JP2010503667A - Bile preparation for colorectal disease - Google Patents

Abstract

  The present invention relates to methods and compositions for treating or reducing at least one symptom of colorectal cancer and / or colorectal adenomatous polyposis (APC). For example, some embodiments of the methods and compositions of the present invention can reduce recurrence of colorectal adenoma and / or extend the life span of patients who have developed colorectal cancer and / or APC. Some embodiments of the invention include maintaining the overall weight of a patient who has developed colorectal cancer and / or APC. In some embodiments, the methods of the invention comprise administering a bile acid composition to a subject. In some embodiments, the bile acid composition comprises an aqueous solution that is free or substantially free of precipitates and particles. The aqueous solution may further comprise (1) bile acid, a water-soluble derivative of bile acid, a bile salt, and / or 7-ketritocholic acid, (2) a carbohydrate, and (3) water. The aqueous composition may further contain an alkali.

Description

  The present invention relates to methods and one or more bile acid compositions that can be used to reduce one or more symptoms of colon disease.

  Colorectal cancer (CRC) is one of the most common forms of gastrointestinal cancer in the world today and is the most common cause of cancer-related death in the world. In the Asia-Pacific region, colon cancer is the earliest gastrointestinal cancer. Colorectal cancer is the third most common cancer in the world and the second leading cause of cancer death in men and women in the United States. Although colon cancer and rectal cancer are rare in developing countries, they are the second most common disease in a rich society. Globally, 940,000 cases occur annually, and the number of deaths due to this disease reaches about 500,000 annually. The American Cancer Society estimated that in the United States, about 106,680 colon cancer patients and about 41,930 rectal cancer patients will newly occur in 2006 in the United States. In addition, about 55,170 people will die from the combination of these two cancers. This disease has a very high mortality and morbidity and is a widespread disease. In 2004, it was estimated that there will be over 1,000,000 new patients and 500,000 deaths worldwide related to the disease.

  For subjects treated at an early stage before colorectal cancer has progressed, the 5-year relative survival rate exceeds 90%. However, the early detection rate of colorectal cancer is only 39%. Once colon cancer metastasizes to adjacent organs or lymph nodes, the 5-year relative survival rate declines. When colon cancer metastasizes to a distant organ (eg, liver or lung), the 5-year survival rate is 10%. Is less than.

  Although it is promising to prevent CRC cancer disorders by endoscopy, it is expensive and difficult to identify high-risk groups. Examining both the high risk group and the average risk group of CRC also has limitations in terms of economics and logic.

  Thus, there is a need for methods and compositions for the treatment of colorectal cancer and / or for alleviating one or more symptoms of colorectal cancer.

  The present invention relates to methods and compositions for reducing or treating at least one symptom of colorectal cancer and / or colorectal adenomatous polyposis coli (APC). For example, the methods and compositions of some embodiments of the present invention can be utilized to reduce recurrence and / or extend lifespan of a subject with colon cancer and / or APC. . Some embodiments of the invention include maintaining the overall weight of a subject who has colorectal cancer and / or APC. The method of the invention includes administering a bile acid composition to a subject. The bile acid composition includes, in some embodiments, an aqueous solution that is free or substantially free of precipitates and particles. Aqueous solutions include (1) bile acids, water-soluble derivatives of bile acids, bile salts, and / or 7-ketritocholic acid, and (2) water-soluble starch conversion products, water-soluble dietary carbohydrates that are not digested and absorbed in the small intestine, And a carbohydrate selected from the group consisting of these, and (3) water. This aqueous solution may further contain an alkali.

  According to some embodiments of the present invention, a method of protecting the large intestine from colorectal adenomatous polyposis in a subject comprises (a) bile acid, a water-soluble derivative of bile acid, bile salt, and 7-ketritocholic acid. A first substance selected from the group, (b) a water-soluble starch conversion product, a water-soluble dietary carbohydrate that is not digested and absorbed in the small intestine, and a carbohydrate selected from the group consisting of combinations thereof, and water. Administering to the subject a composition wherein both the first substance and the carbohydrate maintain a solution state at all pH values of the solution in a selected pH value range (eg, all pH values obtained in an aqueous system). Can be included.

  In some embodiments, the present invention provides: (a) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, and 7-ketritocholic acid; A carbohydrate selected from the group consisting of: a natural starch conversion product, a water-soluble dietary carbohydrate that is not digested and absorbed in the small intestine, and combinations thereof; and (c) water, wherein both the first substance and the carbohydrate are A composition that remains in solution at all pH values of a solution in a selected pH value range (eg, all pH values obtained in an aqueous system) has become colon adenomatous polyposis and / or colorectal cancer, or It also relates to a method for extending the lifespan of said subject comprising administering to a subject at risk of developing colorectal cancer.

  In some embodiments, the present invention provides: (a) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, and 7-ketritocholic acid; A starch selected from the group consisting of a soluble starch conversion product, a water-soluble dietary carbohydrate that is not digested and absorbed in the small intestine, and combinations thereof, and water, wherein both the first substance and the carbohydrate are selected. A method of maintaining the overall weight of the subject, comprising administering to the subject a composition that maintains the solution state at all pH values of a solution in a range of pH values (eg, all pH values obtained in an aqueous system). It is also a thing.

  Also according to some embodiments of the present invention, (a) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, and 7-ketritocholic acid; ) A water-soluble starch conversion product, a water-soluble dietary carbohydrate that is not digested and absorbed in the small intestine, and a carbohydrate selected from the group consisting of these, and water, both the first substance and the carbohydrate, A composition that maintains a solution state at all pH values of a solution in a selected pH value range (eg, all pH values obtained in an aqueous system) has colorectal adenomatous polyposis or has colorectal adenomatous polyposis Provided is a method of treating or alleviating one or more symptoms of colorectal adenomatous polyposis comprising administering to a subject at risk.

  Some embodiments of the present invention include (a) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, and 7-ketritocholic acid, and (b) water-soluble starch. A conversion product, a water-soluble dietary carbohydrate that is not digested and absorbed in the small intestine, and a carbohydrate selected from the group consisting of combinations thereof, and water, wherein both the first substance and the carbohydrate are selected pH A method for reducing recurrence of colorectal adenoma in a subject's large intestine, comprising administering a composition that maintains the solution state at all pH values of a solution in a value range (eg, all pH values obtained in an aqueous system) It is.

  According to some embodiments of the invention, (a) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, and 7-ketritocholic acid; A starch selected from the group consisting of a soluble starch conversion product, a water-soluble dietary carbohydrate that is not digested and absorbed in the small intestine, and combinations thereof, and water, wherein both the first substance and the carbohydrate are selected. A composition that maintains a solution state at all pH values of a solution in a pH range (for example, all pH values obtained in an aqueous system) is applied to a subject who has colorectal cancer or is at risk of developing colorectal cancer. A method of treating or alleviating one or more symptoms of colorectal cancer comprising administering is provided.

  The composition according to some embodiments of the present invention may be transparent (ie, free or substantially free of precipitates or particles), (a) bile acid, a water-soluble derivative of bile acid, A first substance selected from the group consisting of bile salts and 7-ketritocholic acid; and (b) a water-soluble starch conversion product, a water-soluble indigestible maltodextrin (Fibersol 2), and a combination thereof. And (c) both the first substance and the carbohydrate maintain a solution state at all pH values of the solution in the selected pH value range. The weight ratio of the water-soluble starch conversion product to the water-soluble hardly digestible maltodextrin is 0-100: 100-0 (for example, 1-99: 99-1).

  In some embodiments, the compositions of the present invention may be transparent (ie, free or substantially free of precipitates and particles), (a) bile acids, water-soluble derivatives of bile acids A first substance selected from the group consisting of a bile acid salt and a bile acid conjugated with an amine via an amide bond, (b) a second substance containing a high molecular weight water-soluble starch conversion product, and (c) water And both the first material and the second material maintain a solution state at all pH values of the solution in the selected pH value range.

  In some embodiments of the invention, the compositions of the invention can be administered to a subject in a liquid (eg, a clear solution, syrup, paste, jelly, or mucus). According to some embodiments of the invention, the compositions of the invention can also be administered in dry form or in solid form.

  Some specific exemplary embodiments of the present invention can be understood, in part, by reference to the following description and the accompanying drawings.

Representative mice treated with AOM alone (left side) with testicular edema and blood spots (arrows), as well as representative treated with AOM and Formula 15 with normal testes and no blood spots It is a figure which shows a mouse | mouth (right side). It is the image which expanded the blood spot (arrow) of the mouse processed with AOM shown in Drawing 1A. FIG. 5 shows a representative mouse treated with AOM alone, with left eye blindness and tumors. FIG. 4 shows a representative mouse treated with AOM not only with adenomatous polyps (arrows) in the large intestine, but also with edema in the testicles and blood spots (arrows). FIG. 2 shows a representative mouse treated with AOM and Formulation 15 without adenomatous polyps in the large intestine, testicles normal and free of blood spots. FIG. 6 shows a representative mouse treated with AOM with a tumor (arrow) on the back. FIG. 5 shows a representative mouse treated with AOM and Formulation 15 without a tumor on the back. FIG. 4 shows the tail of a representative Balb / c mouse treated with AOM with blood spots (arrows). FIG. 5 shows the tail of a representative Balb / c mouse treated with AOM and Formulation 15 without blood spots. FIG. 6 is a graph showing the survival time of mice treated with AOM with or without Formulation 15. FIG. FIG. 6 is a graph showing the body weight of mice treated with AOM with or without formulation 15 administered. The excised intestinal portion (left side) of a representative mouse treated with AOM alone, with adenomatous polyps (arrows), as well as of a representative mouse treated with AOM and Formulation 15 without adenomatous polyps. It is a figure which shows the resected intestine part (right side). FIG. 6 shows a resected intestinal portion of another representative mouse treated with AOM alone.

DETAILED DESCRIPTION OF THE INVENTION Colon Cancer Although the etiology of colon cancer has not been fully elucidated, multiple factors are thought to play a role in initiating the carcinogenic process. For example, epidemiological studies, case-control studies, and results of cohort studies have shown a correlation between dietary fat and colon cancer. In addition, there may be a positive correlation between the onset of colon cancer and increased bile acid levels in the stool. This is not only consistent with the observation that secondary bile acid secretion increases as dietary fat intake increases, but can be explained in part by these observations.

  Inflammatory bowel disease (IBD) -related colon cancer causes of carcinogenesis include gradual progression from inflammatory and proliferative epithelium to squamous dysplasia and eventually to adenocarcinoma Can do. The carcinogenic phenomenon of IBD-related colorectal cancer may be promoted by chronic inflammation. However, mucinous inflammation can cause colon cancer by one or more mechanisms. Examples of such mechanisms include induction of genetic mutations, increased crypt cell proliferation, changes in crypt cell metabolism, changes in bile acid enterohepatic circulation, changes in bacterial flora, and / or combinations thereof. be able to. One or more of these phenomena may promote the progression of IBD-related colorectal cancer.

  Azoxymethane (AOM) is a pro-carcinogen used to induce colorectal cancer in laboratory animals. Dextran sulfate sodium salt (DSS) is a pro-inflammatory stimulus that can erode epithelial cells of the intestinal tract. This can cause an inflammatory response to take intestinal bacteria and fight the inflammation. For example, in male mice, a single intraperitoneal injection of AOM (10 mg / kg body weight) followed by 1% exposure to 2% DSS in drinking water, along with colitis with tubular adenoma, dysplasia, and mucosal ulcers Colon adenocarcinoma effectively developed (attack rate 100%). Treatment with 2% DSS for 1 week after exposure to AOM sufficiently developed colon adenocarcinoma, suggesting that DSS has a potent tumor-promoting ability in the colon of male ICR mice.

  Colorectal adenomatous polyposis (APC) -related polyposis symptoms include familial adenomatous polyposis (FAP), mild FAP, Gardner syndrome, and turcot syndrome. In the United States, the incidence varies from 1 for 6,850 to 1 for 31,250. FAP is an autosomal dominant genetic disease characterized by the presence of hundreds to thousands of adenomatous polyps throughout the colon. All patients with this syndrome develop at an average age of 16 years (range 7-36 years) and develop into colon cancer unless treated. Until 35 years old, 95% of subjects with FAP have polyps, and unless they undergo colectomy, colon cancer is inevitable. In non-treated subjects, the average age of subjects undergoing colon cancer diagnosis is 39 years (range 34-43 years). Symptoms of extracolonic manifestation are variable, including gastric fundus and duodenal polyps, osteomas, abnormal teeth, congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft tissue tumors, Desmoid tumors and cancers related thereto are included herein. There is a very high risk of developing colon cancer with mild FAP, but there are fewer colon polyps (average 30) than in general FAP, polyps are closer, and older, colon cancer Since it is characterized by receiving a diagnosis, its management method is substantially different. Gardner syndrome is characterized by having typical colon polyposis of FAP, along with osteoma and soft tissue tumors. In turcot syndrome, both colonic polyposis and CNS tumors appear, but the phenotypic characteristics of Gardner syndrome and turcot syndrome are related to the location of APC mutations and are generally expressed from families that have become FAP.

Secondary bile acids Bile acids are the most active end product of cholesterol metabolism. Primary bile acids, namely cholic acid (CA) and chenodeoxycholic acid (CDCA) are synthesized in the liver and secreted into bile. Primary bile acids are reabsorbed in the ileum, of which several percent pass through the ileum to the colon. In the colon, primary bile acids are metabolized by anaerobic bacteria to form secondary bile acids. Secondary bile acids, including deoxycholic acid (DCA) and lithocholic acid (LCA), are found in both stool solids and water.

  Without being limited to a specific mechanism of action, secondary bile acids such as deoxycholic acid (DCA) affect the pathogenesis of colorectal cancer. For example, secondary bile acids break the balance of colon crypt cell proliferation, differentiation, and apoptosis. Secondary bile acids alter intracellular signals and / or gene expression. For example, DCA affects one or more pathways that regulate the activity of activated protein-1.

  Without being limited to a particular mechanism of action, the supply of bile acids can increase surface epithelial cell detachment and / or promote colonic epithelial cell proliferative activity. The increase in epithelial cell detachment is also due to the bile acid purification properties. The increase in cell proliferation is a secondary response to the loss of surface epithelial cells and / or is due to the direct effect of bile acids on the metabolic activity of colonic epithelial cells.

  DCA and other secondary bile acids are cytotoxic to colonic epithelial cells, mutated in bacterial test systems, may be associated with dysplasia and / or have anti-apoptotic properties. Bile acids can regulate colon tumor progression in a laboratory carcinogenesis model using azoxymethane (AOM). In some references, it is clear that one or more secondary bile acids are implicated as auxiliary carcinogens for colon cancer. In fact, some people with colon cancer may excrete secondary bile acids into the stool at high concentrations.

  A subject on a high fat diet may produce or accumulate more bile secondary bile acids than a subject on a low fat content diet. High concentrations of secondary bile acids, especially deoxycholic acid (DCA), can damage the epithelium of the colon and / or promote the carcinogenic process. The formation of colon glandular species or polyps may occur prior to colon cancer. Without limiting the embodiments of the present invention to a specific mechanism of action, the concentration of DCA and other bile acids in the stool aqueous phase can be compared to those in the stool solid phase compared to those in the stool solid phase. Much more important in development because the bile acids in the aqueous phase are more likely to come into contact with colonic epithelial cells.

  According to some embodiments of the invention, dietary carbohydrates include carbohydrates that are not digested and absorbed in the small intestine. For example, dietary carbohydrates can include non-digestible oligosaccharides (carbohydrates having a degree of polymerization of 3-10), resistant starch, and non-starch polysaccharides.

  Examples of dietary carbohydrates include cellulose, hemicellulose (consisting of various heteropolysaccharides including arabinoxylan), and non-starch polysaccharides such as β-glucan and pectin. Resistant starch is another component of vegetable food that is not absorbed and digested in the small intestine and acts at least physiologically like dietary fiber. Non-digestible oligosaccharides can promote the growth of potentially beneficial bacteria such as bifidobacteria in the intestine.

  The concentration of total bile acids and secondary bile acids in the stool is greatly reduced after ingestion of dietary carbohydrates. Therefore, when dietary carbohydrates are ingested, the conversion of primary bile acids to secondary bile acids can be suppressed. Conversely, primary bile acid concentrations were not affected by dietary carbohydrate intake.

  A diet containing sucrose or resistant starch was given to SD (Sprague Dawley) rats for 4 weeks, and the results were compared. It was observed that the amount of total bile acids in the stool was much lower in rats fed resistant starch than in rats receiving sucrose diet. This is due, at least in part, to decreased levels of deoxycholic acid, α-mulicholic acid, and β-mulicholic acid. In addition, it was observed that the pH value of the stool and the pH value of the cecum were much lower in the rats ingested resistant starch than in the rats treated with sucrose diet. It was observed that colonic mucosa growth was much lower in rats fed resistant starch compared to rats receiving sucrose diet. Such reduction was significant in the middle and upper part of the colon crypt. For example, mucosal proliferation, expressed as a percentage of labeled cells in the upper part of the colon crypt, is expressed as the concentration of deoxycholic acid, lithocholic acid, α-mulicholic acid, β-mulicholic acid, cholic acid, and total bile acids in the stool. There was a positive correlation. Resistant starch consumption can reduce colonic mucosal proliferation as a result of reduced formation of cytotoxic secondary bile acids. Reduction in the formation of cytotoxic secondary bile acids is mediated by acidification of the large intestine by the production of short chain fatty acids.

Non-steroidal anti-inflammatory drugs (NSAID: Non-Steroidal Anti-Inflammatory Drugs)
The development of colorectal cancer is a multi-step process involving, for example, molecular and cellular transformations that can generate identifiable precursor lesions, ie adenomatous polyps. Metastasis from normal mucosa to adenoma and its subsequent carcinoma can occur over a long period of time, providing a chance for preventive intervention. For example, nonsteroidal anti-inflammatory drugs (NSAIDs), including Nimesulide, suppressed both colon tumorigenesis and colitis. The correlation between increased expression of cyclooxygenase-2 (COX-2) and colon carcinogenesis and / or inflammation indicates that one or more chemopreventive effects of NSAIDs are mediated, at least in part, by COX suppression. Suggests. Thus, one or more NSAIDs and selective COX-2 inhibitors can reduce CRC incidence and thereby mortality.

  However, long-term use of NSAIDs actually exposes the gastrointestinal tract, which can exacerbate symptoms in IBD patients. NSAID-related gastrointestinal damage is still a serious and clinically significant problem. Gastrointestinal side effects associated with the use of NSAIDs are frequent. NSAID-related dysplasia occurs in as many as 50% of patients using NSAIDs, and heartburn, nausea, vomiting, and abdominal pain are also observed. More important, however, is the link between the use of NSAIDs, gastrointestinal mucosal damage, and related complications. Subcutaneous hemorrhage occurs in up to 100% of patients receiving non-selective NSAIDs, erosions (small and shallow peelings that occur in the gastrointestinal tract mucosa) occur in approximately 50%, and ulcers (spread from the muscular mucosa) in more than 20% Damage).

  The regular use of NSAIDs reduces the incidence of colorectal cancer (CRC) to 30-50% in humans. NSAIDs may also exhibit one or more chemotherapeutic properties when used alone and / or in combination with conventional treatment strategies. For example, sulindac results in degenerating polyps in FAP patients. Traditional NSAIDs (eg, aspirin, nimesulide, and sulindac) are part of their chemopreventive action by inhibiting cyclooxygenases (COXs), a key enzyme in the biosynthesis of prostaglandins (PG). Can be demonstrated. There are at least two isoforms of COX, namely COX-1 and COX-2. COX-1 is constantly expressed in most tissues and is responsible for normal tissue homeostasis, whereas COX-2 is not detected in most normal tissues but is induced by one or more cytokines and / or mitogens be able to. COX-2 can also be increased from 80% to 90% (depending on their size) in CRC and a significant subset of adenomas. Inhibition of COX-1 by traditional NSAIDs causes side effects such as gastric bleeding, whereas inhibition of COX-2 can play a chemopreventive role for NSAIDs. Administration of COX-2 selective NSAIDs (eg, rofecoxib and celecoxib) can reduce the incidence and / or severity of upper gastrointestinal disease associated with COX-1 inhibition. In addition, COX-2 selective NSAIDs have various anti-neoplastic properties of traditional NSAIDs. For example, celecoxib, a COX-2 selective inhibitor, reduces the overall colon polyp number, size, and burden, in FAP patients.

Ursodeoxycholic acid (UDCA)
Ursodeoxycholic acid (UDCA), a tertiary bile acid, has one or more biological activities different from DCA. In some embodiments, the biological activity of UDCA may be the opposite of that of DCA. For example, orally administered UDCA can reduce the amount of DCA in the fecal aqueous phase. UDCA can also inhibit one or more pathways activated by DCA, such as a protein kinase pathway activated by mitogens. In addition, UDCA can block, reduce, or prevent colon cancer development and / or core cell proliferation signal transduction pathways.

For example, in a study using 32-week-old rats, 240 mg / kg of UDCA was administered daily (1,440 mg / m ^2, which is 2.6 times the maximum recommended amount for humans based on body surface area). Colon carcinogenic effect was suppressed. In addition, the UDCA treatment method comprises (1) a decrease in the incidence of colorectal neoplasms in patients with primary biliary cirrhosis, (2) a decrease in the prevalence of colorectal neoplasms in patients with primary sclerosing cholangitis, and (3) ulcers It is associated with eradication of severe colonic mucosal dysplasia in patients with ulcerative colitis and primary sclerosing cholangitis (PSC). In some embodiments, the chemoprotective effect of UDCA begins to appear months (eg, at least 1 month) or years (eg, at least 1 year) after the start of administration. For example, daily administration of 13-15 mg / kg body weight for 12 years is associated with a statistically significant decrease in colon neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis It was observed. In this case, the chemopreventive effect of UDCA began to appear 6 years after the intervention.

  In one study, it was observed that the overall recurrence rate of sporadic colorectal adenoma was reduced when UDCA was administered, but it is not clear whether the difference is statistically significant. A better effect can be shown if the observation period is further increased and / or the dose of UDCA is increased. In this study, it was observed that the rate of recurrence of adenoma with advanced dysplasia was reduced in relation to UDCA administration, which was statistically significant.

  Compared to the control treatment group in the APC mutant Min mouse model for familial colon polyposis, the UDCA treatment group reduced tumors throughout the intestine in a dose-dependent manner. When combined with UDCA and sulindac, which are effective in treating familial colorectal polyposis, the tumor prevention effect was superior throughout the intestine than when either one was used alone to prevent these tumors. . Therefore, UDCA is also a useful drug for the treatment of patients with this rare hereditary disease. Although there was no difference in weight gain, some mortality was observed in mice treated with ursodeoxycholic acid alone (7/8 survival at 500 ppm, 6/8 survival at 1500 ppm). In the group treated with ursodeoxycholic acid and sulindac, 8 out of 8 mice survived, and in the group treated with 1500 ppm ursodeoxycholate and sulindac, 8 Seven of them survived. Administration of about 50-7500 mg of UDCA and sulindac (NSAID) daily will prevent recurrence of colorectal adenoma.

  UDCA is the main component of bear gall. UDCA is useful as an agent that can treat and / or protect the liver against one or more liver disease types. In some embodiments of the present invention, bile acids (eg, UDCA) can dissolve X-ray permeable gallstones and / or primary biliary cirrhosis, primary sclerosing cholangitis, gestational intrahepatic cholestasis, It can be used to treat cholestatic disease selected from the group consisting of cystic fibrosis-related liver disease, several pediatric liver diseases, and chronic graft-versus-host disease of the liver.

  The pharmacological actions of UDCA include (1) replacement and / or displacement of toxic bile acids by UDCA, (2) cytoprotective action, (3) stabilization / protection of cell membrane, (4) anti-apoptotic action, (5) cells Immunoregulatory action by activation of internal glucocorticoid receptor, (6) anti-inflammatory action by inhibition of induction of nitric oxide synthase and NF-kB, (7) stimulation of bile secretion, (8) stimulation of exocytosis, (9) Insertion of tubule membrane transporter, and (10) Antioxidant action, and such action is dose-dependent.

After oral administration, about 30-60% of UDCA is absorbed along the entire length of the jejunum and ileum by nonionic passive diffusion. UDCA is absorbed in the ileum by an active transport mechanism, and small amounts (eg, 20% of intake) are absorbed in the colon. When healthy volunteers were administered 500 mg of UDCA labeled with ¹⁴ C tracer, 30-44% of the dose was secreted in the stool as solid UDCA, which was due to the very slow and incomplete solubility of UDCA and Due to insolubility.

  Once absorbed by hepatocytes, UDCA is conjugated to, for example, TUDCA (tauro-conjugated UDCA) and GUDCA and / or excreted into bile by liver first pass clearance. As a result, the blood concentration of UDCA in the systemic circulation is very low. Bile acids can undergo extensive hepatic recirculation, and free UDCA can be secreted into the bile by hepatocytes. UDCA secreted into the bile is resorbed actively and efficiently by bile duct cells. UDCA and GUDCA are absorbed by both active and passive transport mechanisms, whereas TUDCA is actively transported at the distal ileum.

  In some embodiments of the invention, a formulation is administered to treat and / or eradicate Helicobacter pylori infection and hepatitis C infection. In some embodiments of the invention, UDCA can be administered to efficiently treat acute or chronic inflammatory diseases of the liver and intestines. Inflammatory diseases include, but are not limited to, PBC, PSC, and bowel disease. In some embodiments, administration of UDCA significantly reduced liver cancer incidence. In some embodiments of the invention, UDCA is administered to treat hypercholesterolemia.

  In some embodiments, UDCA is substantially insoluble at pH 1 to pH 8, incompletely absorbed by unsaturated passive absorption in the upper gastrointestinal tract, and actively absorbed in the distal ileum . UDCA is partially metabolized by intestinal bacteria to lithocholic acid, which circulates in the liver, undergoes sulfation and conjugation, and is mainly excreted via the kidneys. Absorbed UDCA circulates in the enterohepatic circulation after conjugation with glycine and taurine in the liver. Bile acids that enter the enterohepatic circulation are excreted by hepatocytes in a very constant and effective manner.

  In some embodiments, the pH in the gastrointestinal tract, including the stomach and colon, may not be advantageous for solubilization of UDCA. Very slow solubilization in the duodenum-jejunum-ileum results in long-term absorption over time, which can result in very low blood levels of UDCA. In general, for drugs that dissolve in the gastrointestinal and jejunum, Tmax and Cmax in the blood depend on passive jejunal absorption. Thus, in the case of UDCA, which has low solubility in the contents of the gastrointestinal tract, there may be further solid ileal absorption of the gradually solubilized UDCA following the early absorption of the solubilized UDCA by the duodenum.

  In some embodiments, UDCA does not dissolve completely in the jejunal contents, but the variable proportion of the drug may be solid. This percentage is not related to the initial intake of UDCA. Solubilization of UDCA in gastric juice-jejunum varies depending on physiological conditions including, for example, fasting pH. UDCA does not substantially dissolve at acidic pH. Actually, UDCA precipitates in a weak alkaline environment (about pH 8).

In some embodiments, UDCA exists in solution and can be in direct contact with the epithelium of the colon to protect the large intestine so that the adenoma does not recur. Thus, the bile acid portion that is not in solution in the stool has little therapeutic significance. Thereby, it is more important to measure the active water-soluble bile acid fraction in stool than the total bile acid in stool, which is mostly in the stool and in an insoluble solid state that is inactive. Bile acids can act as intracellular signaling agents that regulate cell transport, alter intracellular Ca ²⁺ concentrations, and / or activate cell surface receptors.

  In some embodiments, the solubility of UDCA in aqueous solution is about 0.02 g / l to 60 g / l. According to some embodiments of the invention, the solubility of UDCA is about 3,000 times higher than the solubility of commercial UDCA (eg, 0.15 mol vs. 0.05 mmol). The solubility of UDCA is about 300 times higher than that of TUDCA. The solubility of deoxycholic acid (DCA) is 0.24 g / l. DCA is about 70 times more soluble than UDCA.

  In some embodiments, dosage forms of the invention (eg, oral, parenteral) contain, for example, 500 mg of UDCA. This dosage form may have a Cmax that is about 8 times higher than existing commercial UDCA shapes and / or a Tmax that is about 4-6 times faster than existing commercial UDCA shapes. Thus, Tmax is fast and Cmax is high, which means that dissolved UDCA is absorbed very efficiently from the upper gastrointestinal tract. Absorbed dissolved UDCA can pass through the gastric mucosa.

  In some embodiments, dosage forms of the invention (eg, oral, parenteral) contain, for example, 650 mg of UDCA. This dosage form can have a Cmax that is about 5 times higher than existing commercial UDCA shapes and / or a Tmax that is about 1.4 times faster than existing commercial UDCA shapes.

  In some embodiments, the solution viscosity of the present invention affects residence time in an organ (eg, gastrointestinal, duodenum, jejunum, ileum, colon, rectum, and / or blood) and dissolves UDCA into the organ. Affects transportation. Lysed UDCA can pass through cell membranes of, for example, the gastrointestinal, duodenum, jejunum, ileum, colon, and rectum.

  In some embodiments, the solutions of the present invention exhibit a significant increase in water solubility of UDCA, increased membrane permeability, and prevention of epimerization from UDCA to CDCA.

  In some embodiments, a UDCA dose above 10-12 mg / kg daily cannot increase its proportion in bile. Without limiting the embodiments of the present invention, when this occurs, (1) UDCA is biotransformed into CDCA via 7-ketritocholic acid by intestinal bacteria and / or (2) UDCA is 7-β-. This is because the hydroxyl group can be converted into CDCA by epimerization and further converted into lithocholic acid (LCA). Thus, UDCA absorption decreases with increasing UDCA dose.

  In some embodiments, the UDCA composition comprises UDCA dissolved in water that remains in solution at any pH. For example, the compositions of the present invention are free or substantially free of precipitates and particles at any pH.

  The composition of the present invention may contain soluble starch and / or soluble dietary carbohydrate. Without being limited to a specific embodiment, when UDCA, soluble starch, and soluble dietary carbohydrate coexist in the intestine, UDCA biotransforms into hydrophobic bile acids that have been estimated to promote colon cancer Can be reduced or prevented.

  In some embodiments, the compositions of the invention extend the gastrointestinal residence time of solubilized UDCA and / or allow UDCA to reach the epithelium of the entire gastrointestinal tract, including the large intestine. . In some embodiments, the composition of the present invention comprises a non-digestible oligosaccharide (a carbohydrate having a degree of polymerization of 3-10), an indigestible maltodextrin (Fibersol 2), guar gum, locust bean gum, and psyllium fiber. As well as dietary carbohydrates selected from the group consisting of non-starch polysaccharides that are not digested and absorbed in the small intestine. Compositions containing such dietary carbohydrates can reduce the concentration of total and secondary bile acids in the stool.

  In some embodiments, the compositions of the invention can include dietary carbohydrates. Dietary carbohydrates include, but are not limited to, guar gum, pectin, psyllium, oat gum, soy fiber, oat bran, corn bran, cellulose, wheat bran, and resistant maltodextrin (Fibersol 2). Absent.

  In some embodiments, the water-soluble salt of UDCA can be administered by the oral route, and the UDCA salt is protonated and precipitates in the acidic atmosphere of the gastrointestinal tract. Precipitated UDCA can reach the colon via the intestine. Precipitated protonated UDCA may not dissolve in the colon (eg, it is very insoluble). In some embodiments, the protonated UDCA utilizes or requires a relatively high pH for dissolution (eg, pH = 8.7) to efficiently protect the large intestine from adenoma recurrence. To do.

  In some embodiments, the bile acid composition of the present invention does not have one or more undesirable properties of existing commercial UDCA forms. Also, the bile acid composition of the present invention can in some embodiments contact colonic lesions without any precipitation and function as a local agonist in the colon. The bile acid dosage forms according to some embodiments of the invention can be adapted or adapted for oral and / or parenteral administration. In some embodiments, the bile acid composition of the invention comprises a complete molecule of UDCA, a water soluble starch conversion product (eg, a product obtained by hydrolysis of starch), and a soluble diet that is not digested and absorbed in the small intestine. Can contain carbohydrates. Bile acid compositions according to some embodiments of the invention can include solubilized bile acids in water, but in water the bile acids remain as an aqueous solution without any precipitation at any pH.

  In some embodiments, the bile acid composition is free or substantially free of precipitates or particles (eg, by visual inspection and / or light scattering). A composition free of precipitates and particles can be produced, for example, by adding bile acids to a basic solution and mixing until dissolved, and adding a water-soluble starch conversion product. The basic solution includes any common base. Common bases include, but are not limited to, ammonia, sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, calcium hydroxide, and calcium carbonate. The ratio of base to bile acid is about 0.5-20, about 0.5-15, about 0.5-10, about 0.5-5, about 0.5-1.5, about 0.6- 1.3 and / or about 1.0 to 1.3.

  In some embodiments, the method comprises contacting a lesion caused by the NSAID, alcohol, and / or stimulant drug with a pharmaceutically effective amount of dissolved UDCA. The contacting lesion is located in the gastrointestinal tract and / or in the systemic circulation. The method can further comprise administering to the subject a composition of the invention.

  Nonsteroidal anti-inflammatory drugs (NSAIDs), drugs with analgesic, antipyretic, and / or anti-inflammatory effects, are associated with gastrointestinal toxicity that primarily develops in the form of gastrointestinal mucosal damage such as acute hemorrhagic erosion. It can also damage the small intestine and / or the colon.

  The present invention provides (i) one or more soluble bile acids, water-soluble derivatives of bile acids, bile salts, (ii) water, and (iii) a solution that does not form a precipitate at any pH within a predetermined pH range. An aqueous solution comprising an amount of one or more water-soluble starch conversion products and a water-soluble dietary carbohydrate sufficient to produce The composition may contain a bile acid or bile salt that itself has pharmacological effectiveness. Also, in some embodiments of the invention, the compositions of the invention may contain non-bile acid drugs that are incompletely soluble.

  In some embodiments, the bile acids and carbohydrates of the present invention have the advantage of maintaining in solution at any pH from acidic to alkaline without precipitation. These aqueous bile acid systems have no or substantially no precipitates or particles. A further advantage according to some embodiments of the present invention is that the aqueous system can be used for several months (eg 1, 2, 3, 4, 5) under accelerated conditions of storage at 50 ° C. after addition of a strong acid or strong alkali. , 6, 7, 8, 9, 10, 11, or 12 months), no change in physical appearance, such as changes in transparency, color, or smell.

  In some embodiments of the present invention, an aqueous bile acid system is administered orally and exposed to acidic gastric juice, or exposed to alkaline gastrointestinal fluid, but the gastrointestinal tract does not precipitate bile acids. Reach the tube. These solubilized bile acid formulations are effectively absorbed by direct contact of the solubilized bile acid with the intestine. After absorption, solubilized bile acids undergo enterohepatic circulation. One or more bile acids can be dissolved in these aqueous solutions as therapeutic agents, as drug adjuvants, as drug carriers, or as drug solubility enhancers. The composition of the present invention is, in some embodiments, an oral dosage agent, oral cleanser, gargle, nasal drop, ear drop, injection, vaginal cleanser, enema, topical skin preparation, other topical preparations. You may prepare for a formulation and cosmetics.

  The soluble bile acid can be any type of water-soluble bile acid. The bile salt may be a water-soluble salt of any kind of bile acid. Bile salts are more excellent detergents because they exhibit a higher solubilizing ability with respect to phospholipids and cholesterol. More hydrophobic bile salts are more harmful to various membranes both in vivo and in vitro. Water-soluble salts of bile acids can be formed by reacting (1) bile acids with (2) alkalis or amines, where the amines include fatty acids such as trientine, diethylenetriamine, tetraethylenepentamine and the like. Group free amines; basic amino acids such as arginine, lysine, ornithine; ammonia; amino sugars such as D-glucamine and N-alkylglucamine; quaternary ammonium derivatives such as choline; piperazine, N-alkylpiperazine, piperidine, Examples include, but are not limited to, heterocyclic amines such as N-alkylpiperidine, morpholine, N-alkylmorpholine, pyrrolidine, triethanolamine, and trimethanolamine. According to some embodiments of the invention, the soluble bile salt comprises a water-soluble metal salt of a bile acid, a water-soluble metal salt of a bile acid / cyclodextrin-containing compound, and a water-soluble O-sulfonated bile acid. A metallic metal salt may be contained. According to some embodiments of the invention, the soluble bile acid derivative may be a derivative that is as soluble in aqueous solution as the corresponding non-derivatized bile acid, or more soluble in aqueous solution. Bile acid derivatives include, but are not limited to, derivatives formed with functional groups including but not limited to halogens and amino groups at the carboxylic acid group and hydroxyl group of bile acids. Soluble bile acids may include an aqueous formulation of the free acid form of bile acids combined with one of HCl, phosphoric acid, citric acid, acetic acid, ammonia, or arginine. Bile acids that can be used in accordance with the teachings of the present invention include, but are not limited to, ursodeoxycholic acid, hyodeoxycholic acid, 7-oxolithocholic acid, and water-soluble derivatives of bile acids.

  In some embodiments, administration of the compositions of the present invention can result in higher bile acid concentrations in the body than at least some existing commercial formulations. Thus, the therapeutic potential of bile acids can be achieved more completely than other formulations. The bile acid concentration in the body obtained by existing formulations in which bile is incompletely dissolved may be lower and may require administration of higher amounts of bile acid. In contrast, the bile acid concentration in the body obtained by a composition according to an embodiment of the present invention in which bile acids are completely or substantially completely dissolved is higher when equal or lower doses are administered. .

  In some embodiments of the invention, different types of bile acids can be used in a single formulation. A mixture of two or more bile salts of different hydrophobic activity can act as an intermediate hydrophobic active single bile salt. As a result, the detergency and toxicity of a mixture of two or more bile acids of different hydrophobic activity is often intermediate between the individual components.

  A mixture of two or more bile salts of different hydrophobic activity can act as an intermediate hydrophobic active single bile salt. As a result, the detergency and toxicity of a mixture of two or more bile acids of different hydrophobic activity is often intermediate between the individual components.

  Suitable carbohydrates for use in the present invention include water soluble starch conversion products and soluble dietary carbohydrates that are not digested and absorbed in the small intestine. According to some embodiments of the present invention, the water-soluble starch conversion product includes carbohydrates obtained by partial or incomplete hydrolysis of starch under various pH conditions (eg, directly from starch). included. Non-limiting examples include maltodextrin, dextrin, liquid glucose, solid corn syrup (dry powder of liquid glucose), and soluble starch. In some embodiments, as maltodextrin, liquid glucose, and solid corn syrup (dry powder of liquid glucose), for example, MALTRIN® 040 manufactured by Grain Processing Corporation GPC®, Muscatine, Iowa. D.E.4-7), MALTRIN (registered trademark) 050 (DE.4-7), MALTRIN (registered trademark) 070 (DE-6-9), MALTRIN (registered trademark) 0100 (D.E. E.9-12), MALTRIN (registered trademark) 150 (DE.13-17), MALTRIN (registered trademark) 180 (DE16.5-19.5), MALTRIN (registered trademark) 200 ( DE.20-23), MALTRIN (registered trademark) 250 (DE23-27), MALTR N (registered trademark) 440 (DE-4-7), MALTRIN (registered trademark) 500 (DE-9-12), MALTRIN (registered trademark) 550 (DE 13-17), MALTRIN ( (Registered trademark) 580 (DE-4-7), MALTRIN (registered trademark) M585 (DE16.5-19.5), MALTRIN (registered trademark) 600 (DE20-23), Uses MALTRIN 510 (DE-9-12), MALTRIN 520 (DE 9-12), and MALTRIN M700 (DE 9-12) can do. For the purposes of this embodiment, the term “solid corn syrup” is a dry form of liquid glucose. The starch conversion product, in some embodiments, includes at least one reducing end and / or at least one non-reducing end. If the starch conversion product is polymeric, it may be linear or branched. The molecular weight may be about 100 mass units to 106 mass units or more. The high molecular weight water-soluble starch conversion product has a molecular weight exceeding 105 mass units.

  In some embodiments, the cyclodextrin formed by a condensation step whose free ends are eliminated cannot be considered a water-soluble starch conversion product or a water-soluble non-starch polysaccharide. In some embodiments, the compositions of the present invention may be substantially free of cyclodextrins. In some embodiments, the compositions of the present invention may not contain any cyclodextrins. Alternatively, in some embodiments of the invention, the formulations of the invention may contain cyclodextrins in addition to starch conversion products and / or non-starch polysaccharides.

  The amount of soluble dietary carbohydrates and / or high molecular weight water-soluble starch conversion products that are not digested and absorbed in the small intestine used in embodiments of the present invention is determined by the selected bile acids at a given concentration and / or pH or pH. The amount necessary to dissolve in the preparation in the range or more. The ratio of water soluble starch conversion product to soluble dietary carbohydrate (soluble resistant starch) is about 10-100 to about 90-0 on a weight basis.

  In some embodiments of the invention, the approximate minimum weight ratio of maltodextrin to UDCA required to prevent UDCA precipitation is 6: 1 (i.e., 1 in 0.2 mL of UDCA in 100 mL water). 2 g, 6 g for UDCA 1 g, and 12 g for UDCA 2 g). In some embodiments of the invention, the approximate minimum amount of maltodextrin is 30 g for 200 mg chenodeoxycholic acid, 12 g for 200 mg 7-ketolithocholic acid, 10 g for 200 mg cholic acid, 50 g for 200 mg deoxycholic acid. Good. In some embodiments of the present invention, the approximate minimum weight ratio of liquid glucose (commercially available light corn syrup) to UDCA required to prevent precipitation of bile acids from the aqueous dosage forms of the present invention is: Approximately 25: 1 (ie 12.5 g for 500 mg of UDCA in 100 mL of water and 25 g for 1 g of ursodeoxycholic acid in 200 mL of water). In some embodiments of the present invention, a dry powder of liquid glucose (eg, solid corn syrup such as MALTRIN® M200) required to prevent the precipitation of bile acids from the aqueous dosage forms of the present invention. The approximate minimum is 30 g for 1 g of ursodeoxycholic acid in 100 mL of water and about 60 g for 2 g of ursodeoxycholic acid in 200 mL of water. In some embodiments of the present invention, the approximate minimum amount of soluble non-starch polysaccharide required to prevent the precipitation of bile acids from the aqueous dosage forms of the present invention is ursodeoxychol in 100 mL of water. 50 g of guar gum per 500 mg of acid and 80 g of pectin per 500 mg of ursodeoxycholic acid in 100 mL of water. According to some embodiments, the minimum required amount of high molecular weight water soluble starch conversion product and / or soluble non-starch polysaccharide is determined primarily by the absolute amount of bile acids in the solution formulation, not concentration. Good.

  In some embodiments of the invention, the formulation comprises soluble dietary carbohydrates and starch conversion products that are not digested and absorbed in the small intestine, and additional cyclodextrins (as taste masking).

  In some embodiments of the invention, the formulation further comprises an emulsifier. For the purposes of the present invention, the term “emulsifier” includes emulsifiers and suspending agents. Non-limiting examples of emulsifiers include guar gum, pectin, acacia, carrageenan, sodium carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, povidone, tragacanth gum, xanthan gum, and sorbitan esters.

  The selected pH range in which the formulation does not precipitate its bile acids, starch conversion products, soluble dietary carbohydrates that are not digested and absorbed in the small intestine can be any pH level range obtained in aqueous systems. In some embodiments, the range may be about pH 1 to about pH 14 and / or about pH 1 to about pH 10. In some embodiments, the pH range may be a subset of the pH level range where the pharmaceutical formulation is obtained in an aqueous system sufficient to maintain a solution state from preparation to administration, absorption in the body, according to the method of administration. . Thus, the composition can be used as a pharmaceutical formulation in which the pharmaceutical compound and / or bile acid remains in solution without precipitation at any pH level common in the mouth, stomach, and intestine.

In some embodiments of the invention, the solution can be used with a pH adjuster. Non-limiting examples include HCl, H ₃ PO ₄ , H ₂ SO ₄ , HNO ₃ , CH ₃ COOH, citric acid, malic acid, tartaric acid, lactic acid, phosphate, edetic acid, and alkali.

  In some embodiments of the invention, despite the normal insolubility of bile acids under acidic conditions, the bile acids are in a dissolved state as free bile acids under acidic conditions.

  The solution, according to some embodiments, comprises one or more pharmaceutical compounds (eg, a pharmaceutical compound comprises an analgesic agent, antipyretic agent, anti-inflammatory agent, immunoactive agent, antineoplastic agent, antibiotic agent, antitumor agent). Including). Administration of the bile composition of the invention in combination with a pharmaceutical compound, in some embodiments, (a) enhances the response to the pharmaceutical compound, (b) improves the efficacy of the pharmaceutical compound, (c) The required dose of the pharmaceutical compound can be reduced and / or (d) the toxicity of the pharmaceutical compound can be reduced. The solution of the present invention may be administered alone with respect to the route and time of administration. Non-limiting examples of pharmaceutical compounds include aspirin, methyl salicylate, diflunisal, indomethacin, sulindac, diclofenac, ibuprofen, ketoprofen, naproxen, ketorolac, mefenamic acid, piroxicam, meloxicam, coxib celecoxibrofecoxib, valdecoxib, parecoxib, parecoxib , Nimesulide, oxaliplatin, leucovorin, irinotecan, cimetidine, salicylic acid, 2,2-bis (4- (4-amino-3-hydroxyphenoxy) phenyl) adamantane (DPA), paclitaxel, oxaliplatin, 5-fluorouracil, azathioprine, Mycophenolate mofetil, cyclosporine, mycophenolic acid, tacrolimus, sirolimus, basiliximab, daclizumab, Thymocyte globulin (rabbit), allopurinol, palonosetron, dolasetron, pamidronate, rasburicase, aprepitant, amifostine, gefitinib, palifermin, granisetron, sargramostim, levothyroxine, dronabinol, pegfilgrastim, interleukin 11, filgrastim, octreotide Cinacalcet, levothyroxine, liotrix, dexrazoxane, ondansetron, zoledronic acid, celecoxib, fenoprofen, benolylate, faislamine, amoxiprin, carprofen, flurbiprofen, loxoprofen, thiaprofenic acid, Meclofenamic acid, ketorolac, oxaprozin, etodolac, nabumetone, mesalamine, Rusalazide, bevacizumab, alemtuzumab, cetuximab, aldesleukin, ibritumomab tiuxetan, pemetrexed, tositumomab, gemcitabine, imatinib, trastuzumab, altretamine, topotecan, interferon alpha-2b, procarbamiboxelm Throne, denileukin diftitox, rituximab, erlotinib, bexarotene, arsenic trioxide, bortezomib, tretinoin, doxorubicin, dactinomycin, epirubicin, idarubicin, pentostatin, busulfan, temozolomide, melphalanvin, chlorambucil, chlorambucil HC , Cladribine, mercaptopurine, thioguanine, capecitabine, bicalta Mido, flutamide, anastrozole, exemestane, fulvestrant, letrozole, estramustine, leuprolide, triptolymphomote, histrelin, goserelin, porfimer, rotenone, tenoyltrifluoroacetone (TTFA), antimycin A, myxo Thixazole or oligomycin dexamethasone, methylprednisolone, hydrocortisone, prednisolone, rotenone, tenoyltrifluoroacetone (TTFA), antimycin A, myxothiazole, oligomycin, valdecoxib, rofecoxib, parecoxib and etoroxib, atorvastatin, cerivastatin, cerivastatin Lovastatin, pravastatin sodium, simvastatin, rosuvastatin, Basutachin include pitavastatin.

  In some embodiments of the invention, the formulations can be used to treat (eg, ameliorate at least one symptom) human and mammalian diseases.

  In some embodiments of the invention, the composition may be prepared and / or modified so that it can be administered as a liquid, solid, powder, or granule, capsule, and tablet. In some embodiments of the invention, the composition may be contained in parenteral solutions (eg, injection solutions, solutions, syrups, concentrated syrups, or pastes), enemas, jellies, and mucilages. Non-limiting examples of syrups include maltodextrin solutions with a maltodextrin concentration of less than 500 g / L. Non-limiting examples of syrups include maltodextrin solutions with a maltodextrin concentration of 500 g / L to 1.0 kg / L. Non-limiting examples of concentrated syrups include maltodextrin solutions with a maltodextrin concentration of 1.0 kg / L to 1.2 kg / L. Non-limiting examples of pastes include maltodextrin solutions with a maltodextrin concentration greater than 1.2 kg / L.

  A jelly may be a type of gel whose structural coherent matrix contains a high proportion of liquid, usually water. This is similar to a mucus in that it can be made from a similar type of gum, but differs from a mucus in that it has a jelly-like viscosity. Non-limiting examples of jelly include lidocaine jelly USP hydrochloride and therapeutic vaginal jelly. In some embodiments, the jelly may contain a thickener (eg, a synthetic cellulose derivative that swells with water and / or a water-soluble polysaccharide). Non-limiting examples of jelly thickeners include acacia, chondrus, gelatin, xanthan gum, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and / or hydroxypropylmethylcellulose.

  The mucous agent may be a liquid that is thick, sticky, and adhesive. The mucilage can be prepared by dispersing or dissolving the gum in water or extracting the sticky component from the plant material with water. Non-limiting examples of mucus include acacia mucilage and tragacanth mucus. Jelly and mucus are mainly used to prevent the bitter taste of bile acids by minimizing physical contact of dissolved bile acids. In some embodiments, the mucilage may contain a thickener (eg, a synthetic cellulose derivative that swells with water and / or a water-soluble polysaccharide). Non-limiting examples of thickeners include acacia, tsunogata, gelatin, xanthan gum, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and / or hydroxypropylmethylcellulose.

  The stability of the dosage formulation of the present invention is such that at various pH and temperature levels in formulations containing soluble bile acids, soluble carbohydrates (high molecular weight water soluble starch conversion products and dietary carbohydrates), and water. It can be evaluated by measuring the concentration of bile acids over time. By adjusting the residence time (high performance liquid chromatography) of each bile acid as necessary, for example, each bile acid present in a complex sample in which one sample contains multiple types of bile acids is individually Can be analyzed. The stability test can also be performed by evaluating the light scattering characteristics of the test solution. In addition, proven accelerated test conditions may be used.

  In some embodiments, the composition of the present invention is filtered for 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 Week, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 9 months, 12 months, 18 months, and / or more than 24 months, Maintain no precipitate or particles. In some embodiments, the composition of the present invention is 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks later 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 9 months, 12 months, 18 months, and After 24 months, an initial bile concentration greater than about 95%, an initial bile concentration greater than about 96%, an initial bile concentration greater than about 97%, an initial bile concentration greater than about 98%, and / or greater than about 99% Has an initial bile concentration.

  All stability tests performed on the solutions of the present invention were good in that the bile acid concentration measured by HPLC did not change over time at appreciable pH levels. In particular, all bile acid solution formulations tested showed excellent results in the stability test with no precipitation and no change in physical appearance over the test period. Some formulations remain stable for 2 years. The aqueous dosage form according to the present invention is physically and chemically under various pH conditions under accelerated conditions, despite the addition of therapeutic and chemically active agents that are stable and soluble in hydrochloric acid solutions. Did not change. Accordingly, these aqueous systems can be useful pharmaceutical dosage forms for therapeutic bile acid formulations and / or drug (pharmaceutical compound) delivery formulations. In such formulations, bile acids are not stable at various pH conditions (eg, including precipitation under acidic conditions), without drug adjuvants, drugs, carriers, or drug solubility enhancers (eg, by micelle formation). ).

UDCA Dry Form In some embodiments, the solutions of the present invention may be in dry form or in solid form. For the purposes of the present invention, a “primary” aqueous bile acid formulation according to the present invention is prepared from the original combination of bile acid or salt thereof and carbohydrate water (eg, mother liquor). It can manufacture by combining each component simultaneously or in steps. In contrast, a “secondary” aqueous solution for bile acid administration is a solution made from a powder or solid containing bile acids and carbohydrates previously dissolved together. Accordingly, the secondary bile acid aqueous solution administration formulation is different in that at least water is added and then added again after removal.

  In some embodiments, the bile acid composition can be stored or administered in a dry and / or solid form. Accordingly, the present invention relates to a dry or solid formulation of bile acid that forms a clear (ie, free or substantially free of precipitates or particles) solution (eg, secondary solution) when exposed to water. The dry or solid form of the present invention can be made from a clear (ie, free or substantially free of precipitates or particles) bile acid solution (“mother liquor”). The invention also relates to a method for producing and / or solubilizing these dried and / or solid forms. These dry or solid formulations improve bile acid bioavailability, plasma bioavailability, and / or water absorption. Furthermore, the formulations of the present invention improve the bioavailability, plasma bioavailability, and water absorption of one or more pharmaceutical compounds.

  In some embodiments, the solution (eg, mother liquor) of the present invention may be dry or solid. For example, a dry or solid form can be prepared by lyophilizing and / or evaporating a solution formulation of bile acids. The solution can also be partially dried to produce a semi-solid form. The solution can also be completely dried to form solids, powders, and / or granules. The dried or solid form of the aqueous solution is free or substantially free of water. The dried or solid form can be dried by flow method, tray method, spray method, and / or freezing method. The dry or solid form can be administered directly in solid dosage form or can be formulated with water prior to administration.

  The compositions (eg, dry or solid form) of the present invention can further contain a disintegrant. Disintegrants facilitate the degradation or disintegration of the dried or solid form after administration. Disintegrants include starches such as Veegum HV, methylcellulose, agar, bentonite, natural sponges, cation exchange resins, alginic acid, guar gum, citrus pulp, carboxymethylcellulose, clays, celluloses, algins, gums and Cross-linked polymers (crospovidone), cross-linked cellulose (croscarmellose) and cross-linked starch (sodium starch glycolate) are included. The collapse function may be due to capillary action rather than swelling. Generally, the water soluble disintegrant is mixed with the active ingredient prior to drying. The water-insoluble disintegrant may be added to the powder mixture in a dry state with 5% by weight starch. If more rapid disintegration is required, this addition may be increased to 10% or 15%. 2-4% sodium starch glycolate swells 7-12 times within 30 seconds and croscarmellose swells 4-8 times within 10 seconds.

  The evolution of carbon dioxide supports the rapid dissolution of dry or solid forms derived from solution formulations of bile acid compositions. Dry or solid forms containing a mixture of acidulants such as tartaric acid and citric acid and sodium bicarbonate will foam when added to water. The amount of sodium bicarbonate may be about 10 times the amount of bile acids. The amount of acidulant may be 20% greater than the amount of sodium bicarbonate. A sufficient amount of acid is added to cause a neutral or weakly acidic reaction when dissolution in water is rapid and complete.

  The present invention also relates to a method for preparing a solution formulation derived from a dried or solid form of a bile acid composition. In the drying or dissolution of the solid preparation of the present invention, high power sonication can be performed with or without heating at about 60 ° C. During preparation of the solution formulation using a high power sonication system, the precipitated compound can be returned to the solution state. The sonication time, intensity and amplitude effects can be optimized to return the compound to solution. In the formation of the transparent aqueous solution of the present invention, an ultrasonic device that generates acoustic energy of 0 to 1150 watts at 20 kHz can be used.

  In some embodiments, the dry or solid form may be prepared from the mother liquor by wet granulation, dry granulation, and / or fluid bed granulation. If the ingredients have sufficient intrinsic binding or agglomeration properties, granules may be made using a dry granulation method (slagging). The general stages of wet and dry granulation include nominal, mixing, granulating (slugging), and screening. Fluidized bed granulation can be carried out by spraying the granulation solution or solvent into or on the suspended particle layer and then rapidly drying it in air that is floating. In such systems, the suspended particles in dry form derived from the mother liquor may be coated with a granulation solution or solvent containing an enteric polymer. The enteric polymer is cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), methacrylic acid-methacrylic acid ester copolymer, cellulose acetate trimellitate that effectively functions as an enteric coating agent at a pH above pH 6. CAT), carboxymethyl ethyl cellulose (CMEC), and / or hydroxypropyl methyl cellulose acetate succinate (HPMCAS). The granular form containing the enteric polymer remains intact in the gastrointestinal tract and dissolves to release the active ingredient once it reaches the small intestine and colon.

  Spheronization to form a pellet form includes forming spherical particles (spheres) from wet granulation or fluid bed granulation. Bar-shaped cylindrical sections having a diameter in the range of 500 microns to 12 millimeters may be produced using an extruder. After extrusion, the slice is put in a Malmerizer so that it becomes spherical by centrifugal force and frictional force on the rotating plate. The pellets are dried and then coated. In some embodiments of the present invention, a dry or solid form of a solution formulation of a bile acid composition may be manufactured by a spheronization process and then coated with an enteric polymer.

  In some embodiments of the invention, the primary aqueous solution of the bile acid administration formulation may be dried by a spray drying method. The spray drying method may include the steps of sending a highly dispersed liquid and a sufficient volume of hot air to evaporate and dry the droplets. The liquid to be injected may be a solution, slurry, syrup or paste as long as it can be pumped and sprayed. The liquid may be injected into a warm air stream filtered by spraying. The air supplies the heat for evaporation and transports the dried product to the collector before being discharged with moisture. The spray-dried powder particles are homogeneous, have a substantially spherical shape, are almost uniform in size, and often have a hollow shape. The property of having a hollow has the result that the solution speed is high and the volume density is low. This method is useful for protecting an internal substance and controlling its release rate by coating one substance on another. For example, a dry form of an aqueous bile acid formulation may be coated with an enteric polymer for colonic delivery of solubilized UDCA. Dehydration may be accomplished by lyophilization, evaporation, or other dehydration techniques known in the art.

  Dry forms (eg, powders or solids) may be administered directly, or may be reconstituted with water and formulated as a clear secondary bile acid aqueous dosage formulation. Formulations for administration of secondary bile acid aqueous solutions, i.e., aqueous solutions of these formulations prepared from a dry form, may have the same or substantially the same properties as the primary formulation.

  The present invention includes adding additives such as drugs to the dry or solid form as well as primary and secondary bile acid aqueous solutions. When administered in dry or solid form, it may be used in combination with one or more diluents, lubricants, binders, fillers, drugs, disintegrants, or other additives. Thus, the dry or solid form may be prepared as a powder, granule, pill, tablet, or capsule.

  In some embodiments, a dry or solid formulation of the invention, when exposed to water, (1) conjugation with a bile acid, derivative thereof, salt thereof, or amine, (2) water, and (3 ) The solution may contain a sufficient amount of water-soluble starch conversion product for the bile acid and starch conversion product to remain in solution at any pH within the selected pH range. In some embodiments, a dry or solid formulation of the invention, when exposed to water, (1) conjugation with a bile acid, derivative thereof, salt thereof, or amine, (2) water, and (3 ) The solution may contain a sufficient amount of water-soluble non-starch polysaccharide and water-soluble starch conversion product for bile acids and polysaccharides to remain in solution at any pH within the selected pH range.

  The dried or solid form of the present invention may further comprise an indigestible maltodextrin, a water-soluble ginseng extract, a pharmaceutically appropriate amount of a pharmaceutical compound, a water-soluble bismuth compound, or a combination thereof when exposed to water. Good. If the solution contains one or more of these materials, the solution composition is adjusted so that these materials remain in solution.

  Some embodiments of the invention will be understood in connection with the following examples. However, the specific materials, compositions, and results described are merely illustrative of the invention and are not intended and are to be construed as limiting the scope of the disclosure and its various embodiments. Those skilled in the art will readily understand that this is not the case.

Example 1: Preparation of Bile Acid Solution-Formulation 60 A sodium hydroxide solution was prepared by dissolving 5.2 g of extra pure grade (EP) NaOH in 100 mL of USP pharmaceutical grade water. Next, 48 g of UDCA was added to obtain a clear solution A.

  A clear solution B was prepared by completely dissolving 320 g of food grade (NF) maltodextrin and 320 g of food grade (NF) soluble resistant starch in 300 mL of USP pharmaceutical grade water.

  Solution A and Solution B were stirred and mixed, and then an appropriate amount (0.3 g / kg) of food grade sodium bisulfite was added to the clear solution. Food grade dilute phosphoric acid was added to adjust the pH of this final solution (pH: 6-7.5). If necessary, this final solution may be filtered and / or sterilized by heating at 80 ° C to 100 ° C.

Example 2: Preparation of Bile Acid Solution-Formulation 25 A sodium hydroxide solution was prepared by dissolving 2.7 g of EP NaOH in 100 mL of USP pharmaceutical grade water. Next, 25 g of UDCA was added to obtain a clear solution A.

  A clear solution B was prepared by completely dissolving 500 g of NF maltodextrin and 150 g of NF soluble resistant starch in 400 mL of USP pharmaceutical grade water.

  Solution A and Solution B were stirred and mixed, and then an appropriate amount (0.3 g / kg) of food grade sodium bisulfite was added to the clear solution. Food grade dilute phosphoric acid was added to adjust the pH of this final solution (pH: 6-7.5). If necessary, this final solution may be filtered and / or sterilized by heating at 80 ° C to 100 ° C.

Example 3: Preparation of Bile Acid Solution-Formulation 20 A sodium hydroxide solution was prepared by dissolving 2.2 g of EP NaOH in 100 mL of USP pharmaceutical grade water. Next, 20 g of UDCA was added to obtain a clear solution A.

  A clear solution B was prepared by completely dissolving 500 g of NF maltodextrin and 150 g of NF soluble resistant starch in 400 mL of USP pharmaceutical grade water.

  Solution A and Solution B were stirred and mixed, and then an appropriate amount (0.3 g / kg) of food grade sodium bisulfite was added to the clear solution. Food grade dilute phosphoric acid was added to adjust the pH of this final solution (pH: 6-7.5). If necessary, this final solution may be filtered and / or sterilized by heating at 80 ° C to 100 ° C.

Example 4: Preparation of Bile Acid Solution-Formulation 15 A sodium hydroxide solution was prepared by dissolving 1.72 g of EP NaOH in 100 mL of USP pharmaceutical grade water. Next, 15 g of UDCA was added to obtain a clear solution A.

  A clear solution B was prepared by completely dissolving 450 g of NF maltodextrin and 200 g of NF soluble resistant starch in 400 mL of USP pharmaceutical grade water.

  Solution A and Solution B were stirred and mixed, and then an appropriate amount (0.3 g / kg) of food grade sodium bisulfite was added to the clear solution. Food grade dilute phosphoric acid was added to adjust the pH of this final solution (pH: 6-7.5). If necessary, this final solution may be filtered and / or sterilized by heating at 80 ° C to 100 ° C.

Example 5: Preparation of Bile Acid Solution-Formulation 10 A sodium hydroxide solution was prepared by dissolving 1.1 g of EP NaOH in 100 mL of USP pharmaceutical grade water. Next, 10 g of UDCA was added to obtain a clear solution A.

  A clear solution B was prepared by completely dissolving 300 g of NF maltodextrin and 300 g of NF soluble resistant starch in 400 mL of USP pharmaceutical grade water.

  Solution A and Solution B were stirred and mixed, and then an appropriate amount (0.3 g / kg) of food grade sodium bisulfite was added to the clear solution. Food grade dilute phosphoric acid was added to adjust the pH of this final solution (pH: 6-7.5). If necessary, this final solution may be filtered and / or sterilized by heating at 80 ° C to 100 ° C.

Example 6: Preparation of Bile Acid Solution-Formulation 5 A sodium hydroxide solution was prepared by dissolving 0.55 g of EP NaOH in 100 mL of USP pharmaceutical grade water. Next, 5 g of UDCA was added to obtain a clear solution A.

  A clear solution B was prepared by completely dissolving 150 g of NF maltodextrin and 150 g of NF soluble resistant starch in 450 mL of USP pharmaceutical grade water.

  Solution A and Solution B were stirred and mixed, and then an appropriate amount (0.3 g / kg) of food grade sodium bisulfite was added to the clear solution. Food grade dilute phosphoric acid was added to adjust the pH of this final solution (pH: 6-7.5). If necessary, this final solution may be filtered and / or sterilized by heating at 80 ° C to 100 ° C.

Example 7: Preparation of Jelly Containing Bile Acid A sodium hydroxide solution was prepared by dissolving 1.72 g of extra pure grade (EP) NaOH in 100 mL of USP pharmaceutical grade water. Next, 15 g of UDCA was added to obtain a clear solution A.

  Solution B was prepared by adding 450 g of food grade (NF) maltodextrin, 100 g of food grade (NF) hydroxyethylcellulose (thickener) and 100 g of NF soluble resistant starch to 300 mL of USP pharmaceutical grade water.

  Solution A and Solution B were stirred and mixed, and then an appropriate amount (0.3 g / kg) of food grade sodium bisulfite was added to this solution. In order to obtain a completely clear solution and to sterilize, the obtained solution was heated at 80 ° C to 100 ° C.

Example 8: Preparation of Acacia Mucilage Containing Bile Acid A sodium hydroxide solution was prepared by dissolving 1.1 g of EP NaOH in 100 mL of USP pharmaceutical grade water. Next, 10 g of UDCA was added to obtain a clear solution A.

  Solution B was prepared by adding 300 g food grade (NF) maltodextrin and food grade (NF) acacia (gum arabic; thickener) to 400 mL USP pharmaceutical grade water.

  Solution A and Solution B were stirred and mixed, and then an appropriate amount (0.3 g / kg) of food grade sodium bisulfite was added to this solution. In order to obtain a completely clear solution and to sterilize, the obtained solution was heated at 80 ° C to 100 ° C.

Example 9: Animal Experiments-Methods Four week old male ICR mice, each with an initial weight of 23-25 g, were divided into two experimental groups. AOM was administered alone to a first group of 10 animals, and AOM and the bile acid composition of the present invention were administered to a second group of 10 animals.

  AOM (10 mg / kg body weight) was injected once intraperitoneally into the AOM group of mice. One week after the injection of AOM, mice in the AOM group were allowed to drink drinking water containing 1% dextran sulfate sodium (DSS: tumorigenesis promoter) for 7 days without any additional treatment. .

  In the AOM + bile acid group, 0.1 ml of formulation 15 (Example 4) was orally administered daily to mice for one week, and then AOM (10 mg / kg body weight) was injected intraperitoneally once. One week after the injection of AOM, mice in the AOM + bile acid group were allowed to drink drinking water containing 1% dextran sulfate sodium freely for 7 days. This group of mice continued to receive 0.1 ml of Formula 15 daily until the mice died.

Example 10: Animal Experiments-Results According to visual observations, mice in the AOM + bile acid group were generally healthier throughout the experimental period than mice in the AOM group. All mice in the AOM group did not appear healthy. All mice in the AOM group had one or more tumors in the back and head (FIG. 4A), and 5 of the mice in the AOM group were blind (FIG. 2). In mice with tumors in the back and head, abnormal behavior was observed, such as not standing, running, or just falling on the floor. However, only one such abnormal behavior was observed in mice in the AOM + bile acid group.

  The average body weight of the mice in the AOM group and the AOM + bile acid group increased up to 4 weeks, whereas in the AOM group, the average body weight of the mice was significantly reduced before death (FIG. 7). The average body weight of the AOM + bile acid group mice remained substantially stable until death after 4 weeks (FIG. 7).

  There were some blood spots on the tail of all mice in the AOM group (FIG. 5A), whereas no blood spots appeared on the tail of mice in the AOM + bile acid group (FIG. 5B).

  All test mice in the AOM group were greatly swollen and had blood spots in some places, but none of the mice in the AOM + bile acid group were swollen or had blood spots (FIGS. 1A and 1B). ).

  According to visual inspection, several adenomatous polyps were observed in all areas of the large intestine in all mice in the AOM-treated group (FIGS. 3A and 8A (left side)), but almost in the AOM + bile acid group. Not observed (FIG. 3B and FIG. 8B (right side)). In the AOM + bile acid group, only one adenomatous polyp was observed in two animals.

  All mice in the AOM group died within 10 weeks after AOM injection (Figure 6). In the case of mice in the AOM + bile acid group, 60% survived at 10 weeks after injection of AOM, and 40% survived at 14 weeks (FIG. 6). In addition, in the AOM + bile acid group, 20% (2 animals) of the mice survived after 16 weeks (FIG. 6).

  In the AOM + bile acid group, 6 died within 3 weeks, which is presumed to be shock death. Excluding these mice, the survival rate of this group is higher. That is, 86%, 57%, and 29% respectively at the 10th, 14th, and 16th weeks.

Claims (45)

A method of protecting the large intestine from adenomatous polyposis in a subject comprising:
(A) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, and 7-ketritocholic acid;
(B) a carbohydrate selected from the group consisting of a water-soluble starch conversion product, a water-soluble dietary carbohydrate that is not digested and absorbed in the small intestine, and combinations thereof;
(C) contains water,
Administering to the subject a composition in which both the first substance and the carbohydrate maintain a solution state at all pH values of the solution in the selected pH value range. A method of extending the life span of a subject having colorectal adenomatous polyposis comprising:
(A) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, and 7-ketritocholic acid;
(B) a carbohydrate selected from the group consisting of a water-soluble starch conversion product, a water-soluble dietary carbohydrate that is not digested and absorbed in the small intestine, and combinations thereof;
(C) contains water,
Administering to the subject a composition in which both the first substance and the carbohydrate maintain a solution state at all pH values of the solution in the selected pH value range. A method of maintaining the overall weight of a subject having colorectal adenomatous polyposis, comprising:
(A) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, and 7-ketritocholic acid;
(B) a carbohydrate selected from the group consisting of a water-soluble starch conversion product, a water-soluble dietary carbohydrate that is not digested and absorbed in the small intestine, and combinations thereof;
(C) contains water,
Administering to the subject a composition in which both the first substance and the carbohydrate maintain a solution state at all pH values of the solution in the selected pH value range. A method of reducing or treating at least one symptom of colorectal adenomatous polyposis in a subject having or at risk of having colorectal adenomatous polyposis comprising:
(A) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, and 7-ketritocholic acid;
(B) a carbohydrate selected from the group consisting of a water-soluble starch conversion product, a water-soluble dietary carbohydrate that is not digested and absorbed in the small intestine, and combinations thereof;
(C) contains water,
Administering to the subject a composition in which both the first substance and the carbohydrate maintain a solution state at all pH values of the solution in the selected pH value range. A method for reducing recurrence of colorectal adenoma in a subject's large intestine, comprising:
(A) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, and 7-ketritocholic acid;
(B) a carbohydrate selected from the group consisting of a water-soluble starch conversion product, a water-soluble dietary carbohydrate that is not digested and absorbed in the small intestine, and combinations thereof;
(C) contains water,
Administering to the subject a composition in which both the first substance and the carbohydrate maintain a solution state at all pH values of the solution in the selected pH value range. A method for extending the life of a subject having colorectal cancer,
(A) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, and 7-ketritocholic acid;
(B) a carbohydrate selected from the group consisting of a water-soluble starch conversion product, a water-soluble dietary carbohydrate that is not digested and absorbed in the small intestine, and combinations thereof;
(C) contains water,
Administering to the subject a composition in which both the first substance and the carbohydrate maintain a solution state at all pH values of the solution in the selected pH value range. A method of maintaining the overall weight of a subject having colorectal cancer,
(A) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, and 7-ketritocholic acid;
(B) a carbohydrate selected from the group consisting of a water-soluble starch conversion product, a water-soluble dietary carbohydrate that is not digested and absorbed in the small intestine, and combinations thereof;
(C) contains water,
Administering to the subject a composition in which both the first substance and the carbohydrate maintain a solution state at all pH values of the solution in the selected pH value range. A method of reducing or treating at least one symptom of colorectal cancer in a subject having or possibly having colorectal cancer comprising:
(A) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, and 7-ketritocholic acid;
(B) a carbohydrate selected from the group consisting of a water-soluble starch conversion product, a water-soluble dietary carbohydrate that is not digested and absorbed in the small intestine, and combinations thereof;
(C) contains water,
Administering to the subject a composition in which both the first substance and the carbohydrate maintain a solution state at all pH values of the solution in the selected pH value range.   The method according to any one of claims 1 to 4, wherein the composition further comprises a pharmaceutically effective amount of a drug.   9. The method according to any one of claims 5 to 8, wherein the composition further comprises a pharmaceutically effective amount of a drug.   The drug is aspirin, methyl salicylate, diflunisal, indomethacin, sulindac, diclofenac, ibuprofen, ketoprofen, naproxen, ketorolac, mefenamic acid, piroxicam, meloxicam, coxib celecoxibrofecoxib, valdecoxib, parecoxib, pratricoxib, methoroxib Leucovorin, irinotecan, cimetidine, salicylic acid, 2,2-bis (4- (4-amino-3-hydroxyphenoxy) phenyl) adamantane (DPA), paclitaxel, oxaliplatin, 5-fluorouracil, azathioprine, mycophenolate mofetil, cyclosporine , Mycophenolic acid, tacrolimus, sirolimus, basiliximab, daclizumab, antithymocyte glob (Rabbit), allopurinol, palonosetron, dolasetron, pamidronate, rasburicase, aprepitant, amifostine, gefitinib, palifermin, granisetron, sargramostim, levothyroxine, dronabinol, pegfilgrastim, interleukin 11, filgrastim, octreotide, cinacalcide Set, levothyroxine, liotrix, dexrazoxane, ondansetron, zoledronic acid, celecoxib, fenoprofen, benolylate, fislamin, amoxipurine, carprofen, flurbiprofen, loxoprofen, thiaprofenic acid, meclofenamic acid, ketorolac, oxaprozin, etodolac , Nabumeton, mesalamine, balsalazide, bevacizumab, alemts Mab, cetuximab, aldesleukin, ibritumomab tiuxetan, pemetrexed, tositumomab, gemcitabine, imatinib, trastuzumab, altretamine, topotecan, interferon alpha-2b, procarbazine, gemtuzumab ozogamicin, vinothelbin Diftitox, rituximab, erlotinib, bexarotene, arsenic trioxide, bortezomib, tretinoin, doxorubicin, dactinomycin, epirubicin, idarubicin, pentostatin, busulfan, temozolomide, melphalan, chlorambucil, mechlorethamine HC, clofaraclavine vin Purine, thioguanine, capecitabine, bicalutamide, flutamide, anastrozole, Xemestane, fulvestrant, letrozole, estramustine, leuprolide, triptoreplymomoate, histrelin, goserelin, porfimer, rotenone, tenoyltrifluoroacetone (TTFA), antimycin A, myxothiazole or oligomycin dexamethasone, methylprednisolone , Hydrocortisone, prednisolone, rotenone, tenoyltrifluoroacetone (TTFA), antimycin A, myxothiazole, oligomycin, valdecoxib, rofecoxib, parecoxib and etoroxib, atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, simvastatin, rosuvastatin, mevastatin Claims selected from the group consisting of pitavastatin The method according to.   The drug is aspirin, methyl salicylate, diflunisal, indomethacin, sulindac, diclofenac, ibuprofen, ketoprofen, naproxen, ketorolac, mefenamic acid, piroxicam, meloxicam, coxib celecoxibrofecoxib, valdecoxib, parecoxib, pratricoxib, methoroxib Leucovorin, irinotecan, cimetidine, salicylic acid, 2,2-bis (4- (4-amino-3-hydroxyphenoxy) phenyl) adamantane (DPA), paclitaxel, oxaliplatin, 5-fluorouracil, azathioprine, mycophenolate mofetil, cyclosporine , Mycophenolic acid, tacrolimus, sirolimus, basiliximab, daclizumab, antithymocyte glob (Rabbit), allopurinol, palonosetron, dolasetron, pamidronate, rasburicase, aprepitant, amifostine, gefitinib, palifermin, granisetron, sargramostim, levothyroxine, dronabinol, pegfilgrastim, interleukin 11, filgrastim, octreotide, cinacalcide Set, levothyroxine, liotrix, dexrazoxane, ondansetron, zoledronic acid, celecoxib, fenoprofen, benolylate, fislamin, amoxipurine, carprofen, flurbiprofen, loxoprofen, thiaprofenic acid, meclofenamic acid, ketorolac, oxaprozin, etodolac , Nabumeton, mesalamine, balsalazide, bevacizumab, alemts Mab, cetuximab, aldesleukin, ibritumomab tiuxetan, pemetrexed, tositumomab, gemcitabine, imatinib, trastuzumab, altretamine, topotecan, interferon alpha-2b, procarbazine, gemtuzumab ozogamicin, vinothelbin Diftitox, rituximab, erlotinib, bexarotene, arsenic trioxide, bortezomib, tretinoin, doxorubicin, dactinomycin, epirubicin, idarubicin, pentostatin, busulfan, temozolomide, melphalan, chlorambucil, mechlorethamine HC, clofaraclavine vin Purine, thioguanine, capecitabine, bicalutamide, flutamide, anastrozole, Xemestane, fulvestrant, letrozole, estramustine, leuprolide, triptoreplymomoate, histrelin, goserelin, porfimer, rotenone, tenoyltrifluoroacetone (TTFA), antimycin A, myxothiazole or oligomycin dexamethasone, methylprednisolone , Hydrocortisone, prednisolone, rotenone, tenoyltrifluoroacetone (TTFA), antimycin A, myxothiazole, oligomycin, valdecoxib, rofecoxib, parecoxib and etoroxib, atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, simvastatin, rosuvastatin, mevastatin Claims selected from the group consisting of pitavastatin The method according to 0.   The method according to any one of claims 1 to 8, wherein the composition is contained in an enema.   The method according to any one of claims 1 to 8, wherein the composition is contained in a jelly.   The method according to claim 14, wherein the jelly further comprises a thickener selected from the group consisting of water-soluble polysaccharides and synthetic cellulose derivatives swollen with water.   15. The method of claim 14, wherein the mucilage further comprises a thickening agent selected from the group consisting of acacia, genus genus, gelatin, xanthan gum, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.   The method of claim 16, wherein the thickening agent is hydroxyethyl cellulose.   The method according to claim 1, wherein the composition is contained in a mucus.   19. The method of claim 18, wherein the mucilage further comprises a thickener selected from the group consisting of a water soluble polysaccharide and a synthetic cellulose derivative that swells with water.   19. The method of claim 18, wherein the mucilage further comprises a thickening agent selected from the group consisting of acacia, hornworm, gelatin, xanthan gum, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. .   21. The method of claim 20, wherein the thickener is acacia.   9. The method of any one of claims 1-8, wherein the composition is included in a solution dosage form.   The method according to any one of claims 1 to 8, wherein the composition is contained in a suppository.   The method of any one of claims 1 to 10, wherein the subject is a mammal.   The method according to claim 1, wherein the object is a human.   9. The method according to any one of claims 1 to 8, wherein the first substance is present in a therapeutically effective amount.   The said 1st substance is selected from the group which consists of ursodeoxycholic acid, hyodeoxycholic acid, 7-ketritocholic acid, and the sodium salt of ursodeoxycholic acid of any one of Claims 1-8. Method.   The method according to any one of claims 1 to 8, wherein the first substance is ursodeoxycholic acid or a sodium salt of ursodeoxycholic acid.   The method according to any one of claims 1 to 8, wherein the water-soluble starch conversion product is selected from the group consisting of maltodextrin, dextrin, liquid glucose, solid corn syrup, and soluble starch.   The method according to any one of claims 1 to 8, wherein the water-soluble starch conversion product is maltodextrin.   The method according to any one of claims 1 to 8, wherein the water-soluble starch conversion product is a solid corn syrup.   The water-soluble dietary carbohydrate that is not digested and absorbed in the small intestine is selected from the group consisting of non-digestible oligosaccharides, resistant starch, and non-starch polysaccharides. the method of.   35. The method of claim 32, wherein the soluble dietary carbohydrate that is not digested and absorbed in the small intestine is a soluble non-starch polysaccharide.   The soluble dietary carbohydrate that is not digested and absorbed in the small intestine is selected from the group consisting of resistant maltodextrin (Fibersol 2), guar gum, pectin, locust bean gum, cellulose, b-glucan, and psyllium fiber. Item 9. The method according to any one of Items 1 to 8.   35. The method of claim 34, wherein the soluble dietary carbohydrate that is not digested and absorbed in the small intestine is a water-soluble indigestible maltodextrin (Fibersol 2).   The method according to any one of claims 1 to 8, wherein the weight ratio of the water-soluble starch conversion product to the water-soluble dietary carbohydrate that is not digested and absorbed in the small intestine is 1 to 99: 99-1.   9. The method of any one of claims 1-8, wherein the selected pH range is from about 1 to about 10. (A) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, and 7-ketritocholic acid;
(B) a carbohydrate selected from the group consisting of a water-soluble starch conversion product, a water-soluble indigestible maltodextrin (Fibersol 2), and combinations thereof;
(C) contains water,
A clear aqueous solution in which both the first substance and the carbohydrate maintain a solution state at all pH values of the solution in a selected pH value range.   The method according to claim 38, wherein a weight ratio of the water-soluble starch conversion product to the water-soluble hardly digestible maltodextrin (Fibersol 2) is 1 to 99: 99-1. (A) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, and bile acids joined to amines by amide bonds;
(B) a second substance comprising a high molecular weight water-soluble starch conversion product;
(C) contains water,
An aqueous solution in which both the first substance and the second substance maintain a solution state at all pH values of the solution in a selected pH value range.   41. The composition of claim 40, further comprising an alkali.   42. The composition of claim 41, wherein the alkali is selected from the group consisting of ammonia, sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, calcium hydroxide, and calcium carbonate.   42. The composition of claim 41, wherein the ratio of base to bile acid is about 1.0 to about 1.3. A method of protecting the large intestine from adenomatous polyposis in a subject comprising:
(A) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, bile acids conjugated to amines by amide bonds, and combinations thereof;
(B) a second substance selected from the group consisting of water-soluble starch conversion products, indigestible maltodextrins, water-soluble non-starch polysaccharides, and combinations thereof;
(C) A dried form of a water-soluble primary bile acid formulation containing a water-soluble ginseng extract, a water-soluble red ginseng extract, and a third substance selected from the group consisting of these combinations. Administering. (A) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, bile acids conjugated to amines by amide bonds, and combinations thereof;
(B) containing a water-soluble starch conversion product,
A dry form of a water soluble primary bile acid formulation in which both the first substance and the water soluble starch conversion product maintain a solution state at all pH values of the solution in a selected pH value range.