The present disclosure relates to methods and compositions to offset, ameliorate and/or alleviate one or more unwanted and/or adverse gastrointestinal effects. For example, in some embodiments, the present disclosure relates to compositions that include a bile acid, a carbohydrate and/or a pharmaceutical compound, wherein the pharmaceutical is associated with an adverse gastrointestinal effect in a subject (e.g., mammal or human). Non-limiting examples of pharmaceutical compounds may include a nonsteroidal anti-inflammatory drug, a gastric irritating drug (e.g., an antibiotic, an adrenal cortocoid steroid and an anti-cancer drug) and combinations thereof. The disclosure further relates to methods of ameliorating or eliminating at least one adverse gastrointestinal effects of a composition, comprising administering to a subject an aqueous solution comprising a bile acid and a carbohydrate.

Description of the Invention

SUMMARY

Therefore, a need has arisen for methods and compositions that ameliorate or eliminate unwanted and/or adverse gastrointestinal effects associated with consumption and/or administration of alcohol, NSAIDs, and/or gastric irritating drugs. An adverse gastrointestinal effect may include, without limitation, esophageal damage, acid sensitivity of gastrointestinal mucus, gastroduodenal mucosal cell death, gastrointestinal necrosis, gastrointestinal apoptosis, gastroduodenal mucosal lesion, gastroduodenal mucosal erosion, gastroduodenal ulcer, gastrointestinal cancer, gastrointestinal bleeding, perforation, epigastralgia, gastritis, gastrointestinal redness, gastrointestinal edema, malabsorption, intestinal dysmotility, colitis, and combinations thereof.

The present disclosure relates to methods and compositions that may ameliorate or eliminate a toxicity (e.g., a gastrointestinal effect) of a compound. For example, a method of ameliorating or eliminating a gastrointestinal effect of a compound may include co-administering the compound and a bile acid composition. A compound may, in some embodiments, be selected from the group consisting of alcohol (e.g., ethanol), an NSAID, a gastric irritating drug, and combinations thereof. In some embodiments, co-administration may include administering both the pharmaceutical compound and a bile acid in a single composition. It may also include simultaneous administration of a plurality of compositions. Alternatively, coadministration may include administration of a plurality of compositions at different times during the same period (e.g., at different times on the same day).

In some embodiments, the present disclosure provides compositions which include (1) a bile acid, a bile acid derivative, a bile acid salt, or a bile acid conjugated with an amine, (2) water, and (3) a sufficient quantity of an aqueous soluble starch conversion product such that the bile acid and the starch conversion product remain in solution at any pH within a selected pH range.

The disclosure further relates to a composition which comprises (1) a bile acid, a bile acid derivative, a bile acid salt, or a bile acid conjugated with an amine, (2) water, and (3) a sufficient quantity of an aqueous soluble non-starch polysaccharide such that the bile acid and the polysaccharide remain in solution at any pH within a selected pH range.

The disclosure further relates to a pharmaceutical composition which comprises (1) a bile acid, a bile acid derivative, a bile acid salt, and/or a bile acid conjugated with an amine, (2) water, and/or (3) a sufficient quantity of an aqueous soluble starch polysaccharide such that the bile acid in the polysaccharide remain in solution in any pH within a selected pH range.

The disclosure further relates to a pharmaceutical composition which comprises (1) a bile acid, a bile acid derivative, a bile acid salt, or a bile acid conjugated with an amine, (2) water, (3) a pharmaceutical compound in a pharmaceutically appropriate amount and/or (4) a sufficient quantity of an aqueous non-starch conversion product and/or an aqueous non-starch polysaccharide such that the bile acid, the pharmaceutical compound and the carbohydrate remain in solution at any pH within a selected pH range. According to a non-limiting embodiment of the disclosure, a pharmaceutical compound may be selected from the group consisting of alcohol, an NSAID, a gastric irritating drug, and combinations thereof.

The disclosure further relates to solution dosage forms of bile acid compositions. These dosage forms may have improved bioavailability and absorbability of a bile acid. In embodiments in which these compositions further contain a pharmaceutical compound, these compositions may also have improved bioavailability and/or absorbability of the pharmaceutical compound.

In some embodiments of the disclosure, a composition is provided which comprises (1) a bile acid, a bile acid derivative, a bile acid salt, or a bile acid conjugated with an amine, (2) water, and/or (3) a sufficient quantity of carbohydrate such that the bile acid component and the carbohydrate remain in solution at any pH within a selected pH range, wherein the carbohydrate is a combination of an aqueous soluble starch conversion product and an aqueous soluble non-starch polysaccharide. In embodiments containing both soluble non-starch polysaccharide and high molecular weight starch conversion product, the amounts of each are such that when combined together in the composition they are sufficient to allow the bile acid component, the high molecular weight starch conversion product, the soluble non-starch polysaccharide and the pharmaceutical compound, if any, to remain in solution at any pH within a selected pH range.

According to some embodiments of the disclosure, a composition may include an aqueous solution that is substantially free of precipitates and particles. An aqueous solution may include (a) a first material selected from the group consisting of a bile acid, an aqueous soluble derivative of a bile acid, a bile acid salt, and a bile acid conjugated with an amine by an amide linkage; (b) a carbohydrate selected from the group consisting of an aqueous soluble starch conversion product or an aqueous soluble non-starch polysaccharide; and (c) water, wherein the first material and the carbohydrate both remain in solution for all pH values obtainable in an aqueous system. In some embodiments, the condition of an aqueous solution being free of precipitates and/or particles may be a result of formulation the formulation itself, the method of making the composition, and/or other factors. The condition of an aqueous solution being free of precipitates and/or particles may be a result of something other than a filtration step and/or heating above ambient temperature in some embodiments. A composition according to some embodiments of the disclosure may protect at least a portion of a subject's gastrointestinal tract from a noxious or otherwise harmful composition.

In some embodiments of the disclosure, a combination therapy composition is provided which may increase the intensity of a response to or efficacy of a pharmaceutical compound. Such a composition may permit administration of lower dosages of a pharmaceutical compound, attack a disease complex at different points, affect elimination and/or alter absorption of a pharmaceutical compound. Such a composition may lead to or contribute to a reduction in toxicity and/or side effects of a pharmaceutical.

DETAILED DESCRIPTION

Therapeutic benefits of a pharmaceutical compound may be mitigated or even negated if that agent also displays toxicity. Alcohol, NSAIDs and gastric irritating drugs may have desirable and/or therapeutic value. However, their use may be limited due to gastrointestinal effects that may occur upon administration of these agents. For example, without being limited to any particular mechanism of action, excessive ethanol may increase super oxide anion and hydroxyl radical production and lipid peroxidation in the gastro duodenal mucosa. Lipid peroxidation may be mediated by the interaction of hydroxyl radicals with the cell membrane. This may produce lipid-derived free radicals such as conjugated dienes and lipid hydroperoxides extracellularly and/or intracellularly. These radicals may be extremely reactive products and may cause oxidative damage. For example, these products may produce mitochondrial permeability transition and mitochondrial depolarization, which precede apoptotic cell death in gastroduodenal mucosal cells. Acute administration of absolute ethanol to rats may produce gastro duodenal mucosal lesions and erosions similar to those occurring in gastroduodenal ulcer. Moreover, chronic alcohol consumption and heavy smoking may be major risk factors for cancer of the upper aerodigestive tract (e.g., oropharynx, hypopharynx, larynx and/or oesophagus). Alcoholic liver cirrhosis may also be a precancerous condition. Chronic alcohol ingestion even at moderate dosage may enhance carcinogenesis in the colorectum and/or breast, especially in individuals with increased susceptibility to developing cancer. Acetaldehyde may be carcinogenic, mutagenic, may bind to DNA and/or protein, may degrade folate and produce secondary hyperregeneration and may be predominantly responsible for alcohol associated carcinogenesis. Acetaldehyde may be produced by various alcohol dehydrogenases in the liver and/or in the gastrointestinal tract and/or by gastrointestinal bacteria. Acetaldehyde may be degraded by acetaldehyde dehydrogenases to acetate. Synthesis and degradation of acetaldehyde may be modulated in part by polymorphisms and/or mutations of the genes that encode the enzymes in catabolism and/or anabolism.

NSAIDs may be associated with unwanted and/or adverse gastrointestinal effects. Without being limited to any particular mechanism of action gastrointestinal toxicity, for example, may be mediated by both a non-prostaglandin induced local injury and/or systemic inhibition of cyclooxygenase (COX). This may lead to a subsequent reduction in the cytoprotective prostaglandins required for effective mucosal defense. Again, without being limited to any particular mechanism drug induced changes in local eicosanoid metabolism may be coupled with a topical toxic effect. Together these may induce a subsequent increase in the permeability of the mucosa to toxins and luminal antigens such as bile, pancreatic secretion, and bacteria. Enterohepatic recirculation of NSAIDs may be important for this effect.

NSAIDs may induce necrosis and/or apoptosis depending on the treatment conditions. For example, short-term treatment of cells with high concentrations of NSAIDs and long-term treatment of cells with low concentrations of NSAIDs may induce necrosis and apoptosis, respectively. In some embodiments, an NSAID may be indomethacin. Short-term exposure of cells to indomethacin may rapidly decrease cell viability in vitro in a dose-dependent manner (e.g. using primary cultures of guinea pig gastric mucosal cells).

Gastrointestinal mucosa may resist continual onslaught of aggressive agents such as alcohol, NSAIDs and gastric irritating drugs. This resistance, without being limited to any particular mechanism, may be mediated by neuronal modulating processes such as the release of vasodilator mediators. Interactions between endothelium-derived vasodilator mediators, including those prostaglandins may regulate gastrointestinal mucosal microcirculation and integrity. Endothelial cells may also release highly labile humoral vasodilator substances, including for example nitric oxide (NO). NO may mediate vascular relaxation induced by vagal stimulation. However, production of NO from a calcium-independent (inducible) form of the enzyme may lead to cell injury in the endothelium. Thus, induction of NO synthesis may not always be beneficial. For example, formation and interaction between superoxide and NO radicals may be important elements of oxidative challenges in gastrointestinal mucosa. An inflammatory reaction may be initiated and/or amplified by a proinflammatory mediator. A proinflammatory mediator may be released from injured tissues and/or synthesized during an inflammatory reaction. These substances may result in further local tissue injury by release and activation of destructive enzymes and/or production of oxygen-derived free radicals. Thus, without being limited to any particular mechanism of action, removal of oxygen-derived free radicals may stimulate healing of ethanol-induced acute gastroduodenal mucosal injury. Activation of polymorphonuclear leukocytes and macrophages, may result in increased superoxide generation and/or production of NO by inducible NO synthase. Gastritis in animals may lead to a significant increase in the inducible enzyme NO synthase. This in turn may result in production of NO which may react with oxygen or superoxide to yield more reactive oxidants, such as peroxynitrite. Secondary oxidants such as these may be responsible for most biological oxidative damage, and may be a target of antioxidant defense. One or more endogenous proinflammatory mediators may be activated during exposure to noxious agents and/or severe tissue trauma. For example, leukotriene C4 may act as a proinflammatory mediator and lead to microcirculatory disturbances and severe mucosal tissue injury.

Gastroduodenal bleeding may be caused by acute gastroduodenal mucosal lesion. Acute gastroduodenal mucosal lesion may be indicated where a patient displays sudden onset of epigastralgia, epigastric discomfort, vomiting, hematemesis and melena following probable causes. Diagnosis may be facilitated by endoscopy upon findings of gastroduodenal erosion, hemorrhagic gastritis and duodenal ulcer. There are a variety of causes for acute gastroduodenal mucosal lesion including, for example, psychological and physical stress, exposure to NSAIDs, exposure to gastric irritating drugs, alcohol abuse, serious organ failure (e.g. liver, kidney, heart, anisakiasis and combinations thereof). There may also be a variety of endoscopic findings of acute gastroduodenal mucosal lesion including, for example, redness, edema, erosion, ulcer and bleeding. These may vary quickly. The key to management may be prevention; however, once established, hemorrhagic gastritis may be treated with both supportive measures and measures directed toward healing the mucosal damage.

Ursodeoxycholic acid (3.alpha.-7.beta.-dihydroxy-5.beta.-cholanic acid) ("UDCA") may be useful as a pharmaceutical compound for the treatment of and the protection against many types of disease (e.g., liver disease). UDCA, which is hydrophilic, may be present in normal human bile at a low concentration (e.g., about 3% by weight of total bile acids). UDCA may be administered to a subject displaying one or more cholestatic disorders, radiolucent gall stones, biliary dyspepsia, primarily biliary cirrhosis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, cystic fibrosis-associated liver disease, pediatric liver disorder, and chronic graft-versus-host disease of the liver, chronic active hepatitis, hepatitis C, and combinations thereof.

In spite of the extremely valuable therapeutic activities and medical uses of bile acids as therapeutically active agents and as carriers and/or adjuvants, commercial use of bile acids has been limited to pharmaceutical formulations in which the bile acid is present in a solid form (e.g., tablets, capsules, and suspensions). This may be due to the insolubility of bile acids in aqueous media at pH from approximately 1 to 8. Bile has an extremely bitter taste and an equally bitter after-taste that lasts several hours both of which may be due to bile's insolubility. The few aqueous dosage forms that are available are unstable, and have very limited uses because of pH control and maintenance problems. Moreover, some commercial pharmaceutical dosage forms of bile acids have been shown to have scant bioavailability.

The present disclosure provides, in some embodiments, clear, stable solutions of soluble bile acids that offset, ameliorate or alleviate the toxicity of an agent. A solution of the disclosure may be used, for example, as a delivery vehicle for a pharmacological agent with one or more unwanted and/or adverse gastrointestinal effects. Alternatively, a solution of the disclosure may be used alone to offset, ameliorate or alleviate one or more unwanted and/or adverse gastrointestinal effects of an agent (e.g., alcohol) to which a subject is separately exposed. Solutions of the disclosure may be administered separately, in terms of both the route and time of administration, relative to the agent associated with the one or more unwanted and/or adverse gastrointestinal effects to be offset, ameliorated, and/or eliminated. In some embodiments of the disclosure, a bile composition blocks a toxic effect mediated by an oxidative process.

In some embodiments, a bile acid composition of the disclosure may lack one or more of the disadvantageous features of existing commercial dosage forms of UDCA. A bile acid composition of the disclosure may, in some embodiments, contact a gastrointestinal lesion without any precipitation and may function as a locally acting drug in the gastrointestinal tract. Bile acid dosage forms, according to some embodiments of the disclosure, may be suitable or adaptable for oral and/or parenteral administration. In some embodiments, a bile acid composition of the disclosure may include an intact molecule of UDCA and an aqueous soluble starch conversion product (e.g., a product resulting from hydrolysis of starch). A bile acid composition, according to some embodiments of the disclosure, may include solubilized bile acid in water wherein the bile acid remains in aqueous solution without any precipitation at any pH.

The solubility of UDCA in some solutions of the disclosure may be about 3,000 times higher than that of some commercialized forms of UDCA (e.g., 0.15 M vs. 0.05 mM) and may be about 300 times higher than that of TUDCA. In some embodiments, a solution of the disclosure may deliver solubilized UDCA to a subject's stomach, duodenum, jejunum, ileum, colon and/or blood. An oral and/or parenteral dosage form may, in some embodiments, contain, for example, 500 mg of UDCA and may have a Cmax that is at least 8 times higher than an existing commercial UDCA form and a Tmax that is about 4-6 times shorter than an existing commercial UDCA form. A fast Tmax and high Cmax mean that solubilized UDCA may be absorbed from the upper stomach very efficiently. For example, absorbed solubilized UDCA may cross the gastric mucosa.

A solution of the disclosure may be used, in some embodiments, to protect a subject's gastrointestinal track from the use of alcohol, an NSAID and/or a gastric irritating drug. For example, a solution of the disclosure may be administered in connection with administration of a pharmaceutical compound that is associated with an unwanted or adverse gastrointestinal effect, such as an NSAID and/or a gastric irritating drug.

An NSAID, according to some embodiments of this disclosure, may include a Salicylate (e.g., aspirin, methyl salicylate and diflunisal). An arylalkanoic acid (e.g., indomethacin, sulindac and diclofenac), 2-arylpropionic acid (e.g., (profens)ibuprofen, ketoprofen, naproxen and ketorolac), an N-arylanthranilic acid (fenamic acids) (e.g., mefenamic acid), an oxicam (e.g., piroxicam, meloxicam, coxibscelecoxib rofecoxib, valdecoxib, parecoxib and etoricoxib) and a sulphonanilide (e.g., nimesulide). In some embodiments, a gastric irritating drug may include an anti-cancer drug selected from the group consisting of aminoglutethimide, anastrazole, bicalutamide, chlorambucil, cyclophosphamide, cytarabine, dacarbazine, flutamide, letrozole, lomustine, mercaptopurine, methotrexate, nilutamide, plicamycin, procarbazine HCl, tacrolimus hydrate, and adrenal corticoid steroid. A gastric irritating drug, in some embodiments may include cortisol, cortisone, prednisone, prednisolone, desoxycorticosterone acetate, methylprednisolone, triamcinolone, fluprednisolone, bethamethasone, dexamethasone, fludrocortisone and combinations thereof.

Without being limited to any particular mechanism of action, a hydrophobic bile acid salt may induce apoptosis in the liver of a subject. Coadministration of a hydrophobic bile salt and UDCA may inhibit hepatocyte apoptosis in vivo. Both in hepatocytes and in nonhepatic cells apoptosis may be induced with various factors including, for example, hydrophobic acids, ethanol, transforming growth factor-.alpha., an agonistic Fas antibody, and/or okadaic acid. In some embodiments, UDCA may attenuate apoptosis and display cytoprotection without being limited to any particular mechanism of action. UDCA may have this affect by modulating mitochondrial membrane perturbation, Bax translocation and/or cytochrome c release.

Pharmacological action of UDCA may include replacement and/or displacement of toxic bile acids through UDCA in a dose-dependent manner, cytoprotective effects in a dose-dependent manner, stabilization/protection of cell membranes in a dose-dependent manner, antiapoptotic effects in a dose-dependent manner, immunomodulatory effects due to activation of the intracellular glucocorticoid receptor in a dose-dependent manner, antiinflammatory effects due to repression of NF-kB and inhibition of the induction of nitric oxide synthase, stimulation of bile secretion in a dose-dependent manner, Stimulation of exocytosis and insertion of canalicular membrane transporters in a dose-dependent manner.

UDCA is practically insoluble at pH 1 to 8. The solubility of its protonated form is about 0.05 mM. The solubility of its taurine conjugated metabolite (TUDCA; 0.45 mM) is about ten times higher than UDCA solubility. Moreover, TUDCA is the only bile acid (BA) with relatively low solubility when protonated. Following oral administration, approximately 30 to 60% of UDCA is absorbed along the length of the jejunum and ileum by nonionic passive diffusion and is absorbed in the ileum by active transport mechanisms and to a small extent (20% of an ingested dose) in the colon due to the insolubility of crystal UDCA, which causes extremely slow and incomplete dissolution due to the low aqueous solubility of its non-ionized molecules and more lipophilicity than the ionized bile salt species, and can therefore partition into biological membranes.

Once taken up by hepatocytes, UDCA may be conjugated to TUDCA and GUDCA, the latter two being the secreted bile acids in humans and excreted in bile by hepatic first-pass clearance. Consequently, its blood levels are extremely low in the systemic circulation. Bile acids undergo extensive hepatic recycling, or free UDCA may also be secreted by hepatocytes in bile, where it may be actively and efficiently reabsorbed by cholangiocytes. UDCA and GUDCA are absorbed by both active and passive transport mechanisms, while tauro-conjugated UDCA (TUDCA) may be transported actively in the terminal ileum.

In some embodiments, a UDCA dose above 10.+-.12 mg/kg per day may not further increase its proportion in bile since a large quantity of UDCA may be biotransformed to CDCA through 7-keto-lithocholic acid by intestinal bacteria. Alternatively, UDCA may be converted to CDCA by epimerization of the 7.beta.-hydroxyl group and further to lithocholic acid (LCA). Therefore, with increasing doses of UDCA the absorption of UDCA decreases.

In some embodiments, administration of a composition of the disclosure may achieve adequate amounts of solubilized UDCA in lesions caused by NSAIDS, alcohol and gastric irritating drug at the gastrointestinal tract, and/or in the systemic circulation to have a therapeutic effect. A solution of the disclosure may, in some embodiments, display significantly increased aqueous solubility of UDCA, increased membrane permeability, protection from epimerization of UDCA to CDCA.

Without being limited to any particular mechanism of action, the present disclosure provides clear, stable solutions of solubilized bile acids that may protect gastrointestinal tract from necrosis and/or apoptosis by the use of NSAIDs, alcohol and gastric irritating drug (antibiotics, adrenal corticoid steroid, anti-cancer drug).

Bile acids may act as intracellular signaling agents, which modulate cellular transport, alter intracellular Ca.sup.2+ levels, and activate cell surface receptors. Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid with proven clinical efficacy in the treatment of hepatobiliary disorders. UDCA may be rapidly conjugated with glycine or taurine in vivo to produce glycoursodeoxycolic and tauroursodeoxycholic (TUDCA) acids, respectively. UDCA and its derivatives and conjugates may function as cytoprotective agents by inhibiting apoptosis.

The present disclosure relates to an aqueous solution comprising (i) one or more soluble bile acids, aqueous soluble bile acid derivatives, bile acid salts, or bile acid conjugated with an amine, (collectively "bile acid"), (ii) water, and (iii) one or more aqueous soluble starch conversion products or aqueous soluble non-starch polysaccharides in an amount sufficient to produce a solution which does not form a precipitate at any pH within a desired pH range. The composition may contain a bile acid or a bile acid salt which itself has pharmaceutical effectiveness. Formulations of the disclosure may act as a carrier, an adjuvant or enhancer for the delivery of a pharmaceutical material which remains dissolved in the composition of the disclosure across the desired pH range. Alternatively, according to some embodiments of the disclosure, the composition may comprise a non-bile acid pharmaceutical that is incompletely soluble.

In some embodiments, it may be an advantage of this disclosure that the bile acid and the carbohydrate remain in solution without precipitation at any pH from acidic to alkaline. These aqueous solution systems of bile acid are substantially free of precipitate or particles. A further advantage of this disclosure is that the aqueous solution systems demonstrate no changes in physical appearance such as changes in clarity, color or odor following the addition of strong acids or alkali even after several months (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) observation under accelerated conditions of storage at 50.degree. C.

In some embodiments of the disclosure, an aqueous solution system of a bile acid is administered orally whereupon it reaches the gastrointestinal track without precipitation of bile acids by exposure to acidic gastric juices and alkaline juices of the gastrointestinal track. These solubilized bile acid formulations demonstrate intact solution systems in the intestine can be effectively and completely absorbed by the direct contact between solubilized bile acid and intestine and, consequently, undergo enterohepatic cycling. According to an embodiment of the disclosure, bile acid solubility (e.g. precipitation and changes in physical appearance) is affected by whether a carboxylic acid side chain of certain bile acids can be protonated (non-ionized; in acidic stomach), is ionized (in small intestine), or is a simple carboxylic acid (in cell).

The ionization state of a bile acid carboxylic acid side chain may affect the hydrophobicity and the hydrophilicity of the bile acid in some aqueous solution systems. In some embodiments of the disclosure, that ionization state is manipulated by adjusting the pH to control the toxicity, absorption, and amphiphilicity of bile acids. One or more bile acids may be dissolved in these aqueous solution systems as a therapeutically active agent, as an adjuvant of a drug, as a carrier of a drug or as an enhancer of drug solubility. These aqueous solution systems may be prepared for oral consumption, mouthwashes, gargles, nasal preparations, otic preparations, injections, douches, enemas, topical skin preparations, other topical preparations, and cosmetic preparations which have a desired pH without the disadvantage of precipitation or deterioration in physical appearance after long periods of time.

Soluble bile acids are any type of aqueous soluble bile acids. A bile acid salt is any aqueous soluble salt of a bile acid. Bile salts exhibit greater solubilizing capacity for phospholipid and cholesterol and are consequently better detergents. More hydrophobic bile salts may be more injurious to various membranes, both in vivo and in vitro. Aqueous dissolved salts of bile acids may be formed by the reaction of bile acids described above and an amine including but not limited to aliphatic free amines such as trientine, diethylene triamine, tetraethylene pentamine, and basic amino acids such as arginine, lysine, ornithine, and ammonia, and amino sugars such as D-glucamine, N-alkylglucamines, and quaternary ammonium derivatives such as choline, heterocyclic amines such as piperazine, N-alkylpiperazine, piperidine, N-alkylpiperidine, morpholine, N-alkylmorphline, pyrrolidine, triethanolamine, and trimethanolamine. According to some embodiments of the disclosure, soluble bile acid salts may also include aqueous soluble metal salts of bile acids, bile acid/cyclodextrin inclusion compounds, and aqueous soluble O-sulfonated bile acids.

Soluble bile acid derivatives, according to some embodiments of this disclosure, may be those derivatives which are as soluble in aqueous solution as or more soluble in aqueous solution than is the corresponding underivatized bile acid. Bile acid derivatives include, but are not limited to derivatives formed at the hydroxyl and carboxylic acid groups of the bile acid with other functional groups including but not limited to halogens and amino groups. Soluble bile acid may include an aqueous preparation of a free acid form of bile acid combined with one of HCl, phosphoric acid, citric acid, acetic acid, ammonia, or arginine.

Bile acids that may be used in accordance with the teachings of this disclosure include, without limitation, ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, hyodeoxycholic acid, deoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iocholic acid, tauroursodeoxycholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, taurolithocholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, and their derivatives at a hydroxyl or carboxylic acid group on the steroid nucleus.

In some embodiments, administration of a composition of the disclosure may result in higher in vivo levels of bile acids than at least some existing commercial preparations. Therefore, the therapeutic potential of bile acid may be more fully achieved than other formulations. In vivo levels of bile acids attainable with existing formulations in which bile is incompletely solubilized may be lower and require administration of larger amounts of bile acids. Completely dissolving all or substantially all bile according to some embodiments of the disclosure, by contrast, may permit higher in vivo levels of bile acid to be achieved, even though the same or lower doses are administered.

In some embodiments of the disclosure, a plurality of bile acids may be used in a single formulation. Mixtures of two or more bile salts of differing hydrophobic activity may behave as a single bile salt of an intermediate hydrophobic activity. As a result, detergent properties and the toxicity of mixtures of two bile acids of differing hydrophobic activity often are intermediate between the individual components.

Mixtures of two or more bile salts of differing hydrophobic activity may behave as a single bile salt of an intermediate hydrophobic activity. As a result, detergent properties and the toxicity of mixtures of two bile acids of differing hydrophobic activity often are intermediate between the individual components.

Carbohydrates suitable for use in the disclosure include aqueous soluble starch conversion products and aqueous soluble non-starch polysaccharides. According to some embodiments of the present disclosure, aqueous soluble starch conversion products include carbohydrates obtained from the partial or incomplete hydrolysis of starch under various pH conditions. Non-limiting examples include maltodextrin, dextrin, liquid glucose, corn syrup solid (dried powder of liquid glucose), and soluble starch, (e.g., maltodextrin or corn syrup solid). In some embodiments, MALTRIN.RTM. M200, a corn syrup solid, and MALTRIN.RTM. M700, a maltodextrin, may be used. MALTRIN.RTM. M200 and MALTRIN.RTM. M700 are manufactured by GPC.RTM., Grain Processing Corporation of Muscatine. For the purpose of this embodiment, the term "corn syrup" may include both corn syrup and liquid glucose.

In some embodiments, aqueous soluble starch conversion products arise from only hydrolytic and/or catabolic activity on starch. A starch conversion product may, in some embodiments, include at least one reducing end and/or at least one non-reducing end. If it is polymeric, it may be linear or branched. The molecular weight may be from about 100 mass units to over 106 mass units. High molecular weight aqueous soluble starch conversion products are those having a molecular weight over 105.

According to some embodiments of the present disclosure, aqueous soluble non-starch polysaccharides may be formed under various pH conditions by various hydrolytic or synthetic mechanisms. Non-limiting examples include to dextran, guar gum, pectin, indigestible soluble fiber. If polymeric, the polymer has at least one reducing end and/or at least one non-reducing end. The polymer may be linear or branched. The molecular weight may be from about 100 mass units to over 106 mass units. For example, the molecular weight is over 105 mass units.

In some embodiments, cyclodextrin, the formation of which involves a condensation step that eliminates its free ends, may be regarded as neither an aqueous soluble starch conversion product nor an aqueous soluble non-starch polysaccharide. In some embodiments, a composition of the disclosure may be substantially free of cyclodextrin. In some embodiments, a composition of the disclosure may be completely free of cyclodextrin. Alternatively, in some embodiments of the disclosure, a formulation a composition of the disclosure may comprise cyclodextrin in addition to a starch conversion product and/or a non-starch polysaccharide.

The amount of high molecular weight aqueous soluble starch conversion product and/or soluble non-starch polysaccharide used in embodiments of the disclosure is at least the amount needed to render the bile acid(s) in the preparation soluble over the concentration and/or pH range desired.

In some embodiments of the disclosure, the approximate minimal weight ratio of maltodextrin to UDCA required to prevent UDCA precipitation may be 6:1 (i.e. 1.2 g for every 0.2 g of UDCA, 6 g for every 1 g of UDCA, and 12 g for every 2 g of UDCA in 100 mL of water).

In some embodiments of the disclosure, the approximate minimal quantity of maltodextrin may be 30 g for every 200 mg of chenodeoxycholic acid, 12 g for every 200 mg of 7-ketolithocholic acid, 10 g for every 200 mg of cholic acid and 50 g for every 200 mg of deoxycholic acid.

In some embodiments of the disclosure, the approximate minimal weight ratio of liquid glucose (commercial light corn syrup) to UDCA required to prevent the precipitation of bile acids from the aqueous solution dosage forms of the disclosure may be about 25:1 (i.e. 12.5 g for every 500 mg UDCA in 100 mL water and 25 g for every 1 g ursodeoxycholic acid in 200 mL water).

In some embodiments of the disclosure, the approximate minimal quantity of dried powder of liquid glucose (corn syrup solid, e.g. MALTRIN.RTM. M200) required to prevent the precipitation of bile acids from the aqueous solution dosage forms of the disclosure is 30 g for every 1 g ursodeoxycholic acid in 100 mL water, and approximately 60 g for every 2 g of ursodeoxycholic acid in 200 mL water.

In some embodiments of the disclosure, the approximate minimal quantity of soluble non-starch polysaccharide required to prevent the precipitation of bile acids from the aqueous solution dosage forms of the disclosure may be 50 g guar gum for every 500 mg ursodeoxycholic acid in 100 mL water and 80 g of pectin for every 500 mg of ursodeoxycholic acid in 100 mL water. The minimal required quantity of high molecular weight aqueous soluble starch conversion products and/or soluble non-starch polysaccharide, according to some embodiments, may be primarily determined by the absolute quantity of bile acids in the solution formulation rather than the concentration.

In some embodiments of the disclosure, the formulation further comprises dietary fiber. Non-limiting examples of dietary fiber include guar gum, pectin, psyllium, oat gum, soybean fiber, oat bran, corn bran, cellulose and wheat bran.

In some embodiments of the disclosure, the formulation further comprises emulsifying agents. For the purpose of the disclosure, the term "emulsifying agent" includes emulsifying agents and suspending agents. Non-limiting examples of emulsifying agents include guar gum, pectin, acacia, carrageenan, carboxymethyl cellulose sodium, hydroxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinyl alcohol, povidone, tragacanth gum, xanthan gum, and sorbian ester.

The selected pH range for which the formulation will not precipitate its bile acid, starch conversion product, soluble non-starch polysaccharide or its pharmaceutical compound may be any range of pH levels obtainable with an aqueous system. In some embodiments, the range may be between about pH 1 and about pH 14 and/or between about pH 1 and about pH 10. In some embodiments, a pH range may be any subset of the range of pH levels obtainable in an aqueous system sufficient for a pharmaceutical formulation to remain in solution from preparation, to administration, to absorption in the body, according to the method of administration. Thus, the composition may be used as a pharmaceutical formulation wherein the pharmaceutical compound remains in solution without precipitation at prevailing pH levels in the mouth, stomach and intestines. In some embodiments of the disclosure, a bile acid remains dissolved under acidic conditions as a free bile acid in spite of the general insolubility of bile acids under acidic conditions.

A solution, according to some embodiments, may be administered with one or more pharmaceutical compounds (e.g., a pharmaceutical compound includes hormones, hormone antagonists, analgesic, antipyretics, anti-inflammatory drugs, immunoactive drugs, antineoplastic drugs, antibiotics, anti-inflammatory agents, sympathomimetic drugs, anti-infective drugs, anti-tumor agents, anesthetics, and drug for targeting or affecting liver, cardiovascular system, and respiratory system). Administration of a bile composition of the disclosure with pharmaceutical compound may, in some embodiments, (a) increase the intensity of a response to the pharmaceutical compound, (b) increase the efficacy of the pharmaceutical compound, (c) decrease the required dose of the pharmaceutical compound, and/or (d) decrease the toxicity of the pharmaceutical compound. Solutions of the disclosure may also be administered separately, in terms of both the route and time of administration.

In some embodiments of the disclosure, a bile composition may comprise a pharmaceutical compound including, without limitation, an NSAID and/or a gastric irritating drug. Non-limiting examples of pharmaceutical compounds include insulin, heparin, calcitonin, ampicillin, octreotide, sildenafil citrate, calcitriol, dihydrotachysterol, ampomorphine, yohimbin, trazodone, acyclovir, amantadine.HCl, rimantadine.HCl, cidofovir, delavirdine.mesylate, didanosine, famciclovir, forscarnet sodium, fluorouracil, ganciclovir sodium, idoxuridine, interferon-.alpha., lamivudine, nevirapine, penciclovir, ribavirin, stavudine, trifluridine, valacyclovir.HCl, zalcitabine, zidovudine, indinavir.H.sub.2SO.sub.4, ritonavir, nelfinavir.CH.sub.3SO.sub.3H, saquinavir.CH.sub.3SO.sub.3H, d-penicillamine, chloroquine, hydroxychloroquine, aurothioglucose, gold sodium thiomalate, auranofin levamisole, dacarbazine, diethyldithiocarbamate, isoprinosine, methyl inosine monophosphate, muramyl dipeptide, diazoxide, hydralazine.HCl, minoxidil, dipyridamole, isoxsuprine.HCl, niacin, nylidrin.HCl, phentolamine, doxazosin.CH.sub.3SO.sub.3H, prazosin.HCl, terazocin.HCl, clonidine.HCl, nifedipine, molsidomine, amiodarone, acetylsalicylic acid, verapamil, diltiazem, nisoldipine, isradipine, bepridil, isosorbide.dinitrate, pentaerythrytol.tetranitrate, nitroglycerin, cimetidine, famotidine, nizatidine, ranitidine, lansoprazole, omeprazole, misoprostol, sucralfate, metoclopramide.HCl, erythromycin, bismuth compound, alprostadil, albuterol, pirbuterol, terbutaline.H.sub.2SO.sub.4, salmetrol, aminophylline, dyphylline, ephedrine, ethylnorepinephrine, isoetharine, isoproterenol, metaproterenol, n-docromil, oxy triphylline, theophylline, bitolterol, fenoterol, budesonide, flunisolide, beclomethasone.dipropionate, fluticasone.propionate, codeine, codeine sulfate, codeine phosphate, dextromethorphan.HBr, triamcinolone.acetonide, montelukast sodium, zafirlukast, zileuton, cromolyn sodium, ipratropium bromide, nedocromil sodium benzonate, diphenhydramine.HCl, hydrocodone.bitartarate, methadone.HCl, morphine sulfate, acetylcysteine, guaifenesin, ammonium carbonate, ammonium chloride, antimony potassium tartarate, glycerin, terpin.hydrate, colfosceril palmitate, atorvastatin.calcium, cervastatin.sodium, fluvastatin.sodium, lovastatin, pravastatin.sodium, simvastatin, picrorrhazia kurrva, andrographis paniculata, moringa oleifera, albizzia lebeck, adhata vasica, curcuma longa, momordica charantia, gymnema sylvestre, terminalia arjuna, azadirachta indica, tinosporia cordifolia, metronidazole, amphotericin B, clotrimazole, fluconazole, haloprogin, ketoconazole, griseofulvin, itraconazole, terbinafin.HCl, econazole.HNO.sub.3, miconazole, nystatin, oxiconazole.HNO.sub.3, sulconazole.HNO.sub.3, cetirizine.2HCl, dexamethasone, hydrocortisone, prednisolone, cortisone, catechin and its derivatives, glycyrrhizin, glycyrrhizic acid, betamethasone, ludrocortisone.acetate, flunisolide, fluticasone.propionate, methyl prednisolone, somatostatin, lispro, glucagon, proinsulin, insoluble insulins, acarbose, chlorpropamide, glipizide, glyburide, metformin.HCl, repaglinide, tolbutamide, amino acid, colchicine, sulfinpyrazone, allopurinol, piroxicam, tolmetin sodium, indomethacin, ibuprofen, diflunisal, mefenamic acid, naproxen, and trientine.

Additional examples of pharmaceutical compounds that may be included in a formulation may include any compound that remains soluble in the formulation. With an additional pharmaceutical compound in the formulation, a bile acid in solution may act as an adjuvant, carrier, and/or enhancer for the solubility of certain therapeutically active agents, including, but not limited to, insulin (pH 7.4-7.8), heparin (pH 5-7.5), calcitonin, ampicillin, amantadine, rimantadine, sildenafil, neomycin sulfate (pH 5-7.5), apomorphine, yohimbin, trazodone, ribavirin, paclitaxel and its derivatives, retinol, and tretinoin, which are soluble and stable in acid and/or alkali and can be added as needed into these aqueous solution dosage forms of certain concentrations of bile acids in this disclosure. Certain therapeutically active agents, including, but not limited to, metformin HCl (pH 5-7), ranitidine HCl, cimetidine, lamivudine, cetrizine 2HCl (pH 4-5), amantadine, rimantadine, sildenafil, apomorphine, yohimbine, trazodone, ribavirin and dexamethasone, hydrocortisone, prednisolone, triamcinolone, cortisone, niacin, taurine, vitamins, naturally occurring amino acids, catechin and its derivatives, glycyrrhizal extract and its main constituents such as glycyrrhizin and glycyrrhizic acid, water soluble bismuth compounds (e.g., bismuth sodium tartrate), and which are soluble and stable in acid and/or alkali can be added as needed into these aqueous solution dosage formulations containing ursodeoxycholic acid in this disclosure.

Some embodiments of the disclosure may be practiced with pH adjustable agents. Non-limiting examples include HCl, H.sub.3PO.sub.4, H.sub.2SO.sub.4, HNO.sub.3, CH.sub.3COOH, citric acid, malic acid, tartaric acid, lactic acid, phosphate, eidetic acid and alkalies.

In some embodiments of the disclosure, a formulation may be used to treat (e.g., ameliorate at least one symptom) human and mammalian diseases. In some embodiments, a composition of the disclosure may be used to treat gastrointestinal disorders, liver diseases, gall stones, and/or hyperlipidemia. Non-limiting examples of gastrointestinal diseases include any disease and/or disorder of the stomach and/or intestine. Additional non-limiting examples of gastrointestinal diseases include any disease and/or disorder that effects the stomach and/or intestine. Non-limiting examples of liver diseases may include alcohol-induced liver diseases and non-alcohol-induced liver diseases. Non-limiting examples of gastrointestinal disorders may include chronic gastritis, reflux gastritis, and peptic ulcer disease. Non-limiting examples of non-alcohol-induced liver diseases may include primary biliary cirrhosis, acute and chronic hepatitis, primary sclerosing cholangitis, chronic active hepatitis, and excess accumulation of fat in the liver.

In some embodiments, a composition of the disclosure may be used to treat viral, bacterial and/or fungal diseases. In some embodiments of the disclosure, a formulation may be administered to treat and/or eradicate Helicobacter pylori infection. In some embodiments, a composition of the disclosure may be used to treat and/or eradicate hepatitis C virus infection, influenza A, Influenza C, parainfluenza 1, sendai, rubella, and/or pseudorabies virus.

In some embodiments, a composition of the disclosure may be used to treat an acute and/or chronic inflammatory disease. Non-limiting examples of inflammatory diseases may include bronchitis, chronic pharyngitis, and/or chronic tonsillitis. In some embodiments of the disclosure, a formulation may be administered to treat hypercholersterolemia.

In some embodiments of the disclosure, a composition may be prepared and/or modified such that it may be administered as a liquid, solid, powder or tablet. In some embodiments of the disclosure, a composition may be comprised in a parenteral solution (e.g., an injectable solution, a solution, a syrup, a thick syrup or a paste. A non-limiting example of a syrup is a solution of maltodextrin wherein the concentration of maltodextrin is less than 500 g/L. A non-limiting example of a syrup is a solution of maltodextrin wherein the concentration of maltodextrin is between 500 g/L and 1.0 kg/L inclusive. A non-limiting example of a thick syrup is a solution of maltodextrin wherein the concentration of maltodextrin is between 1.0 kg/L and 1.2 kg/L inclusive. A non-limiting example of a paste is a solution of maltodextrin wherein the concentration of maltodextrin is greater than 1.2 kg/L. Other non-limiting examples of a syrup, a thick syrup, and/or a paste may have a viscosity that is within about .+-.10% of the foregoing, respective example.

The stability of dosage formulations of the disclosure may be evaluated by measuring the concentration of the relevant bile acid over time in preparations comprising soluble bile acid, a high molecular weight aqueous soluble starch conversion product, and water at various pH and temperature levels. The retention time (high performance liquid chromatography) of each bile acid may be adjusted as needed to permit individual analysis each bile acid present in complex samples, i.e. a sample having a plurality of bile acids. Stability tests may also be performed by assessing the light-scattering properties of a test solution. In addition, established accelerated testing conditions may be used.

In some embodiments, a composition of the disclosure may, without being filtered, remain substantially free of precipitates and particles for over one day, over two days, over three days, over one week, over two weeks, over three weeks, over four weeks, over five weeks, over six weeks, over seven weeks, over eight weeks, over nine weeks, over ten weeks, over eleven weeks, over twelve weeks, over fifteen weeks, over eighteen weeks, over twenty-one weeks, over twenty-four weeks, over nine months, over twelve months, over eighteen months, and/or over twenty-four months. In some embodiments, a composition of the disclosure may have greater than about 95% of the starting bile concentration, greater than about 96% of the starting bile concentration, greater than about 97% of the starting bile concentration, greater than about 98% of the starting bile concentration, and/or greater than about 99% of the starting bile concentration after one day, after two days, after three days, after one week, after two weeks, after three weeks, after four weeks, after five weeks, after six weeks, after seven weeks, after eight weeks, after nine weeks, after ten weeks, after eleven weeks, after twelve weeks, after fifteen weeks, after eighteen weeks, after twenty-one weeks, after twenty-four weeks, after nine months, after twelve months, after eighteen months, and/or after twenty-four months.

All stability tests performed on solutions of the disclosure were satisfactory in that the concentration of bile acid as measured by HPLC did not change appreciably over time at various pH levels. Particularly, all bile acid solution formulations tested showed excellent results in the stability tests with no precipitation and no physical appearance changes over the test period. Some formulations remain stable for over 2 years. The aqueous solution dosage forms according to this disclosure that were tested did not change either physically or chemically at various pH conditions under accelerated conditions despite the addition of therapeutically and chemically active agents that are stable and soluble in hydrochloric acid solution. Therefore, these aqueous solution systems may be useful pharmaceutical dosage forms for therapeutically active bile acids preparations, and/or drug (pharmaceutical compound) delivery preparations. In such preparations, a bile acid may play a role as a drug adjuvant, a drug carrier, or a drug solubility enhancer (e.g., by micelle formation) at various pH conditions without stability problems (e.g., including precipitation in acidic conditions).

Human cells (neuron) were treated with a solution of the disclosure and 50 .mu.M of hydrogen peroxide and/or cisplatin. Hydrogen peroxide may be a strong oxidant. Cisplatin may stimulate production of reactive oxygen species (ROS), which may interfere with antioxidant defense system. Cell viability, cell proliferation, and apoptosis were then analyzed by measurement of MTT reduction. Several studies, using exogenous ROS, and H.sub.2O.sub.2, in particular, demonstrate that exposure of human and rat peripheral vascular smooth muscle cells (VSMCs) to relatively low levels of oxidant stress, for short periods promotes cell growth, whereas prolonged exposure to higher concentrations leads to cell death, either by apoptosis or necrosis.

Cell viability for hydrogen peroxide with and without solution of the disclosure was evaluated by using the MTT assay. Cells treated with a solution of the disclosure (0.2 mg/mL solubilized UDCA) and hydrogen peroxide (50 .mu.M) displayed the highest cell viability (75% compared to control, 100%). The lowest cell viability (26% compared to control, 100%) was observed in cells treated with hydrogen peroxide (50 .mu.M) alone. These effects were found in a dosage-dependent fashion.

Cell viability in the presence of cisplatin was evaluated in like manner. The highest cell viability (87% compared to control, 100%) was observed in cells treated with both cisplatin (20 .mu.M) and a solution of the disclosure (1 mg/mL soluble UDCA), whereas the lowest cell viability (35% compared to control, 100%) was observed in cells treated with cisplatin (20 .mu.M) alone. These effects were also found in a dosage-dependent fashion. According to the MTT assays, a solution of the disclosure may block almost completely hydrogen peroxide-induced oxidative cytotoxicity and may completely block cisplatin-induced oxidative cytotoxicity. In conclusion, a composition of the disclosure may possess strong antioxidative properties and non-cytotoxicity.
 

Claim 1 of 29 Claims

1. A method of ameliorating or eliminating in a subject at least one adverse gastrointestinal effect of a composition, said method comprising: administering the composition to the subject; and administering to the subject an aqueous solution substantially free of precipitates or particles comprising: (a) a first material selected from the group consisting of a bile acid, a bile acid salt, and a bile acid conjugated with an amine by an amide linkage; (b) a carbohydrate selected from the group consisting of an aqueous soluble starch conversion product or an aqueous soluble non-starch polysaccharide; and (c) water, wherein the first material and the carbohydrate both remain in solution for all pH values obtainable in an aqueous system; wherein the composition comprises over about 20% ethanol (w/w).

 

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