a human) having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions as described herein can inhibit lipases that can hydrolyze triglycerides (e.g., neutral triglycerides). Examples of lipids that can be hydrolyzed by lipases that can be inhibited by lipase inhibitors that can be used to treat a mammal (e.g., a human) having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions as described herein include, but are not limited to, linolein (e.g., glyceryl trilinoleate). Lipase inhibitors can inhibit lipase polypeptide activity or lipase polypeptide expression. Examples of compounds that can reduce or eliminate lipase polypeptide activity include, but are not limited to, antibodies (e.g., neutralizing antibodies) and small molecules that target (e.g., bind to) lipases (e.g., 767). When the compound that can reduce or eliminate the polypeptide activity of a lipase is a small molecule that targets (e.g., binds to) a lipase, the small molecule can be in the form of a salt (e.g., a pharma- ceutically acceptable salt).Examples of compounds that can reduce or eliminate lipase polypeptide expression include, but are not limited to, nucleic acid molecules (e.g., siRNA or shRNA molecules), antisense molecules, and miRNAs designed to induce RNA interference of lipase polypeptide expression. In some embodiments, a lipase inhibitor that can be used to treat one or more pancreatic diseases, disorders, and / or conditions described herein can be 767 or a pharma- ceutically acceptable salt thereof, and has the following structure: [ka] .

[0036] In some embodiments, lipase inhibitors that can be used to treat one or more pancreatic diseases, disorders, and / or conditions described herein can be as described elsewhere (see, e.g., WO2019 / 014434).

[0037] In some cases, one or more (e.g., one, two, three, four, or more) lipase inhibitors can be formulated into compositions (e.g., pharma- ceutically acceptable compositions) for administration to a mammal (e.g., a human) having, or at risk of developing, one or more pancreatic diseases, disorders, and / or conditions. For example, one or more lipase inhibitors can be formulated with one or more pharma- ceutically acceptable carriers (additives), excipients, and / or diluents.Examples of pharma- ceutically acceptable carriers, excipients, and diluents that may be used in the compositions described herein include, but are not limited to, cyclodextrins (e.g., β-cyclodextrin, such as KLEPTOSE®), dimethyl sulfoxide (DMSO), sucrose, lactose, starch (e.g., starch glycolate), cellulose, cellulose derivatives (e.g., modified cellulose, such as microcrystalline cellulose, and cellulose ethers, such as hydroxypropyl cellulose (HPC) and the cellulose ether hydroxypropyl methylcellulose (HPMC), xylitol, sorbitol, mannitol, gelatin, polymers (such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), cross-linked polyvinylpyrrolidone (crospovidone), calcined cellulose, cellulose derivatives (such as modified cellulose, such as microcrystalline cellulose, and cellulose ethers, such as hydroxypropyl cellulose (HPC) and the cellulose ether hydroxypropyl methylcellulose (HPMC)), xylitol, sorbitol, mannitol, gelatin, polymers (such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), cross-linked polyvinylpyrrolidone (crospovidone), calcined cellulose, cellulose derivatives (such as modified cellulose, such as microcrystalline cellulose, and cellulose ethers, such as hydroxypropyl cellulose (HPC ...methylcellulose (HPMC)), calcined cellulose, cellulose derivatives (such as Ingredients that may be used include, but are not limited to, carboxymethylcellulose, polyethylene-polyoxypropylene block polymers, and crosslinked sodium carboxymethylcellulose (croscarmellose sodium), titanium dioxide, azo dyes, silica gel, fumed silica, talc, magnesium carbonate, vegetable stearin, magnesium stearate, aluminum stearate, stearic acid, antioxidants (e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium), citric acid, sodium citrate, parabens (e.g., methylparaben and propylparaben), petrolatum, dimethyl sulfoxide, mineral oil, serum proteins (e.g., human serum albumin), glycine, sorbic acid, potassium sorbate, water, salts or electrolytes (e.g., salines such as phosphate buffered saline, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyacrylates, waxes, wool fat, lecithin, corn oil, and the like.

[0038] In some cases, when a composition comprising one or more (e.g., one, two, three, four or more) lipase inhibitors is administered to a mammal having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions (e.g., a human having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions), the composition may be designed for oral or parenteral administration to the mammal, including but not limited to subcutaneous, intramuscular, intravenous, intradermal, intracerebral, intrathecal, intraperitoneal, and intraperitoneal injection (e.g., peripancreatic). Compositions suitable for oral administration include, but are not limited to, liquids, tablets, capsules, pills, powders, gels, and granules. Compositions suitable for parenteral administration include, but are not limited to, aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient.

[0039] In some cases, the composition containing one or more (e.g., one, two, three, four or more) lipase inhibitors may be in the form of a sterile injectable suspension (e.g., a sterile injectable aqueous or oleaginous suspension). The suspension may be formulated, for example, using suitable dispersing or wetting agents (e.g., Tween 80, etc.) and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Examples of acceptable vehicles and solvents that may be used include, but are not limited to, saline, mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be used as a solvent or suspending medium. In some cases, non-irritating fixed oils such as synthetic mono- or di-glycerides may be used.

[0040] In some cases, compositions containing one or more (e.g., 1, 2, 3, 4 or more) lipase inhibitors may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a lyophilized condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use.

[0041] A composition comprising one or more (e.g., one, two, three, four or more) lipase inhibitors can be administered in any therapeutically effective amount (e.g., any suitable dose) to a mammal (e.g., a human) having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions. A therapeutically effective amount of a composition comprising one or more lipase inhibitors can be any amount that can treat a mammal having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions described herein without causing significant toxicity to the mammal. A therapeutically effective amount can remain constant or can be adjusted as a sliding scale or variable dose depending on the mammal's response to treatment. Various factors can affect the actual therapeutically effective amount used for a particular application. For example, the actual therapeutically effective amount administered may need to be increased or decreased depending on the frequency of administration, duration of treatment, use of multiple therapeutic agents, route of administration, and / or severity of one or more pancreatic diseases, disorders, and / or conditions in the mammal being treated.

[0042] A composition comprising one or more (e.g., one, two, three, four or more) lipase inhibitors can be administered at any suitable frequency to a mammal (e.g., a human) having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions. The frequency of administration can be any frequency that can treat a mammal having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions without causing significant toxicity to the mammal. For example, the frequency of administration can be from about twice a day to about once every other day, from once a day to about once a week, from about once a week to about once a month, or from about twice a month to about once a month. The frequency of administration can remain constant or can vary during the treatment period. As with the therapeutically effective amount, various factors can affect the actual frequency of administration used for a particular application. For example, the therapeutically effective amount, the duration of treatment, the use of multiple therapeutic agents, and / or the route of administration may require an increase or decrease in the frequency of administration.

[0043] A composition comprising one or more (e.g., one, two, three, four or more) lipase inhibitors can be administered to a mammal (e.g., a human) having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions for any suitable period of time. The effective period for administering or using a composition comprising one or more lipase inhibitors can be any period during which a mammal having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions can be treated without causing significant toxicity to the mammal. For example, the effective period can vary from weeks to months, months to years, or years to a lifetime. Several factors can affect the actual effective period used for a particular treatment. For example, the effective period can vary depending on the frequency of administration, the therapeutically effective amount, the use of multiple therapeutic agents, and / or the route of administration.

[0044] In some embodiments, a method for treating a mammal (e.g., a human) having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions described herein (e.g., by administering one or more lipase inhibitors) can include administering to the mammal one or more (e.g., one, two, three, four, or more) lipase inhibitors as the only active ingredients for treating the mammal. For example, a composition comprising one or more lipase inhibitors can include one or more lipase inhibitors as the only active ingredients in a composition effective to treat a mammal having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions.

[0045] In some embodiments, a method for treating a mammal (e.g., a human) having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions described herein (e.g., by administering one or more lipase inhibitors) also includes administering to the mammal one or more (e.g., one, two, three, four, five or more) additional agents used to treat one or more pancreatic diseases, disorders, and / or conditions and / or administering to the mammal a therapy used to treat one or more pancreatic diseases, disorders, and / or conditions. For example, a combination therapy used to treat one or more pancreatic diseases, disorders, and / or conditions can include administering to the mammal (e.g., a human) one or more lipase inhibitors described herein and one or more (e.g., one, two, three, four, five or more) agents used to treat one or more pancreatic diseases, disorders, and / or conditions. Examples of drugs that can be administered to a mammal to treat pancreatitis (e.g., chronic pancreatitis) include, but are not limited to, acetaminophen, ibuprofen, opioids (e.g., codeine and morphine), pancreatic enzymes, anti-inflammatory drugs, and any combination thereof. Examples of drugs that can be administered to a mammal to treat pancreatic cancer include, but are not limited to, gemcitabine, 5-fluorouracil (5-FU), oxaliplatin, albumin-bound paclitaxel, capecitabine, cisplatin, irinotecan, and any combination thereof. Examples of drugs that can be administered to a mammal to treat pancreatic fistula include, but are not limited to, somatostatin, somatostatin analogs, and any combination thereof. When one or more lipase inhibitors are used in combination with additional agents used to treat one or more pancreatic diseases, disorders, and / or conditions, the one or more additional agents may be administered simultaneously (e.g., in a single composition containing both the one or more lipase inhibitors and the one or more additional agents) or separately. For example, one or more lipase inhibitors described herein can be administered first and one or more additional agents second, or vice versa.

[0046] In some embodiments, the combination therapy used to treat one or more pancreatic diseases, disorders, and / or conditions may include administering one or more (e.g., one, two, three, four, or more) lipase inhibitors described herein to a mammal (e.g., a human) and administering to the mammal one or more (e.g., one, two, three, four, five, or more) additional therapies used to treat one or more pancreatic diseases, disorders, and / or conditions. Examples of therapies used to treat pancreatitis (e.g., chronic pancreatitis) include, but are not limited to, endoscopic retrograde cholangiopancreatography, surgical removal of the gallbladder, and / or surgical removal of pancreatic juice. Examples of therapies used to treat pancreatic cancer include, but are not limited to, surgery, radiation therapy, surgery to remove one or more tumors in the pancreas, and / or surgical removal of all or part of the pancreas. Examples of therapies used to treat pancreatic fistula include, but are not limited to, total parenteral nutrition and / or fistulectomy.When one or more lipase inhibitors described herein are used in combination with one or more additional therapies used to treat one or more pancreatic diseases, disorders, and / or conditions, the one or more additional therapies can be administered simultaneously or independently with the administration of one or more lipase inhibitors described herein.For example, one or more lipase inhibitors described herein can be administered before, during, or after the administration of one or more additional therapies.

[0047] In certain embodiments, the course of treatment and the severity of one or more symptoms associated with the condition being treated (e.g., one or more pancreatic diseases, disorders, and / or conditions) can be monitored. Any suitable method can be used to determine whether the severity of the symptoms has decreased. For example, the severity of the symptoms of one or more pancreatic diseases, disorders, and / or conditions can be evaluated at different time points using abdominal ultrasound, CT scan, and / or blood test (e.g., for increased amylase and / or lipase, such as levels above about 3 times the upper limit of normal).

[0048] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. EXAMPLES

[0049] Example 1: Lipase inhibition to prevent adhesions and chronic pancreatitis This example describes the use of lipase inhibitor 767 (also called RABI-767) to prevent adhesions and / or chronic pancreatitis.

[0050] Materials and Methods Reagents and mice A homogeneous suspension of 25% glyceryl trilinoleate (GTL) in saline was prepared by heating, mixing, and sonication.

[0051] Drug 767 was dissolved in a 25% sonicated suspension of GTL in saline, which was prepared by adding 0.5 µl of the 25% GTL suspension to 10 mg of 767 at room temperature. The solution was then mixed, gently heated to 37-40 °C, and sonicated to ensure a homogenous emulsion.

[0052] Four male CD-1 mice (35–39 g) were used in each experiment.

[0053] group: Two mice were each given 0.2 mL of 25% GTL via intraperitoneal injection.

[0054] Two mice were administered 0.2 mL of 767 in 25% GTL by intraperitoneal injection.

[0055] Endpoints: Mice were sacrificed 1 week later and intraperitoneal nodules were evaluated.

[0056] result The peritoneum and histological appearance of the GTL-treated mice were examined. The peritoneal cavity of the control mice appeared normal (Figure 1, panel A). The peritoneal cavity of the GTL-treated mice contained nodules and filaments (Figure 1, panels B and C). These nodules and filaments were also seen in the en bloc resected pancreas, duodenum, and spleen (Figure 2). In the control mice, the plane between the duodenum, pancreas, and spleen was well maintained (Figure 2, panel A). The organs of the GTL-treated mice were adherent and difficult to separate. The organs of the GTL-treated mice contained numerous nodules and filaments (Figure 2, panel B). These appearances are consistent with chronic pancreatitis without the need for induction of pancreatitis.

[0057] Morphological evaluation of stained sections of the organs shown in Figure 2 revealed an extensive fibrotic appearance in the area between the pancreas and spleen (Figure 3). The stained sections correspond to the large threads of fibrosis between the pancreas and spleen in panel B of Figure 2.

[0058] H&E staining of the nodules reveals lobules of material that have been partially washed out (Figure 4, Panel A). The nodules also stain with von Kossa staining, with weakly von Kossa-positive spherules indicating partially hydrolyzed GTL (Figure 4, Panel B). However, the mice did not exhibit pancreatitis abnormalities when examined by blood urea nitrogen (BUN), glucose, or albumin concentrations. The nodules also stain with Sirius Red, and the walls of the nodules were strongly positive for fibrosis (Figure 4, Panel C). Fibrosis was also seen when the nodules were stained with Masson's Trichrome (Figure 5, Panel B). This fibrosis is adjacent to weakly positive von Kossa areas (asterisks in Figure 5, Panel A).

[0059] Significant adhesions and fibrosis were observed around lipid vesicles that were resistant to organic solvents used in histology (e.g., xylene, alcohol). However, no adhesions were observed around neutral lipids that were washed away during tissue processing. Neutral triglyceride lipids, such as GTL, are typically washed away from cells, such as adipocytes, during processing. Thus, the finding of fibrosis around lipid vesicles that were not washed away by organic solvents suggests that low-grade chronic lipolysis of triglycerides results in saponification of the fatty acids produced, resulting in fibrosis. Therefore, we investigated whether inhibition of intraperitoneal lipolysis could prevent adhesions and chronic pancreatitis.

[0060] Mice were administered GTL with or without 767, and the peritoneal and histological findings of the mice were examined. Mice administered GTL had clearly identifiable nodules in the peritoneal cavity (top row) and around the pancreas (bottom row) (Figure 6, Panel A). Mice administered both GTL and 767 had no noticeable nodules in the peritoneal cavity (top row) and around the pancreas (bottom row) (Figure 6, Panel B).

[0061] 767 also prevented intraperitoneal adhesions in the space distal to the pancreas (Figure 1, panels B and C, and Figure 6, panel A).

[0062] Taken together, these results demonstrate that one or more lipase inhibitors can be used to treat pancreatitis (eg, chronic pancreatitis).

[0063] Example 2: Lipase inhibition and postoperative pancreatic fistula This example describes the use of lipase inhibitor 767 to prevent postoperative pancreatic fistula.

[0064] method The fatty acid composition and amount in the pancreatic juice collected after surgery were measured using gas chromatography and mass spectrometry. The proportion of fatty acids was classified into unsaturated fatty acids (with double bonds) and saturated fatty acids (without double bonds).

[0065] result The data are shown in Figure 7. The four black dots in Figure 7 Panel A indicate early collection and are the same as the black dots in Figure 7 Panel B. Note that the black dots in Figure 7 Panel B also have the highest amount of NEFA. In the later postoperative state, there is less amount of NEFA. This is indicated by some of the grey dots following the black dots.

[0066] Postoperative fistulas develop in an environment high in unsaturated fatty acids, which can damage tissue and cause adhesions.

[0067] These results demonstrate that one or more lipase inhibitors can be used to treat postoperative pancreatic fistulas.

[0068] Example 3: Treatment of postoperative pancreatic fistula A human identified as having chronic pancreatitis is administered one or more lipase inhibitors (e.g., a composition comprising one or more lipase inhibitors such as 767) by intraperitoneal or intraperitoneal injection. The administered inhibitors can reduce the severity of one or more symptoms of chronic pancreatitis.

[0069] Example 4: Prevention of postoperative pancreatic fistula A human identified as being at risk for developing chronic pancreatitis is administered one or more lipase inhibitors (e.g., a composition comprising one or more lipase inhibitors, such as 767) by intraperitoneal or intraperitoneal injection. The administered inhibitor can delay or prevent the onset of one or more symptoms of chronic pancreatitis.

[0070] Example 5: Treatment of postoperative pancreatic fistula A human identified with one or more postoperative pancreatic fistulas is administered one or more lipase inhibitors (e.g., a composition including one or more lipase inhibitors, such as 767) via intraperitoneal or intraabdominal injection. The administered inhibitors can reduce the severity of one or more symptoms of the postoperative pancreatic fistula.

[0071] Example 6: Prevention of postoperative pancreatic fistula A human identified as being at risk for developing one or more postoperative pancreatic fistulas is administered one or more lipase inhibitors (e.g., a composition including one or more lipase inhibitors, such as 767) by intraperitoneal or intraabdominal injection. The administered inhibitors can delay or prevent the development of a postoperative pancreatic fistula.

[0072] Other embodiments While the present invention has been described in conjunction with its detailed description, it is to be understood that the foregoing description is intended to illustrate, but not to limit, the scope of the invention, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. Use of a composition containing a lipase inhibitor to reduce adhesions and / or fibrosis in the pancreas and / or abdominal cavity of mammals.

2. The use according to claim 1, wherein the mammal is a human.

3. The use according to claim 1, wherein the inhibitor is 767 or a pharmaceutically acceptable salt thereof.

4. The use according to claim 1, wherein the inhibitor comprises the following structure: 【Chemistry 1】 。

5. A lipase inhibitor for use as a pharmaceutical agent to reduce adhesions and / or fibrosis in the pancreas and / or abdominal cavity of mammals.

6. A lipase inhibitor used to reduce adhesions and / or fibrosis in the pancreas and / or abdominal cavity of mammals.

7. The lipase inhibitor according to claim 5 or 6, wherein the mammal is a human.

8. The lipase inhibitor according to claim 5 or 6, wherein the inhibitor is 767 or a pharmaceutically acceptable salt thereof.

9. The lipase inhibitor according to claim 5 or 6, comprising the following structure: 【Chemistry 2】 。

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