JP2008521800A - Dry form of water-solubilized bile acid dosage formulation, production method and use thereof - Google Patents

Abstract

  Compositions for pharmaceutical and other uses, including clear aqueous solutions of bile acids that do not form any detectable precipitate in the selected pH range of the clear aqueous solution of bile acids, and the production of this solution A method is disclosed. The disclosed composition comprises bile acids in the form of water and bile acids, bile salts, or bile acids conjugated by amines and amide bonds, water soluble starch conversion products and water soluble non-starch polysaccharides. Either one or both are included. The composition is in solution without forming a precipitate in the range of all pH values obtained with aqueous systems. The composition, according to some embodiments, further comprises a pharmaceutically effective amount of a pharmacological compound. The present invention also provides a primary water-solubilized bile acid dosage form in dry form and a method for producing the dry form.

Description

  The present invention provides (i) one or more bile acids (collectively “bile acids” selected from the group consisting of soluble bile acids, water-soluble bile acid derivatives, bile salts, or bile acids conjugated with amines. )) (Ii) water and (iii) an amount of one or more water-soluble starch convertibles or water-soluble non-starch sufficient to produce a solution that does not form a precipitate at any pH within the desired pH range. The present invention relates to an aqueous solution containing a polysaccharide.

  Bile salts, cholesterol-derived organic acids, are natural ionic components that play a central role in lipid absorption, transport and secretion. The term primary bile acid means newly synthesized by the liver. In humans, primary bile acids are cholic acid (3α, 7α, 12α-trihydroxy-5β-cholanic acid) (“CA”) and chenodeoxycholic acid (3α, 7α-dihydroxy-5β-cholanoic acid) (“CDCA”). including. The dehydroxylation of these bile acids by intestinal bacteria results in more hydrophobic secondary bile acids: deoxycholic acid (3α, 12α-dihydroxy-5β-cholanic acid) (“DCA”) and lithocholic acid (3α -Hydroxy-5 [beta] -cholanic acid) ("LCA"). These four bile acids CA, CDCA, DCA and LCA generally constitute 99% or more of the bile salt pool in humans. Further, secondary bile acids metabolized by the liver may be referred to as tertiary bile acids.

  Keto-bile acids are produced by humans as a result of oxidation of bile acid hydroxyl groups, particularly the 7-hydroxyl group, as a result by colonic bacteria. However, keto-bile acids are rapidly reduced by the liver to the corresponding α or β-hydroxy bile acids. For example, the corresponding keto bile acid of CDCA is 7-ketritocholic acid, and one of the products reduced by the corresponding β-hydroxy bile acid is ursodeoxycholic acid (3α-7β-dihydroxy-5β- Colanic acid) ("UDCA").

  Bile acids containing 6β-hydroxyl groups found in rats and mice are known as muricholic acid, and 6α-hydroxy bile acids produced by pigs are called hyocholic acid and hyodeoxycholic acid. The 23-hydroxy bile acids of aquatic mammals are known as phocecholic acid and phocedeoxycholic acid.

  In general, over 99% of naturally occurring bile salts secreted into human bile are conjugated. Conjugates have secondary organic substituents (eg, glycine, taurine, glucuronate, sulfate or, in rare cases, other substituents) attached to the side chain carboxylic acid via an ester, ether or amide linkage, or to a ring hydroxyl group. Bile acid bound to one. Thus, the ionization properties of bile acids conjugated with glycine or taurine are determined by the acidity of the substituted glycine or taurine.

PK _a value of the free unconjugated bile acid monomer is about 5.0. However, glycine-conjugated bile acids have an average pK _a value of 3.9, and taurine-conjugated bile acids have an average pK _a value of less than 1.0. Therefore, the effect of conjugation is to reduce the pK _a of _the bile acids so large fraction is ionized at pH given arbitrarily. Since the ionized salt form is more water soluble than the protonated acid form, conjugation increases solubility at low pH. Free bile salts precipitate from aqueous solutions at pH 6.5-7. In contrast, precipitation of glycine conjugated bile acids occurs only below pH 5. Taurine-conjugated bile acids are in aqueous solution under very strong acidic conditions (pH 1 or lower). However, any bile acids such as UDCA or CDCA are not soluble in the gastric pH range.

  Conjugation of the bile acid side chain with glycine or taurine has less impact on the hydrophobic activity of fully ionized bile salts. A more hydrophobic bile salt expresses a greater ability to dissolve phospholipids and cholesterol, and thus can be said to be a better cleaning agent. Also, the more hydrophobic bile salts are more harmful to various membranes both in vivo and in the examiner.

  Natural bile salt pools always contain a large number of bile salts. A mixture of two or more bile salts having different hydrophobic activities has a property as a single bile salt having an intermediate hydrophobic activity. As a result, the detergent properties and toxicity of a mixture of two bile acids with different hydrophobic activities may be intermediate between each component.

  Bile acids have a variety of properties. For example, UDCA is a useful immuno-modulating agent. It can also suppress the induction of nitric oxide synthase (NOS) in human intestinal epithelial cells and in vivo. As for bile acids, UDCA is the most powerful, but it may act as a pepsin inhibitor. In addition, bile acids may have membrane stabilizing properties. UDCA is a prototype of a novel selective glucocorticoid receptor (GR) modulator, and suppresses NF-kB without inducing the transcription-promoting function of GR. In addition, UDCA is responsible for the unique role of adjusting the apoptotic threshold for various formulations that act through different apoptotic pathways in both hepatocytes and non-hepatocytes. Finally, UDCA has specific antioxidant properties. Note that the OH free radical scavenger ability of UDCA is about 10 times higher than that of the known pharmacological scavenger mannitol and the physiological scavenger glucose or histidine. Should. This scavenger activity can increase the ability of UDCA to suppress deoxycholic acid-induced apoptosis by modulating mitochondrial membrane potential and reactive oxygen species production.

A bile acid stream is generated by the flow of bile salts through the liver. Ursodeoxycholic acid can promote bile flow by stimulating body fluid and electrolyte secretion in the downstream bile duct epithelium through changes in cytoplasmic Ca ⁺⁺ after hepatocytes release ATP into bile. . Bile salts in the enterohepatic circulation are thought to regulate bile acid synthesis by suppressing or decreasing the activity of cholesterol 7-hydroxylase, a rate-limiting enzyme in the bile acid biosynthesis pathway. Bile formation represents an important pathway for the solubility and secretion of organic compounds such as bilirubin, endogenous metabolites such as amphiphilic derivatives of steroid hormones, various drugs and other xenobiotics.

  Bile acid can regulate the rate of lipid protein cholesterol intake in the liver by acting as a regulator of liver lipid protein receptor (apo BE). On the other hand, the secretion of bile salts into bile is linked to the secretion of two different bile lipids, phosphatidylcholine (lecithin) and cholesterol. The link between bile salt output and lecithin and cholesterol output provides the main pathway for removal of hepatic cholesterol. Bile acids act directly on hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, or indirectly regulate cholesterol absorption in the intestine, thereby contributing to the regulation of cholesterol synthesis But there is. Bile salt dissolves cholesterol in bile in a mixed form of micelles and vesicles together with lecithin. In the intestine, the mixed micelle form of bile salt is involved in the intravascular dissolution, transport and absorption of cholesterol, fat-soluble vitamins and other lipids. Bile salts are involved in the transport of calcium and iron from the intestinal lumen to the brush border.

  UDCA, the main component of bear gall, has been used as the main pharmaceutical formulation for the treatment and prevention of many types of liver disease. Its pharmaceutical uses include the treatment of radiotransparent gallstones, bile dyspepsia, primary biliary cirrhosis, primary sclerosing cholangitis, chronic active hepatitis and hepatitis C. High concentrations of bile acids significantly inhibit hepatitis C virus growth.

  The hydrophilic nature of UDCA can confer cytoprotection of hepatic necroinflammatory disease. UDCA also significantly improves the aminotransferase and cholestasis enzyme index of liver damage in chronic hepatitis and alleviates alcoholic fatty liver. Bile salt deficiency and the reduced cholesterol solubility in the bile is responsible for the pathogenesis of cholesterol gallstones.

Bile acids may also have important therapeutic value in treating many other disease states, including affecting the heart and gastrointestinal tract. For example, UDCA has a vasodilatory effect on the systemic vascular bed but does not change pulmonary vascular function or heart function. With respect to the gastrointestinal tract, bile acids substantially inhibit the growth of Helicobacter pylori ( H. pylori ).

  Despite the potentially valuable pharmaceutical uses of bile acids as therapeutically active agents and as carriers and / or adjuvants, commercial uses of bile acids are tablets, capsules and suspensions. Limited to pharmaceutical formulations having a solid form of bile acids. This is due to the insolubility of bile acids in aqueous media at about pH 1-8. This is also due to the very bitter taste of bile and an equivalent bitter aftertaste that lasts for several hours. The few available water-soluble dosage forms are unstable and have limitations in use due to pH control and maintenance issues. In addition, some commercial pharmaceutical dosage formulations of bile acids have been reported to have insufficient bioavailability. The same applies to solid bile acid formulations.

  Thus, a need has arisen for liquid and solid bile acid formulations that are (liquid) or that form a clear aqueous solution (solid).

  The bile acid composition is preferably stored or administered in a dry or solid form. Accordingly, the present invention relates to dry or solid formulations (or dosage forms) of bile acids that form clear or particulate-free solutions when exposed to water. The dry or solid form of the present invention is made from a clear or particulate-free solution of bile acids (“mother liquor”). The present invention also relates to a process for producing and / or solubilizing this dried or solid form. The advantages of these dosage forms include improved bioavailability, plasma bioavailability and absorbability of bile acids. Additional advantages of the dosage forms of the present invention include improved bioavailability, plasma bioavailability and absorbability of one or more pharmaceutical compounds.

  In some preferred embodiments, the dry or solid formulations of the invention are exposed to water to (1) bile acids, their derivatives, their salts or their conjugates with amines, (2) water and ( 3) A solution containing a sufficient amount of water-soluble starch conversion product so that the bile acid and starch conversion product are in solution at any pH within the selected pH range. According to some preferred embodiments, the dry or solid formulations of the invention are exposed to water to (1) bile acids, their derivatives, their salts or their conjugates with amines, (2) water and (3) A solution containing a sufficient amount of a water-soluble non-starch polysaccharide and a water-soluble starch conversion product so that the bile acid and the polysaccharide are in a solution state at any pH within the selected pH range.

  The dried or solid form of the present invention is exposed to water to become a solution further comprising a resistant maltodextrin, water soluble ginseng extract, a pharmaceutically appropriate amount of a pharmaceutical compound, a water soluble bismuth compound or a combination thereof. Can do. When the solution contains one or more substances as described above, the solution composition can be adjusted to ensure that these substances remain in solution.

  The dry or solid preparation of the present invention can contain one or more disintegrants. In some embodiments of the invention, the solution formulation of the bile acid composition includes a disintegrant to facilitate destruction or disintegration of its dry form after administration. The pH of the solution of the present invention may be adjusted with acid under high power sonication. In some non-limiting embodiments of the invention, high power sonication accelerates the solubilization of dry or solid bile acid formulations.

  The dry or solid form of the present invention is made from a mother liquor that is transparent or particulate free. In some embodiments of the invention, the dried form derived from the solution dosage form of the bile acid composition is granulated by a granulation method developed from fluid bed drying techniques. In this method, the soluble fiber solution (granulation solution) is rapidly dried in floating air after being jetted into or onto the suspended dry form.

  In some embodiments of the invention, (1) bile acids, their derivatives, their salts or their conjugates with amines, (2) water and (3) bile acid components and carbohydrates were selected. A composition is provided comprising a sufficient amount of carbohydrate to be in solution at any pH within the pH range, wherein the carbohydrate is a combination of a water soluble starch conversion product and a water soluble non-starch polysaccharide. In embodiments containing both a soluble non-starch polysaccharide and a high molecular weight starch conversion product, the respective amounts, when they are combined together in the composition, are the bile acid component, the high molecular weight starch conversion product, the soluble non-starch product. The polysaccharide, and the pharmaceutical compound, if present, need only be sufficient to be in solution at any pH within the selected pH range.

  In some embodiments of the invention, combination therapy compositions are provided that increase the intensity of drug response or efficacy. Such compositions can allow administration of low dosages of pharmaceutical compounds, attack complex diseases at different points, and alter and / or eliminate absorption of pharmaceutical compounds. Such compositions result in or contribute to a decrease in drug toxicity and / or side effects.

  In some embodiments, the bile solution of the present invention is dried. The invention further relates to a dried form derived from a solution formulation of a bile acid composition by lyophilization, evaporation or any other technique of dehydration known in the art. The solution can be partially dried to produce a semi-solid form. The solution can also be completely dried to produce solids, powders and granules. The dried form of the aqueous solution may be substantially free of water. The dried form may be dried by a flow method, a tray method, a spray method or a freezing method. The dry form may also be administered directly in a dry dosage form or may be combined with water prior to administration.

  The invention further relates to a method for treating or preventing human or animal diseases comprising the administration of the composition of the invention.

  The present invention provides (i) one or more bile acids (collectively “bile acids” selected from the group consisting of soluble bile acids, water-soluble bile acid derivatives, bile salts, or bile acids conjugated with amines. )) (Ii) water and (iii) an amount of one or more water-soluble starch convertibles or water-soluble non-starch sufficient to produce a solution that does not form a precipitate at any pH within the desired pH range. The present invention relates to an aqueous solution containing a polysaccharide.

  The composition contains a bile acid or salt thereof having pharmacological effectiveness by itself. The formulations of the present invention act as carriers, adjuvants or enhancers for the transport of pharmaceutical substances that are dissolved in the compositions of the present invention at the desired pH range. In some embodiments of the invention, the non-bile acid drug is used without necessarily being in solution.

  An advantage of the present invention is that bile acids and carbohydrates are in solution without precipitation at any pH from acidic to alkaline. An aqueous system of bile acids is free of any precipitates or particles. Another advantage of the present invention is that there is no change in physical appearance such as change in transparency, color or odor after addition of strong acid or alkali after observing for 7 months under accelerated conditions stored at 50 ° C. It is in a proven point.

  In some embodiments of the present invention, an aqueous bile acid system is exposed to acidic gastric fluid when orally administered and travels through the gastrointestinal tract, and the bile acid precipitates as a solid upon exposure to the intestinal alkaline environment. It will not be done. These dosage forms demonstrate that the bile acid solution system that is unchanged in the gastrointestinal tract is effectively and completely absorbed.

  According to the present invention, bile acid solubility (eg, precipitation or change in physical appearance) is determined by whether the carboxylic acid side chain of any bile acid is protonated (non-ionized), ionized, or simply It is not affected by whether it is a carboxylic acid. The ionization state of the bile acid carboxylic acid side chain greatly affects the ability of micelle formation by bile acids in these aqueous solutions. In some embodiments of the invention, the ionized state is combined with the drug to use these aqueous systems as therapeutically active agents, as drug adjuvants, as drug carriers, or as drug solubility enhancers. It is manipulated by adjusting the pH to control the formation of bile acid micelles. These aqueous systems are oral consumers, enemas, mouth washes, gargles, nasal formulations, having the desired pH without the disadvantage of reduced precipitation or physical appearance even after a long period of time. Manufactured for ear preparations, injections, cleansers, topical skin preparations, other topical preparations and cosmetic preparations.

  A soluble bile acid is any type of water-soluble bile acid. A bile salt is a water-soluble salt of any bile acid. The soluble bile acid derivative of the present invention is a derivative that is soluble in an aqueous solution, or is more soluble in an aqueous solution than this non-derivatized bile acid, as is the corresponding non-derivatized bile acid. The bile acid derivatives include, but are not limited to, derivatives in which the hydroxyl group or carboxylic acid group of the bile acid is replaced with other functional groups, but not limited thereto, halogen and amino groups. Aqueous salts of bile acids include the bile acids and amines described above, but are not limited to these, and aliphatic free amines such as trientine, diethylenetriamine, and tetraethylenepentamine; basics such as arginine, lysine, and ornithine. Amino acids; amino sugars such as D-glucamine and N-alkylglucamine; quaternary ammonium derivatives such as choline; heterocyclic rings such as piperazine, N-alkylpiperazine, piperidine, N-alkylpiperidine, morpholine, N-alkylmorpholine, pyrrolidine Formula amines; formed by reaction with amines such as triethanolamine and trimethanolamine. According to the present invention, the soluble bile salts include water-soluble metal salts of bile acids or water-soluble O-sulfonated bile acids.

  The bile acids of the present invention include chenodeoxycholic acid, cholic acid, hyodeoxycholic acid, deoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iocolic acid, tauroursodeoxycholic acid, taurochenodeoxycholic acid, tauro It is selected from the group consisting of deoxycholic acid, taurolithocholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid and their derivatives at the hydroxyl or carboxylic acid group in the steroid nucleus. The bile acid of the present invention is selected from primary, secondary and tertiary bile acids.

UDCA is substantially insoluble at pH <7. PK _a of UDCA is 5.1, the solubility of its protonated form is 9 [mu] mol / L. The solubility of UDCA in the solution formulation is approximately 100 mg / mL, which corresponds to approximately 30,000 times the solubility of the original UDCA. Thus, the main advantage of the present invention is that high in vivo levels of bile acids (bile, blood, etc.) that far exceed other formulations are achieved by the transfer of solubilized bile acids in solution. Therefore, the therapeutic capacity of bile acids is more fully achieved with a high concentration of appropriate bile acids at each lesion by systemic feeding than with existing dosage forms. In vivo levels of bile acids obtained by existing dosage forms in which bile is gradually and gradually solubilized are lower. Furthermore, its low absorbency and enterohepatic circulation action cause the failure to detect therapeutically active bile acids such as UDCA in the blood. Since bile acids are completely dissolved in the dosage forms of the invention, higher in vivo bile acid levels are achieved even when lower volumes are administered.

  In some embodiments of the invention, multiple bile acids are used in a single formulation. A mixture of two or more bile salts with different hydrophobic activities can act as a single bile salt with an intermediate hydrophobic activity. As a result, mixtures of two or more bile salts have unique physiological benefits such as increased detergent properties and lower toxicity than individual bile acids.

  Carbohydrates suitably used in the present invention include water soluble starch conversion products and water soluble non-starch polysaccharides. Water soluble starch conversion is obtained from partial or incomplete hydrolysis of starch under various pH conditions. They also have a dextrose equivalent (DE) of about 4-40. DE is a quantitative measure of the degree of hydrolysis of the starch polymer. This is measured by comparing the reducing power with dextrose standard 100. A higher DE means a higher degree of starch hydrolysis. As the product is further hydrolyzed (higher), the average molecular weight decreases. Non-limiting examples include maltodextrin, dextrin, liquid glucose, corn syrup solids (dry powder of liquid glucose) and soluble starch, preferably maltodextrin or corn syrup solids, Most preferred is corn syrup solids. For the purposes of the present invention, the term “corn syrup” includes both corn syrup and liquid glucose. Water-soluble non-starch polysaccharides are water-soluble fibers such as guar gum, pectin, psyllium, oat gum, soy fiber, oats, corn peel, cellulose and bran.

  The amount of high molecular weight water soluble starch conversion used in the present invention is that amount necessary to impart solubility to the selected bile salt at least at the desired concentration and within the desired pH range. The approximate minimum amount of maltodextrin required to prevent the precipitation of bile acids from the aqueous dosage form of the invention depends on its DE value. In a preferred embodiment of the present invention, it is necessary to prevent the precipitation of bile acids from the aqueous formulation of the present invention, Maltri® M150, Maltrin® M180, Maltrin® M200, Maltrin®. The approximate minimum amount of maltodextrin having a DE value of 15-25 such as M250 (corn syrup solids), liquid glucose and soluble starch is about 30 g for CDCA which is 0.2 g bile acid, UDCA About 5 g, 7-ketritocholic acid (KLCA) about 12 g, cholic acid about 10 g, deoxycholic acid about 50 g, hyodeoxycholic acid about 3.5 g. In a preferred embodiment of the present invention, the approximate minimum amount of maltodextrin (DE5-10) such as Maltri® M040, Maltrin® M100 is about CDCA, which is 0.2 g bile acid. 18 g, about 3 g for UDCA, about 7 g for 7-ketritocholic acid (KLCA), about 6 g for cholic acid, about 30 g for deoxycholic acid, about 2.1 g for hyodeoxycholic acid It is.

  Digestible maltodextrin is a water-soluble dietary fiber. This soluble maltodextrin is produced by conscious conversion of some of the normal alpha-1,4 glucose bonds from corn starch with random 1,2-, 1,3- and 1,4-alpha or beta bonds ( It is similar to the conventional maltodextrin production process). The human digestive system effectively digests only alpha 1,4-linkages, and other bonds provide molecules that are resistant to digestion. Thus, other bonds that are generated pass through the large intestine without being absorbed in the small intestine. This resistant maltodextrin is partially fermented in the large intestine and secretes unused fractions. This water soluble maltodextrin helps to maintain normal healthy levels of serum cholesterol, blood triglycerides, blood glucose levels, intestinal regularity and intestinal microflora. In some embodiments of the invention, the solution formulation may include a water-soluble digestible maltodextrin.

  In some embodiments of the invention, the formulation can also include a cyclodextrin.

  Drugs are most often administered orally by solid dosage forms such as powders, dry granule masses, tablets and capsules. The solid dosage form facilitates handling, highlights the physical appearance and improves stability. In many cases, the solubility and other physicochemical properties of the drug are known to affect the physiological utility from the solid dosage form. The dry form contains water soluble bile acids that facilitate solubilization, easily soluble high molecular weight starch conversion products and disintegrants. The increased solubility of bile acids results in an increased dissolution rate. As a result, the absorption rate is greatly increased by the increased dissolution rate.

  The compositions of the present invention further comprise a disintegrant that facilitates degradation or disintegration of the dried or solid form after administration. Disintegrants include Veegum HV, methylcellulose, agar, bentonite, natural sponge, cation exchange resin, alginic acid, guar gum, citrus pulp, carboxymethylcellulose, clays, celluloses, algins, gums, cross-linked polymers ( Starches such as crospovidone), cross-linked cellulose (croscamellose) and cross-linked starch (sodium starch glycolate). The collapse function is due to capillary action rather than swelling. Generally, the water soluble disintegrant is mixed with the active ingredient before drying. In the case of a water-insoluble disintegrant, 5% by weight starch is added to the dry powder formulation. If more rapid disintegration is desired, this amount is increased to 10 or 15%. 2-4% sodium starch glycolate is swollen 7 to 12 times in 30 seconds or less, and cross-camerulose is swollen 4 to 8 times in 10 seconds or less.

  Carbon dioxide release is an effective way to cause rapid dissolution of dry forms derived from solution formulations of bile acid compositions. A dry form containing a mixture of sodium bicarbonate and a sour agent such as tartaric acid or citric acid should produce a foam when added to water. The amount of sodium bicarbonate is about 10 times the amount of bile acids. The amount of acidulant is 20% or more of the amount of sodium bicarbonate. When enough acid is added, a neutral or weakly acidic reaction will occur if dissolution in water is rapid and complete.

  The present invention also relates to the production of solution formulations derived from bile acid compositions. High power sonication with or without heating at about 60 ° C. is useful to solubilize the dry or solid formulations of the present invention. A high power sonication system is used to flush the precipitated compound back into the solution during manufacture of the solution dosage form. The effects of ultrasound time, power and amplitude are optimized to flush the compound back into solution. A 0-1150 watt sonicator that generates 20 kHz acoustic energy would be used to form the clear aqueous solution of the present invention.

  The dry form is produced from the mother liquor by wet granulation, dry granulation and fluid bed granulation. If each component has sufficient intrinsic binding and cohesiveness, dry granulation (slagging) is used for granule production. The general stages of wet and dry granulation are nominal, mixing, granulating (slugging) and screening. Fluidized bed granulation is carried out by spraying the granulation solution or solvent into or on the suspended particle bed and then quickly drying it in floating air. In these systems, the suspended particles, which are in dry form derived from the mother liquor, may be coated with a granulating solution or solvent containing an enteric polymer. Enteric polymers are cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), methacrylic acid-methacylic acid ester copolymer, cellulose acetate that effectively function as an enteric coating at a pH of 6 or higher. Includes trimellitate (CAT), carboxymethyl ethyl cellulose (CMEC) and hydroxypropyl methyl cellulose acetate succinate (HPMCAS). The granulated form having these enteric polymers remains in the stomach as it is, but once it reaches the intestine and large intestine, it should dissolve and release the active ingredient.

  Spheronization, which is a pelletized form, means forming spherical particles (spheres) from wet granulation or fluid bed granulation. Bar-shaped circumferential pieces in the 500 micron to 12 mm diameter range are manufactured through an extruder. After extruding, the pieces are placed in a Marumerizer, and they are shaped into spheres by centrifugal and frictional forces on a rotating plate. The pellets are coated after being dried. In some embodiments of the invention, the dry form of the solution form of the bile acid composition is manufactured by a spheronization process and then coated with an enteric polymer.

  The selected pH range in which the dosage form does not precipitate its bile acids, starch conversions, soluble non-starch polysaccharides or pharmaceutical compounds thereof is any range of pH levels obtained in aqueous systems. This range is preferably about pH 1 to pH 14, and more preferably about pH 1 to pH 10. Furthermore, the range is any sub-set of pH levels obtained in an aqueous system sufficient to maintain the pharmaceutical dosage form in solution from the formulation and be administered and absorbed by the body, depending on the method of administration. In some embodiments of the invention, the bile acid is in a dissolved state under acidic conditions as free bile acid, despite the general insolubility of bile acids under acidic conditions. In some embodiments of the invention, the composition is used as a pharmaceutical dosage form in which the pharmaceutical formulation is placed in solution without being precipitated at a prevailing pH level in the oral cavity, stomach or intestine. .

The present invention envisions the use of a wide range of pharmaceutical substances. Non-limiting examples include hormones, hormone antagonists, analgesics, antipyretic drugs, anti-inflammatory drugs, immunoactive drugs, anti-neoplastic drugs, antibiotics, anti-inflammatory drugs, sympathomimetic drugs, anti-infective drugs, anti-infective drugs Includes oncology and euphoric agents. Further, non-limiting examples include drugs that target or affect the gastrointestinal tract, liver, cardiovascular system and respiratory system. In addition, non-limiting examples of pharmaceutical compounds include insulin, riluzole, heparin, calcitonin, ampicillin, octreotide, sildinafil citrate, calcitriol, dihydrotaxosterol, apomorphine, yohimbine, trazadone, acyclovir, amantadine HCl , Rimantadine / HCl, cidofovir, delavirdine mesylate, didanosine, famciclovir, foscarnet sodium, fluorouracil, ganciclovir sodium, idoxuridine, interferon-α, interferon-β, interferon-γ, lamivudine, nevirapine , Penciclovir, ribavirin, stavudine, trifluridine, valaciclovir HCl, zalcitabine, zidovudine, indina Building _· H 2 SO _4, ritonavir, nelfinavir _· CH 3 _SO 3 H, saquinavir _· CH ₃ SO ₃ H, d- penicillamine, chloroquine, hydroxychloroquine, aurothioglucose, gold sodium thiomalate, auranofin lever Mi sole, DTC, isoprinosine, methylinosine monophosphate, muramyl dipeptide, diazoxide, hydralazine / HCl, minoxidil, dipyridamole, isoxsuprine / HCl, niacin, nyridrin / HCl, phentolamine, doxazosin / CH ₃ SO ₃ H, prazosin / HCl, terazosin / HCl, clonidine / HCl, nifedipine, molsidomine, amiodarone, acetylsalicylic acid, verapamil, diltiazem, nisoldipine, isradipine, bepridi , Isosorbide dinitrate, pentaerythritol tetranitrate, nitroglycerin, cimetidine, famotidine, nizatidine, ranitidine, lansoprazole, omeprazole, misoprostol, sucralfate, metoclopramide HCl, erythromycin, bismuth compound, alprostadil, albuterol terbuterol H ₂ SO ₄ , salmeterol, aminophylline, diphylline, ephedrine, ethyl norepinephrine, isoethalin, isoproterenol, metaproterenol, n-docromil, oxtriphyrin, theophylline, vitorterol, fenoterol, budesonide, flunisolide, beclomethasone dipropionate Fluticasone propionate, codeine, sulfate In, codeine phosphate, dextromethorphan HBr, triamcinolone acetonide, montelukast sodium, zafirlukast, zileuton, cromoglycate sodium, ipratropium bromide, nedocromil sodium benzoate, diphenhydramine HCl, hydrocodone ditartrate, methadone HCl , Morphine sulfate, acetylcysteine, guaifenesin, ammonium carbonate, ammonium chloride, potassium antimony tartrate, glycerin, terpine hydrate, colphosceryl palmitate, atorvastatin calcium, cerivastatin sodium, fluvastatin sodium, lovastatin, pravastatin sodium, simvastatin , Picrorrhazia kurroa, Andrography spanish Rata, Moringa Oleifera, Albizzia lebeck, Adhatodabashika, Curcuma longa, Momordica charantia, Gymnema sylvestre, Terminalia arjuna, Azadela Cuchanindica, tinosporia cordifolia, metronidazole, amphotericin B, clotrimazole, fluconazole, haloprozine, ketoconazole, griseofulvin, itraconazole, terbinafine HCl, econazole HNO ₃ , miconazole, oxyconazole · HNO _3, sulconazole · HNO _3, cetirizine · 2HCl, dexamethasone, hydrocortisone, prednisolone, cortisone, catechin and its derivatives, Lysyl lysine, glycyrrhizic acid, betamethasone, rudolocortisone acetate, flunisolide, fluticasone propionate, methylprednisolone, somatostatin, lispro, glucagon, proinsulin, insoluble insulin, acarbose, chlorpropamide, glipizide, glyburide, metformin HCl, repaglinide, Tolbutamide, amino acid, colchicine, sulfinpyrazone, allopurinol, piroxicam, tolmetine sodium, indomethacin, ibuprofen, diflunisal, mefenamic acid, naproxen, trientine, vitamin E, vitamin C, superoxide dismutase (SOD), N-acetylcysteine, lazaloid , 21-aminosteroids such as U74389F and U74006F, potassium Talase (CAT), putrescine-modified catalase (PUT-CAT), estrogen, alpha-lipoic acid, selegiline, desferrioxamine, d, l-penicillamine, alpha and beta-carotene, retinol, selenium, ginkgo ( gingko Biloba), riluzole, flupirtine, pifithrin-alpha, CGP3466B / TCH346, CPI-1189, CEP-1347 and coenteam Q10.

  Moreover, the bile acid composition of the present invention can contain carrots. Carrots contain vitamins A, B-6 and the mineral zinc, which helps produce the thymic hormones necessary to activate the defense system. The main active ingredient in ginseng is more than 25 triterpenoid glycosides called “ginsenosides”. These steroid-like components provide adaptogenic properties that allow ginseng to balance and respond to stress effects. Glycosides have been shown to act on the adrenal glands in response to physical, chemical or biological stress, helping to prevent adrenal hypertrophy and excessive corticosteroid production. The pharmacokinetic effects of carrots have been demonstrated in the CNS and in the cardiovascular, endocrine and immune systems. Carrots and their constituents are also said to have anti-neoplastic, stress relieving and antioxidant activities. It is also a medicinal plant with many active ingredients, and many studies have proven that ginseng has an advantageous effect. Ginseng has been proven to have a combined effect with various herbal medicines to increase the intensity of response or efficacy, reduce individual toxicity, offset undesirable effects and alter long-term absorption.

  The pharmacological effects of ginseng have been demonstrated in the CNS and in the cardiovascular, endocrine and immune systems. Carrots and their water soluble constituents are also said to have anti-neoplastic, stress relieving and antioxidant activities. In some embodiments of the invention, the solution dosage form comprises water soluble ginseng (caucasian ginseng and red ginseng) extract.

  Thus, the present invention envisions a wide range of pharmaceutical substance applications. Any pharmaceutical substance that is soluble and / or in a soluble state is used in the dosage forms of the invention. Along with the additional pharmaceutical compound in the formulation, the bile acid in solution acts as an adjuvant, carrier or enhancer for the solubility of any therapeutically active agent. Examples of these include insulin (pH 7.4 to 7.8), heparin (pH 5 to 7.5), calcitonin, ampicillin, amantadine, rimantadine, sildenafil, neomycin sulfate (pH 5 to 7.5), apomorphine, yohimbine, Examples include, but are not limited to, trazadone, ribavirin, paclitaxel and its derivatives, retinol and tretinoin. These are soluble and stable in acid and / or alkali, and are added, if necessary, in the aqueous solution formulation of a predetermined concentration of bile acids in the present invention. Certain therapeutic actives, including but not limited to metformin HCl (pH 5-7), ranitidine HCl, cimetidine, lamivudine, cetirizine 2HCl (pH 4-5), amantadine, rimantadine, sildenafil, apomorphine, yohimbine, trazadone , Ribavirin and dexamethasone, hydrocortisone, prednisolone, triamcinolone, cortisone, niacin, taurine, vitamins, naturally occurring amino acids, catechin and its derivatives, glycyrrhizal extract, its main components glycyrrhizin and glycyrrhizic acid, and water-soluble Any therapeutically active agent that is soluble and stable in acid and / or alkali, such as a bismuth compound (eg, bismuth sodium tartrate) may optionally be added to the ursode of the present invention. It is added to the aqueous solution dosage formulations containing Kishikoru acid.

  According to the invention, the bismuth compound comprises a water soluble reaction product between bismuth ions and chelates. Non-limiting examples of this chelate include citric acid, tartaric acid, malic acid lactic acid and edetic acid. Non-limiting examples include bismuth citrate, bismuth sulfate, bismuth oxynitrate, bismuth hypocarbonate, bismuth subsalicylate or bismuth gallate.

The present invention envisions the use of a pH adjuster. Non-limiting examples include HCl, H ₂ SO ₄ , HNO ₃ , CH ₃ COOH, citric acid, malic acid, tartaric acid, lactic acid, phosphate and edetic acid or alkalis.

In some embodiments of the invention, the formulation is used to treat a human disease or a mammalian disease. The present invention contemplates the treatment of gastrointestinal disorders, liver disease, gallstones or hyperlipidemia. Non-limiting examples of liver disease include alcohol-induced liver disease and non-alcohol-induced liver disease. Non-limiting examples of gastrointestinal disorders include chronic gastritis, reflux gastritis and peptic ulcer disease. Non-limiting examples of non-alcohol-induced liver disease include primary biliary cirrhosis, acute and chronic hepatitis, primary sclerosing cholangitis, chronic active hepatitis and excess fat accumulation in the liver. The present invention also envisages the treatment of viral, bacterial or fungal diseases. In some embodiments of the invention, the formulation is administered to treat and / or eradicate Helicobacter pylori infection. In some embodiments of the invention, the prescription comprises hepatitis C virus infection, influenza A, influenza C, type 1 parainfluenza, sendai, rubella and Pseudorabies virus. Administered to treat and / or eradicate. In some embodiments of the invention, the dosage form is administered to treat an acute or chronic inflammatory disease. Non-limiting examples of inflammatory diseases include bronchitis, chronic pharyngitis and chronic tonitis. In some embodiments of the invention, the dosage form is administered to treat hypercholesterolemia.

  In some embodiments of the invention, the formulation is modified to be administered as a liquid, solid, powder or tablet. In some embodiments of the invention, the formulation consists of syrup, thick syrup or paste. A non-limiting example of a syrup is a maltodextrin solution with a maltodextrin concentration of less than 1.0 kg / L. A non-limiting example of a concentrated syrup is a maltodextrin solution having a maltodextrin concentration of 1.0 kg / L or more and 1.2 kg / L or less. A non-limiting example of a paste is a maltodextrin solution with a maltodextrin concentration greater than 1.2 kg / L.

  The aqueous solution of the present invention may be dried. For the purposes of the present invention, a “primary” aqueous bile acid dosage formulation according to the present invention is produced by the original combination of bile acid or salt thereof and carbohydrate with water. This is produced by a simultaneous or stepwise combination of each component. In contrast, a “secondary” aqueous bile acid dosage formulation is a solution made from a powder or solid containing bile acids and carbohydrates previously co-dissolved. Thus, the secondary aqueous bile acid dosage regimen differs in that at least water is added, removed and re-added.

  In some embodiments of the invention, the primary aqueous bile acid dosage formulation is dried by spray drying. Spray drying consists of sending a highly dispersed liquid and a sufficient volume of hot air to evaporate and dry the droplets. The feed liquid can be pumped and is a sprayable solution, slurry, syrup or paste. The liquid supply is injected into the warm filtered air stream. The air supplies heat for evaporation and transports the dried product to a collector, which is then exhausted with moisture. The spray-dried powder particles are homogeneous, are approximately spherical in shape, are approximately uniform in size, and are often hollow. The latter feature results in low volume density along with the rapid rate of solution. This process is useful for coating one substance on another to protect internal substances or to control their release rate. For example, a dry form of an aqueous bile acid dosage formulation is coated with an enteric polymer for colonic delivery of solubilized UDCA. Dehydration may be performed by lyophilization, evaporation or any other dehydration technique known in the art.

  The resulting dry form, such as a powder or solid, can be administered directly or recombined with water to form a secondary clear aqueous bile acid dosage formulation. Secondary aqueous bile acid dosage formulations, i.e. those made from dry form, have substantially the same properties as the primary dosage form.

  The present invention contemplates adding additives such as drugs to the dry form as well as primary and secondary bile acid aqueous solutions. When administered in dry form, the dried material may be combined with one or more diluents, lubricants, binders, fillers, drugs, disintegrants or other additives. As described above, the dry form consists of powders, granules, pills, tablets or capsules.

The stability of the dosage formulation of the present invention is evaluated by measuring the concentration of bile acids over time for preparations containing soluble bile acids, high molecular weight water soluble starch conversion products and water at various pH and temperature levels. It was. Stability testing was performed by HPLC and light microscopy at various pH conditions under normal and accelerated conditions. Solution stability tests including concentration analysis for each bile acid were performed by the following HPLC. The eluting solvent was 0.02M KH ₂ PO ₄ : acetonitrile at a pH of 3.01, in a ratio of 55:45, the flow rate was 0.8 mL / min, the injection volume was 20 μl, and the detection wavelength was 195 nm. The residence time of each bile acid is adjusted as necessary so that individual analysis of each bile acid present in a sample having a plurality of bile acids is possible. In the table, the concentration of bile salts from the three tests and their average values are recorded in each column. The percentage indicates the relative concentration of bile salts after culturing for a predetermined time compared to the initial concentration.

Accelerated conditions for testing pharmaceutical compositions are already known (see literature [Remington, The Science and Practice of Pharmacy , 19th ed., P. 640]). All these stability test results were satisfactory in that the concentration of bile acids measured by HPLC did not change enough to be evaluated over time at various pH levels. Thus, the example formulations are suitable for producing commercially available liquid dosage forms. In particular, all solution formulations containing bile acids showed excellent results in the stability test because there was no precipitation over the test period and no change in physical appearance. Some formulations are stably maintained over 2 years.

  Stability testing was also performed on an aqueous formulation containing a mixture of water soluble UDCA according to Example IV, branched chain amino acids (leucine, isoleucine, valine) and maltodextrin. This formulation is a typical solution formulation in which bile acids function as therapeutically active agents, adjuvants or carriers, pharmaceutically active agents, and solubility enhancers. According to the test results, there was no transparency change, discoloration or precipitation. Also, impurities that can be detected from degradation of UDCA or branched chain amino acids when investigated by HPLC under various pH conditions such as pH 1, 3, 5, 7, 9 or 10 under accelerated conditions (eg, cultured at 50 ° C.) There was no.

  The aqueous solution formulation according to the present invention does not change physically or chemically at various pH conditions under accelerated conditions, despite the addition of therapeutic and chemically active agents that are stable and soluble in hydrochloric acid solutions. It was. These aqueous systems are therefore highly valuable pharmaceutical dosage formulations for the delivery of therapeutically active bile acids and / or drugs. In drug (pharmaceutical compound) delivery formulations, without being limited to any particular mode of action, bile acids can also function as adjuvants, carriers or solubility enhancers (eg, micelle formation).

  The stability test was performed on three different aqueous systems. First, according to Example I, an aqueous solution containing bile acid and high molecular weight water-soluble starch conversion product was tested. The results are shown in Table 1A and Table 1B. Secondly, according to Example II, an aqueous solution containing a mixed bile acid and high molecular weight water soluble starch conversion product was tested. The results are shown in Table 2. Thirdly, according to Example IV, tested in aqueous solutions containing bile acids, high molecular weight water soluble starch conversion products and branched chain amino acids (eg, leucine, isoleucine, valine or other amino acids having branched side chains). The results are shown in Tables 3A to 3F.

Example I
According to the following guidelines, the first series of solution formulations made with soluble bile acids (as free acids) and high molecular weight water soluble starch conversion products showed no precipitation at any pH tested.
────────────────────────────────────
Soluble bile acid Starch conversion (minimum amount)
────────────────────────────────────
If CDCA is 200mg, about 30g
If UDCA 200mg, about 5g
If KLCA 200mg, about 12g
If cholic acid is 200mg, about 10g
Deoxycholic acid 200mg is about 50g
If hyodeoxycholic acid is 200 mg, about 3.5 g
Purified water (total volume produced) 100 mL
────────────────────────────────────
An aqueous solution (100 mL) in which one of the soluble bile acids was dissolved was prepared. Maltodextrin, which is one of high-molecular-weight water-soluble starch conversion products, was stirred at about 60 to 80 ° C. and dissolved therein to obtain a transparent solution. The pH of the resulting clear solution was adjusted with acid to produce oral dosage forms, topical formulations and solutions. Purified water was added to bring the total volume to 100 mL. In the present invention and all examples, the purified water is deionized water, distilled water or deionized-distilled water, or any of the grades commonly used in pharmaceutical formulations. Good.
Based on these formulations, high molecular weight water soluble starch conversion products (eg, Maltrin® M150 (DE) with any concentration of any bile acid (or salt) and their corresponding minimum amount of DE15-25. = 15), Maltrin® M180 (DE = 18), Maltrin® M200 (DE = 20), Maltrin® M250 (corn syrup solids; DE = 25), liquid glucose) or soluble Aqueous dosage forms with non-starch polysaccharides (eg, guar gum, pectin, gum arabic) were prepared.

Example II
According to the following guidelines, the second series of solution formulations made with soluble bile acid (as free acid) and high molecular weight water soluble starch conversion showed no precipitation at any pH tested.
────────────────────────────────────
Soluble bile acid Starch conversion (minimum amount)
────────────────────────────────────
If CDCA is 200mg, about 18g
If UDCA 200mg, about 3g
If it is 200 mg of KLCA, about 7.2 g
About 6g of cholic acid 200mg
Deoxycholic acid 200mg is about 30g
If hyodeoxycholic acid is 200 mg, about 2.1 g
Purified water (total volume produced) 100 mL
────────────────────────────────────
An aqueous solution (100 mL) in which one of the soluble bile acids was dissolved was prepared. Maltodextrin, which is one of high-molecular-weight water-soluble starch conversion products, was added to the obtained solution, and the mixture was stirred and dissolved at room temperature to obtain a transparent solution. The pH of the resulting clear solution was adjusted with acid under high power sonication to produce oral dosage forms, topical formulations and solutions. Purified water was added to bring the total volume to 100 mL.
Based on these formulations, high molecular weight water soluble starch conversion products (eg, Maltrin® M040, Maltrin) with various concentrations of any bile acids (or salts) and their corresponding minimum amounts of DE5-10. (R) M100) or soluble non-starch polysaccharides (eg guar gum, pectin, gum arabic) were prepared.

Example III
According to the following guidelines, a third series of solution formulations made with soluble bile acids (as free acids) and high molecular weight water soluble starch conversion products did not show any precipitation at pH 6.5-8.
────────────────────────────────────
Soluble bile acid Starch conversion (minimum amount)
────────────────────────────────────
If CDCA is 200mg, about 15g
If UDCA 200mg, about 1.5g
If it is 200 mg of KLCA, about 3.6 g
If cholic acid is 200mg, about 3g
If deoxycholic acid is 200 mg, about 15 g
If hyodeoxycholic acid is 200 mg, about 3.5 g
Purified water (total volume produced) 100 mL
────────────────────────────────────
An aqueous solution (100 mL) in which one of the soluble bile acids was dissolved was prepared. Maltodextrin, which is one of high-molecular-weight water-soluble starch conversion products, was added to the obtained solution, and the mixture was stirred and dissolved at room temperature to obtain a transparent solution. The pH of the resulting clear solution was adjusted with acid under high power sonication to produce injectable, colon-specific, topical and eye drop dosage forms. Purified water or water for injection was added to make the total volume 100 mL.
Based on these formulations, high molecular weight water soluble starch conversion products (eg, Maltrin® M040, Maltrin (Maltri®) with various concentrations of any bile acids (or salts) and their corresponding minimum amounts of DE5-10. Aqueous dosage forms with M100) or soluble non-starch polysaccharides (eg guar gum, pectin, gum arabic) were prepared.

Example IV
According to the following guidelines, the fourth series of solution formulations made with soluble bile acids (as free acids), high molecular weight water soluble starch conversion products and non-starch polysaccharides showed no precipitation at any pH tested. .
────────────────────────────────────
Soluble bile acids 200mg KLCA (10mg-3g)
Starch conversion (minimum amount) about 24g (0.6g-75g)
20g soluble fiber (5g-30g)
Purified water (total volume produced) 100 mL
────────────────────────────────────
An aqueous solution (60 mL) in which soluble KLCA was dissolved was prepared. Maltodextrin, which is one of high-molecular-weight water-soluble starch conversion products, was added to the obtained solution and dissolved by stirring at room temperature to obtain a transparent solution. The pH of the resulting clear solution was adjusted with acid under high power sonication to produce injection and topical dosage forms. Next, soluble non-starch polysaccharides (eg guar gum, pectin, gum arabic) and soluble maltodextrin were added. Purified water or water for injection was added to bring the total volume to 100 mL.
Table 1A shows the results of a stability test over time of a solution formulation of CA, 7-ketritocholic acid, CDCA and DCA containing maltodextrin prepared according to Example I at pH 7, 50 ° C. The bile acid concentration was measured by HPLC, and the percentage of bile acid on day 0 concentration was listed in the column labeled Percentage.
Table 1B shows the results of a stability test over time of a solution formulation of CA, 7-ketritocholic acid, CDCA and DCA containing maltodextrin prepared according to Example I at pH 10, 50 ° C.
Table 2 shows the results of a stability test over time of a solution formulation of CA, 7-ketritocholic acid, CDCA and DCA containing maltodextrin prepared according to Example II at pH 1, 50 ° C.

Example V
According to the following guidelines, the fifth series of solution formulations made with soluble bile acids (as free acids), high molecular weight water soluble starch conversion products and non-starch polysaccharides showed no precipitation at any pH tested. .
────────────────────────────────────
Soluble bile acid 200mg UDCA (10mg-3g)
Starch conversion (minimum amount) about 5g (0.25g-75g)
Resistant maltodextrin 15g (5g-30g)
Purified water (total volume produced) 100 mL
────────────────────────────────────
An aqueous solution (100 mL) in which soluble UDCA was dissolved was prepared. Maltodextrin, which is one of high-molecular-weight water-soluble starch conversion products, was added to the obtained transparent liquid and dissolved by stirring at room temperature to obtain a transparent solution. The pH of the resulting clear solution was adjusted with acid under high power sonication to produce oral and topical dosage forms. Next, soluble maltodextrin was added. Purified water or water for injection was added to bring the total volume to 100 mL.
Based on these recipes, high molecular weight water soluble starch conversion products with various concentrations of UDCA (or salts) and their corresponding minimum amounts of DE 5-40 (eg, Maltrin® M150, Maltrin®). Aqueous formulations with M180, Maltrin® M200, Maltrin® M250, Maltrin® M040, Maltrin® M100, or soluble maltodextrin were prepared.

Example VI
According to the following guidelines, the sixth series of solution formulations made with soluble bile acid (as free acid), high molecular weight water soluble starch conversion and ginseng extract showed no precipitation at any pH tested.
────────────────────────────────────
Soluble bile acid 200mg UDCA (10mg-3g)
Starch conversion (minimum amount) about 5g (0.25g-75g)
Water-soluble carrot extract 200mg (50mg-3g)
Purified water (total volume produced) 100 mL
────────────────────────────────────
An aqueous solution (80 mL) in which soluble UDCA was dissolved was prepared. Maltodextrin, which is one of high-molecular-weight water-soluble starch conversion products, was added to the obtained transparent solution and dissolved by stirring at room temperature to obtain a transparent solution. The pH of the resulting clear solution was adjusted with acid under high power sonication to produce oral and topical dosage forms. Next, soluble ginseng extract was added. Purified water or water for injection was added to bring the total volume to 100 mL.
Based on these recipes, aqueous formulations with varying concentrations of UDCA (or salt) and their corresponding minimum amounts of high molecular weight water soluble starch conversion (with DE 5-40) were prepared. Water-soluble ginseng extracts include extracts from red ginseng and white ginseng.

Example VII
According to the following guidelines, the seventh series of solution formulations produced by soluble bile acid (as free acid), high molecular weight water soluble starch conversion and carrot extract showed no precipitation at any tested pH.
────────────────────────────────────
Soluble bile acid 200mg UDCA (10mg-3g)
Starch conversion (minimum amount) about 5g (0.25g-75g)
Water soluble carrot extract 200mg (50mg ~ 5g)
Soluble non-starch polysaccharide 5-20g
Purified water (total volume produced) 100 mL
────────────────────────────────────
An aqueous solution (80 mL) in which soluble UDCA was dissolved was prepared. Maltodextrin, which is one of high-molecular-weight water-soluble starch conversion products, was added to the obtained transparent solution and dissolved by stirring at room temperature to produce a transparent solution. The pH of this clear solution was adjusted with acid under high power sonication to produce oral and topical formulations. Next, water soluble ginseng extract and soluble non-starch polysaccharides (eg guar gum, pectin, gum arabic) or soluble maltodextrin were added. Purified water or water for injection was added to bring the total volume to 100 mL.
Based on these formulations, aqueous formulations with various concentrations of UDCA (or salt) and their corresponding minimum amounts of high molecular weight water soluble starch conversion (with DE 5-40) were prepared. Water soluble ginseng extract includes extracts from red ginseng and white ginseng. The soluble fiber was a soluble non-starch polysaccharide (eg guar gum, pectin, gum arabic) or a soluble maltodextrin.
FIG. 6 is the NMR spectrum that it shows when the UDCA of the composition produced by Example III is completely free UDCA. That is, the carboxylic acid of UDCA at C-24 is in the free form (R-COOH), and the two hydroxy groups at C-3 and C-7 are in the free form (R-OH).
Also, the HPLC profile of UDCA in the composition prepared according to Example III (FIG. 7) is similar to the profile of UDCA dissolved in methanol (FIG. 8). This data indicates that there is no UDCA-complex compound. There is only free UDCA. A non-aqueous UDCA standard solution was prepared by dissolving 100 mg of UDCA in 100 mL of methanol. As the mobile phase, a mixture of acetonitrile 51, water 49 and acetic acid 1 was used.

Example VIII
In accordance with the following guidelines, the eighth series of solution formulations made with soluble bile acids (as free acids), high molecular weight water soluble starch conversion products and branched chain amino acids (eg, leucine, isoleucine, valine) were tested No precipitation was observed even at a pH of.
────────────────────────────────────
Soluble bile acid 200mg UDCA (10mg-3g)
Starch conversion (minimum amount) about 5g (0.25g-75g)
Branched chain amino acid 15g (1g-35g)
Purified water (total volume produced) 100 mL
────────────────────────────────────
An aqueous solution (85 mL) in which soluble UDCA was dissolved was prepared. Maltodextrin, which is one of high-molecular-weight water-soluble starch conversion products, was added to the obtained transparent solution and dissolved by stirring at room temperature to obtain a transparent solution. The pH of the resulting clear solution was adjusted with acid (from pH 4 to pH 7) under high power sonication to produce oral and topical dosage formulations. Next, branched chain amino acids were added. Purified water or water for injection was added to bring the total volume to 100 mL.
Based on these formulations, aqueous formulations with varying concentrations of UDCA (or salts) and their corresponding minimum amounts of high molecular weight water soluble starch conversion (with DE 5-40) can be obtained with varying amounts of branched chain amino acids. (Total amount of leucine, isoleucine and valine).
Tables 3A to 3F show the stability test results over time for formulations prepared with amino acids according to Example IV. All stability tests were performed at 50 ° C. The stability test results at pH 1 (Table 3A), pH 3 (Table 3B), pH 5 (Table 3C), pH 7 (Table 3D), pH 9 (Table 3E) and pH 10 (Table 3F) are displayed.

Example IX
According to the following guidelines, the ninth series of solution dosage forms produced by soluble bile acids (as free acids) and high molecular weight water soluble starch conversion products show precipitation at any pH within the selected desired pH range. There wasn't. This dosage form is modified based on known analytical data for bear gall.
───────────────────────────────
Soluble bile acid 21gUDCA
Soluble bile acid 9gCA
Soluble bile acid 9gCDCA
750g starch conversion product
Purified water (total volume produced) 1.0L
───────────────────────────────
An aqueous solution (400 mL) of soluble UDCA was prepared. Next, a high molecular weight water-soluble starch conversion product was added to obtain a transparent solution. Soluble CDCA and soluble CA were added to the resulting clear solution. The pH of this solution was adjusted with acid under high power sonication to produce oral and topical dosage forms. Purified water or water for injection was added to bring the total volume to 1.0L.

Example X
According to the following guidelines, the 10th series of solution dosage forms produced by soluble bile acids (as free acids) and high molecular weight water soluble starch conversion products show precipitation at any pH within the selected desired pH range. There wasn't. This dosage form was modified based on known analytical data on bear gall.
───────────────────────────────
Soluble bile acid 21gUDCA
Soluble bile acid 9gCA
Soluble bile acid 9gCDCA
750g starch conversion product
20 g of water-soluble carrot extract
Purified water (total volume produced) 1.0L
───────────────────────────────
An aqueous solution (400 mL) of soluble UDCA was prepared. Next, a high molecular weight water-soluble starch conversion product was added to obtain a transparent solution. To the resulting clear solution, soluble CDCA, soluble CA and water-soluble carrot extract were added. The pH of this solution was adjusted with acid under high power sonication to produce oral and topical dosage forms. Purified water or water for injection was added to bring the total volume to 1.0L.

Example XI
An aqueous formulation according to the present invention containing 200 mg of ursodeoxycholic acid (UDCA) was prepared by the method described in Example III above and administered to 3 healthy men with normal weight after fasting. The blood levels of UDCA and glycoUDCA were evaluated by known analytical methods. After injecting buffered serum into the sep-pak column, the methanol eluate was derivatized with phenacyl bromide at 80 ° C. for 45 minutes. These phenacyl bromide derivatives were dissolved in acetonitrile for HPLC. The experimental results of absorption measured at a given time after administration are the total absorption expressed as the area under the serum concentration-time curve (AUC: μg / mL × hour), the maximum blood concentration obtained (C _max ; μg / mL) and the time (T _max ; hour) when the maximum concentration was obtained. These results are recorded in Table 4, FIG. 1 and FIG.
An experimental pharmacokinetic study of the aqueous formulation according to the present invention performed on males shows that AUC, C _max and T _max compared to the best results with any currently known dosage form Showed a substantial improvement. The maximum blood concentration (C _max ) in Table 4 averages 8.43 ± 1.69 μg / mL, and is at least 2 times higher than reported for the use of enteric coated sodium salts in UDCA formulations At the same time, it was 4 times higher than that obtained using the normal UDCA tablet formulation. Furthermore, the peak concentration time (T _max ) closely related to the absorption rate of UDCA from the aqueous formulation was 0.25 hours, at least 3 times faster than the fastest known T _max .
Tables 4A and 4B show the plasma concentrations of UDCA and GUDCA measured in 3 men over time after oral administration of UDCA and GUDCA-containing dosage forms according to Example VI. The comparison result with what adopted is shown.
Table 5 shows the pharmacokinetic parameters of UDCA in humans after oral administration of a liquid formulation of UDCA. C _max is displayed.
Looking at the data in Tables 4 and 5 and FIGS. 3 and 4 together, it is shown that the formulation of the present invention is superior to the conventional formulation for C _max and T _max . The solution of the present invention was effective without any disruption of the solution system caused by the pH of the stomach and intestinal environment. The therapeutic potential of bile acids and other drugs added thereto will be more fully realized using the formulations of the present invention. If the therapeutically active ingredient in the form of an aqueous solution is not precipitated as a solid by the acidic gastric juices in the stomach and by the various alkaline pH levels of the intestines, the dosage form should, as a natural consequence, be somewhat unexpected Insufficient bioavailability due to missing results is eliminated and release rate problems due to disintegration, dissolution and / or dispersion are eliminated.

Example XII
According to the following guidelines, an eleventh series of products made with soluble bile acids (as free acids), high molecular weight water soluble starch conversion products and non-starch polysaccharides (dry powders of liquid glucose, eg, commercially available corn syrup solids) The solution dosage form did not precipitate at any pH within the selected desired pH value range.
────────────────────────────────────
Soluble bile acid 200mg UDCA (10mg-3g)
Liquid glucose dry powder 25g (0.25g-75g)
Soluble non-starch polysaccharide 25g (0.25-75g)
Purified water (total volume produced) 100 mL
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An aqueous solution of soluble UDCA (45 mL) was prepared. Next, a high molecular weight water-soluble starch conversion product (ie, dried liquid glucose) having a DE of 5 to 40 was added to obtain a transparent solution. The pH of this solution was adjusted with acid under high power sonication to produce oral and topical dosage forms. Purified water or water for injection was added to bring the total volume to 1.0 L.
Soluble non-starch polysaccharides (guar gum, pectin, etc.) were added to the resulting clear solution, i.e., the clear solution whose pH was adjusted by stirring. Purified water was added to bring the total volume to 100 mL.

Example XIII: Mixed Solution The dosage forms of Examples VIII, IX and X include bismuth compounds. In each of these examples, a solution formulation was prepared by adding an amount of ammonium salt of bismuth sulfate sufficient to provide the indicated amount of bismuth hydroxide.
In accordance with the following guidelines, the twelfth series of solution formulations made with soluble bile acids (as free acids), high molecular weight water soluble starch conversion products and bismuth compounds can be used at any pH within the selected desired pH value range. No precipitation was shown.
───────────────────────────────
Soluble bile acid 20gUDCA
Bismuth citrate 5g
Corn syrup solids 500g
Citric acid appropriate amount
Purified water (total volume produced) 1.0L
───────────────────────────────
After pouring 3 mL of 1N NaOH into water (200 mL), UDCA was added. Bismuth citrate was added to the resulting clear solution while maintaining pH 9-10 with 200 mL of water. Next, corn syrup solids, which is one of the high molecular weight water-soluble starch conversion products, were added little by little to the obtained transparent solution and dissolved by stirring to obtain a transparent solution. The pH of the resulting clear solution was adjusted with citric acid (pH 3 to pH 5) under high power sonication to promote solubilization of the bismuth compound. Purified water was added to adjust the total volume to 1.0 L.

Example XIV: UDCA-concentrated syrup (30 g UDCA / L)
A thirteenth series of solution formulations made according to the following guidelines showed no precipitation at any pH within the selected desired pH value range.
───────────────────────────────
Soluble bile acid 30gUDCA
1N NaOH 4mL
750 g of maltodextrin
Citric acid or lactic acid
Purified water (total volume produced) 1.0L
───────────────────────────────
First, UDCA was dissolved in 1N NaOH solution and then diluted with 250 mL of water. Next, maltodextrin, one of high molecular weight water-soluble starch conversion products having a low DE, was vigorously stirred and added little by little. The pH of the resulting clear solution was adjusted by adding citric acid (to pH 3) under high power sonication. Purified water was added to adjust the total volume to 1.0 L.

Example XV: UDCA-Paste (45 g UDCA / L)
The 14th series of solution formulations produced according to the following guidelines showed no precipitation at any pH within the selected desired pH value range.
───────────────────────────────
Soluble bile acid 45gUDCA
1N NaOH 135mL
Maltodextrin 1,575g
Citric acid or lactic acid
Purified water (total volume produced) 1.0L
───────────────────────────────
First, UDCA was dissolved in 135 mL of 1N NaOH solution. Next, bismuth citrate and 200 mL of water were added to the resulting clear solution. Next, 1,575 g of maltodextrin was added little by little with vigorous stirring. The obtained solution was adjusted to pH 3 by dropwise addition of citric acid. Purified water was added to adjust the total volume to 1.0 L.
Five subjects were administered the dosage formulation produced by this example. The results are shown in Tables 5A and 5B and the graphs of FIGS. Comparison of the sharp peak in FIG. 3 with the broad peak in FIG. 4 showed that the clinician can adjust bile acids C _max and T _max by adjusting the dosing regimen.
Helicobacter pylori was cultured in CRAB (Columbia Blood Agar Base) medium containing the formulation of Example IX. A 2 L CRAB plate was prepared by containing 9.9 g CRAB, 9.1 g tryptic soy agar, 50 mL sheep blood, vancomycin, amphotericin B, polymyxin B, 2 mL of Example IX and 358 mL distilled water. After 48 or 72 hours of microaerobic culture, the bacteria were fixed with Karnovsky fixative and embedded in Epon. Electron micrographs of Helicobacter pylori cells are displayed in FIGS. 5A-5C.

Example XVI: UDCA-Paste (45 g UDCA / L)
Fifteenth series of solution formulations made according to the following guidelines did not precipitate at any pH within the selected desired pH value range.
───────────────────────────────
Soluble bile acid 45gUDCA
1N NaOH 135mL
Corn syrup solids 2300g
Citric acid or lactic acid 50g
Purified water (total volume produced) 1.0L
───────────────────────────────
First, UDCA was dissolved in 135 mL of 1N NaOH solution. Next, bismuth citrate and 150 mL of water were added to the resulting clear solution. Next, 2,300 g of corn syrup solids were added in portions with vigorous stirring. The obtained solution was adjusted to pH 3 by dropwise addition of citric acid. Purified water was added to adjust the total volume to 1.0 L.

EXAMPLE XVII: Mixed Solution of UDCA (22 g) and CDCA (3 g) The 16th series of solution formulations made according to the following guidelines showed no precipitation at any pH within the selected desired pH range.
───────────────────────────────
UDCA 22g
1N NaOH 75mL
CDCA 3g
875 g of maltodextrin
Bismuth citrate 4g
Citric acid or lactic acid
Purified water (total volume produced) 1.0L
───────────────────────────────
First, UDCA and CDCA were dissolved in 75 mL of 1N NaOH solution. Next, bismuth citrate and 240 mL of water were added to the resulting clear solution. Then, 875 g of maltodextrin was added little by little with vigorous stirring. The resulting solution was brought to pH 3 by adding citric acid dropwise. Purified water was added to adjust the total volume to 1.0 L.

Example XVIII: Mixed Solution of UDCA (22 g) and CDCA (3 g) The 17th series of solution formulations made according to the following guidelines showed no precipitation at any pH within the selected desired pH value range. .
───────────────────────────────
UDCA 22g
1N NaOH 75mL
CDCA 3g
Corn syrup solids 1,320g
Bismuth citrate 4g
Citric acid or lactic acid
Purified water (total volume produced) 1.0L
───────────────────────────────
First, UDCA and CDCA were dissolved in 75 mL of 1N NaOH solution. Next, bismuth citrate and 240 mL of water were added to the resulting clear solution. Then, 1,320 g of corn syrup solids were added little by little with vigorous stirring. The resulting solution was brought to pH 3 by adding citric acid dropwise. Purified water was added to adjust the total volume to 1.0 L.

Example XIX
The effect of treating mice infected with Helicobacter pylori with the solution formulation of the present invention was tested. Six-week-old C57BL / 6 female mice were infected with a diet containing Helicobacter pylori , SS1 strain 10 ⁹ CFU / mL. These animals consumed this meal twice at weekly intervals. Then 0.2 mL of the solution dosage formulation according to Example XIII was administered once daily to 4 infected animals over a week. Two of these animals were sacrificed one week after the last volume of the solution of the invention was administered. The remaining two animals were sacrificed at 4 weeks after the last dose of the invention was administered. All stomachs were washed with saline to remove mucosa and tissue debris. CLO testing was performed on gastric tissue samples from each animal using a rapid urease test kit (Delta West, Australia). Each remaining stomach was fixed with 10% formalin solution and embedded in paraffin. Fragments (4 μm thick) were taken on glass slides and stained with H & E staining solution and Warthin staining solution. The pathological state of these tissues was evaluated with a normal optical microscope.
The results summarized in Table 6 indicate that the urease test results are negative for mice one week after discontinuation of the liquid dosing regimen and Helicobacter pylori is not visible in the Warthin test. One of the remaining two mice showed a negative urease test result and Helicobacter pylori was not seen by the Wartin test. However, the remaining one was positive for the urease test, although only a small number of Helicobacter pylori was seen in the wartin test.

Example XX
Assays for the growth of Helicobacter pylori in media containing UDCA, bismuth citrate or both UDCA and bismuth citrate were performed. The following media were used for these assays.
000112B-1 having a pH of 4.0 and containing 525 g / L of maltodextrin and 15 g / L of UDCA.
OSABY having a pH of 3.7 and containing 1 kg / L corn syrup solids and 6 g / L bismuth citrate.
Three assays were performed to assess the ability of Helicobacter pylori to grow in the presence of UDCA, bismuth or both, with varying pH, concentration and exposure length.
First, Helicobacter pylori was suspended in physiological saline so as to be about 10 ⁹ organisms / mL. 50 μl of this inoculum was transferred to a tube containing 1 mL of citrate-phosphate buffer at pH 3.0, 4.0 and 4.5. A tube was prepared in which a tube having 6 mM urea was paired with a tube having no urea. After incubation for 30 minutes at room temperature, this suspension was subcultured on agar plates containing 000112B-1 using 1 μl of platinum loops. The plate was microaerobically cultured at 37 ° C. for 72 hours. This procedure is illustrated in FIG.
As shown in Table 7 , Helicobacter pylori did not grow well on the pH 3 and pH 4 control medium. Table 7 also showed that Helicobacter pylori was not grown on pH 3 and pH 4 media containing UDCA. “3 mL”, “4 mL” and “5 mL” refer to the total volume of 000112B-1 medium per plate. “PBS” is phosphate buffered saline at pH 7.0.

In the second assay, Helicobacter pylori was suspended in saline to approximately 10 ⁹ organisms / mL. 50 μl of this inoculum, plate medium in various concentrations, for example 1/10, 1/30, 1/50, 1/100, 1/200, 1/500, 1/800, 1/1000, 1/2000, etc. Were transferred to a tube containing 1 mL of citrate-phosphate buffer with a concentration of All tubes were made to have 6 mM urea. After incubation at room temperature for 30 minutes, this suspension was subcultured on agar plates using 1 μl platinum ears. These plates were substantially free of bismuth and bile acids. The plate was microaerobically cultured at 37 ° C. for 72 hours. This procedure is illustrated in FIG.
Table 8 shows urease test results after 72 hours of growth of Helicobacter pylori on media made with UDCA (000112B-1), bismuth citrate (OSABY) or a dilution of both UDCA and bismuth citrate. Indicates. Insufficient growth of Helicobacter pylori was observed on media containing UDCA or bismuth citrate (Table 8). Helicobacter pylori growth was even less when cultured in media containing both UDCA and bismuth citrate (Table 8).

In the third assay, Helicobacter pylori was suspended in saline to approximately 10 ⁹ organisms / mL. 50 μl of this inoculum was placed in tubes containing 1 mL of citrate-phosphate buffer at various concentrations, 1/2, 1/4 and 1/10 for 15 minutes, 1/2, 1/4 and 1/30 for 30 minutes. 10 and then transferred at 1/2, 1/4 and 1/10 etc. for 45 minutes. A tube having a pair of 6 mM urea and one not having 6 mM urea was produced. After incubation at room temperature for 30 minutes, this suspension was subcultured on agar plates using 1 μl platinum ears. These plates were substantially free of bismuth and bile acids. The plate was microaerobically cultured at 37 ° C. for 72 hours. This procedure is illustrated in FIG.
Table 9 shows the results of urease tests after 72 hours of growth of Helicobacter pylori on media prepared with UDCA (000112B-1), bismuth citrate (OSABY) or dilutions of both UDCA and bismuth citrate. Show. As indicated, the longer the exposure time, the greater the harmful effect of the solution on Helicobacter pylori .

Example XXI
In some embodiments of Examples I-XX, the dry form was prepared by evaporation under vacuum. The solution formulation of the bile acid composition was dried with a rotary evaporator under a vacuum of 1.3 × 10 ⁻¹ Pa and a temperature of 90 to 95 ° C.
In some embodiments of Examples I-XX, the spray-dried dry form is produced in a spray-drying manner equipped with a centrifugal sprayer under the following conditions. The feed liquid used in this system was about 30-40% water soluble starch inversion product solution, the feed flow rate was 50-70 mL / min, the inlet temperature was 150-180 ° C., and the outlet temperature was 50-100 ° C. Met. The feed liquid was nebulized by a centrifugal nebulizer with a rotational speed of 30,000 rpm.
In some embodiments of Examples I-XX, granules derived from a solution dosage form of a bile acid composition were produced in a fluidized bed. Dry powder from a solution formulation of bile acid composition (20 kg, 100-200 mesh) and corn starch (9 kg) was placed in the fluidized bed and mixed using air. A binder solution (700 g of hydroxypropyl methylcellulose in 22 L of water) was sprayed onto the fluidized powder bed using a peristaltic pump. The spraying process was performed by setting process variables for a specific process. During the spraying process, samples ± 10 g were taken every 10 minutes from the powder bed to measure moisture loss during drying. Spraying was continued until all of the binder solution was used. These were fluidized at an inlet air temperature of 75 ° C. to dry the wet granules. The drying cycle was terminated when the outlet air temperature reached 35 ° C, indicating that the granules were fully dried.
In some embodiments of Examples I-XX, enteric coated granules derived from a solution formulation of a bile acid composition may be top spray granulator, bottom spray granulator or tangential spray granulator. Manufactured with. Ethylcellulose N100 (1.6 kg) was dissolved in absolute ethanol and this solution and any additional ethanol was sprayed onto a fluidized dry powder of bile acid composition (9 kg). When good quality granules were produced, the injection was stopped. Dry to about 3% moisture.
Assay. (Table 10 and FIG. 12). The increase in maltodextrin (DE = 15) as a water-soluble starch conversion product in the primary solution is especially associated with an increase in the solubility of the dry substance at a low pH in the secondary solution within 2 minutes. These results indicate that maltodextrin is an excellent resolubilizer for primary water solubilized bile acid dosage forms in dry form.

5 is a graph of serum concentration versus time for UDCA (squares) and GUDCA (triangles) after administration of dosage formulations according to Examples II and VI and Table 4. FIG. 5 is a graph of serum concentration of UDCA versus time after administration of a bile acid dosage formulation according to Examples III and VI and Table 4. FIG. FIG. 2 is a diagram showing the average (n = 5) of UDCA pharmacokinetic parameters in Group I after oral administration to humans of a liquid formulation of UDCA produced by Example IX without bismuth. FIG. 2 is a diagram showing the average (n = 5) pharmacokinetic parameters of UDCA in Group II after oral administration to humans of a liquid formulation of UDCA produced by Example IX. It is a transmission electron micrograph of Helicobacter pylori cultured in Colombia medium. FIG. 4 is a transmission electron micrograph of Helicobacter pylori after 48 hours of treatment with UDCA and bismuth citrate produced by Example IX. It is a transmission electron micrograph of Helicobacter pylori after 72 hours of treatment with UDCA and bismuth citrate. 3 is NMR data for UDCA in a liquid formulation dosage form made according to Example III without preservatives, flavoring agents and sweeteners. 2 is an HPLC diagram of UDCA in a liquid formulation dosage form produced according to Example III without preservatives, flavoring agents and sweeteners. FIG. FIG. 2 is an HPLC diagram of a UDCA standard. It is the figure which displayed the Helicobacter pylori culture method. It is the figure which displayed the Helicobacter pylori culture method. It is the figure which displayed the Helicobacter pylori culture method. FIG. 7 is a plot of the clarity versus pH of a secondary water-solubilized bile acid solution dosage formulation produced by Example XIX for a two-minute redissolution of a dry form derived from a primary water-solubilized bile acid formulation. . However, each 100 mL of the primary solution is configured to contain 200 mg of UDCA and maltodextrin (DE = 15) in an amount of 4 g. FIG. 7 is a plot of the clarity versus pH of a secondary water-solubilized bile acid solution dosage formulation produced by Example XIX for a two-minute redissolution of a dry form derived from a primary water-solubilized bile acid formulation. . However, each 100 mL of the primary solution contains UDCA 200 mg and maltodextrin (DE = 15) in an amount of 5 g. FIG. 7 is a plot of the clarity versus pH of a secondary water-solubilized bile acid solution dosage formulation produced by Example XIX for a two-minute redissolution of a dry form derived from a primary water-solubilized bile acid formulation. . However, each 100 mL of the primary solution is configured to contain 200 mg of UDCA and maltodextrin (DE = 15) in an amount of 6 g. FIG. 7 is a plot of the clarity versus pH of a secondary water-solubilized bile acid solution dosage formulation produced by Example XIX for a two-minute redissolution of a dry form derived from a primary water-solubilized bile acid formulation. . However, each 100 mL of the primary solution is configured to contain 200 mg of UDCA and maltodextrin (DE = 15) in an amount of 7 g. FIG. 7 is a plot of the clarity versus pH of a secondary water-solubilized bile acid solution dosage formulation produced by Example XIX for a two-minute redissolution of a dry form derived from a primary water-solubilized bile acid formulation. . However, each 100 mL of the primary solution is configured to include 200 mg of UDCA and maltodextrin (DE = 15) in an amount of 8 g. FIG. 7 is a plot of the clarity versus pH of a secondary water-solubilized bile acid solution dosage formulation produced by Example XIX for a two-minute redissolution of a dry form derived from a primary water-solubilized bile acid formulation. . However, each 100 mL of the primary solution is configured to contain 200 mg of UDCA and maltodextrin (DE = 15) in an amount of 9 g.

Claims (42)

A primary water-solubilized bile acid dosage form in dry form,
(A) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, bile acids conjugated by amine and amide bonds, and combinations thereof;
(B) a water-soluble starch conversion product,
A primary water-solubilized bile acid in dry form, wherein the first substance and the water-soluble starch conversion product are both in solution for all pH values of a solution within a selected pH value range. Dosage form. A primary water-solubilized bile acid dosage form in dry form,
(A) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, bile acids conjugated by amine and amide bonds, and combinations thereof;
(B) a water-soluble starch conversion product having a dextrose equivalent (DE) of about 5-10,
Both the first substance and the water-soluble starch conversion product are in a solution state with respect to all pH values in the range of pH 6.5 to pH 8, and the primary water-solubilized bile acid agent in dry form form. A primary water-solubilized bile acid dosage form in dry form,
(A) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, bile acids conjugated by amine and amide bonds, and combinations thereof;
(B) a second substance comprising a water-soluble starch conversion product;
(C) a third substance selected from the group consisting of resistant maltodextrins and water-soluble non-starch polysaccharides,
The primary water-solubilized bile acid agent in dry form, wherein the first substance, the second substance, and the third substance are in a solution state with respect to all pH values of the solution within a selected pH value range. form. A primary water-solubilized bile acid dosage form in dry form,
(A) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, bile acids conjugated by amine and amide bonds, and combinations thereof;
(B) a second substance selected from the group consisting of a water-soluble starch conversion product, a resistant maltodextrin, a water-soluble non-starch polysaccharide, and combinations thereof;
(C) a water-soluble ginseng extract, a water-soluble red ginseng extract and a third substance selected from a combination thereof,
The primary water-solubilized bile acid agent in dry form, wherein the first substance, the second substance, and the third substance are in a solution state with respect to all pH values of the solution within a selected pH value range. form. A primary water-solubilized bile acid dosage form in dry form,
(A) a first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, bile acids conjugated by amine and amide bonds, and combinations thereof;
(B) a second substance selected from the group consisting of water-soluble starch conversion products, non-starch polysaccharides, and combinations thereof,
A primary water-solubilized bile acid dosage form in dry form, wherein the first substance and the second substance are both in solution for all pH values of a solution within a selected pH value range .   6. The primary water-solubilized bile acid dosage form of claim 5, further comprising riluzole, wherein the solid form is an oral solid dosage form.   6. The primary water-solubilized dry form of claim 5, wherein the primary water-solubilized bile acid dosage form further comprises a suspended insoluble bismuth compound and the solid form is an oral solid dosage form. Bile acid dosage form.   The bile acids are ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, hyodeoxycholic acid, deoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iocholic acid, tauroursodeoxycholic acid, tauro Chenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, their derivatives at the hydroxyl or carboxylic acid group in the steroid nucleus, their salts, or conjugates with these amines The primary water-solubilized bile acid dosage form according to claim 5, which is selected from the group consisting of:   The water-soluble starch conversion product is Maltri (registered trademark) M040 (DE = 5, maltodextrin), Maltrin (registered trademark) M050 (DE = 5, maltodextrin), Maltrin (registered trademark) M100 (DE = 10, maltodextrin). Dextrin), Maltrin® M150 (DE = 15, maltodextrin), Maltrin® M180 (DE = 18, maltodextrin), Maltrin® M200 (DE = 20, corn syrup solids) and 6. A primary form of dry water according to claim 5, characterized in that it is selected from hydrolyzed starches having a DE of 4 to 40, such as Maltri (R) M250 (DE = 25, corn syrup solids). Solubilized bile acid dosage form.   The primary water-solubilized bile acid dosage form according to claim 1, wherein the primary water-solubilized bile acid dosage form further comprises a solubilizer.   The primary water-solubilized bile acid dosage form according to claim 10, wherein the solubilizer is maltodextrin.   The dried primary water according to claim 1, wherein the primary water-solubilized bile acid dosage form further comprises a branched chain amino acid selected from the group consisting of leucine, isoleucine, valine and mixtures thereof. Solubilized bile acid dosage form.   6. The primary water-solubilized bile acid dosage form according to claim 5, wherein the primary water-solubilized bile acid dosage form further comprises a water-soluble reaction product between bismuth ions and a chelate.   The dry form primary water of claim 13, wherein the chelate is selected from the group consisting of citric acid, tartaric acid, malic acid, lactic acid, edetic acid and alkalis and combinations thereof. Solubilized bile acid dosage form.   The primary water-solubilized bile acid dosage form according to claim 13, wherein the bismuth compound is selected from the group consisting of bismuth citrate, bismuth sulfate, and bismuth hyponitrate.   The primary water-solubilized bile acid dosage form according to claim 13, wherein the bismuth compound is selected from the group consisting of bismuth subcarbonate, bismuth subgallate or bismuth subsalicylate.   The primary water-solubilized bile acid dosage form further comprises one or more additional bile acids, water-soluble derivatives of bile acids, bile salts and amine-conjugated bile acids conjugated by amide bonds. The primary water-solubilized bile acid dosage form according to claim 5, characterized in that   6. The primary water-solubilized bile acid in dry form according to claim 5, wherein the second substance is a water-soluble non-starch polysaccharide selected from the group consisting of guar gum, pectin, cellulose, glycogen and inulin. Dosage form.   6. The primary water-solubilized bile acid dosage form according to claim 5, wherein the primary water-solubilized bile acid dosage form further comprises a disintegrant.   The disintegrant is Veegum HV, methylcellulose, agar, bentonite, natural sponge, cation exchange resin, alginic acid, guar gum, citrus pulp, carboxymethylcellulose, clays, celluloses, algins, rubbers, cross-linked polymers (crospovidone) 21) The primary water-solubilized bile acid dosage form in dry form according to claim 19, wherein the dosage form is selected from the group consisting of crosslinked cellulose (crosscamellose) and crosslinked starch (sodium starch glycolate).   The primary water-solubilized bile acid dosage form according to claim 5, wherein the dry form includes granules coated with a film, and the film includes a polymer and a plasticizer.   The primary water-solubilized bile acid in dry form according to claim 21, wherein the polymer is selected from the group consisting of hydroxypropyl methylcellulose ether, methylcellulose ether, methacrylate copolymer, and methyl methacrylate copolymer. Dosage form.   The dry form of claim 21, wherein the plasticizer is selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, triacetin, acetylated monoglyceride, triethyl citrate and dithyl phthalate. Primary water-solubilized bile acid dosage form.   The polymer is a cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), methacrylic acid-methacylic acid ester copolymer, cellulose acetate trimellitate which can function effectively as an enteric coating at pH 6 or higher. The primary water in a dry form according to claim 21, which is an enteric polymer selected from the group consisting of (CAT), carboxymethyl ethyl cellulose (CMEM) and hydroxypropyl methyl cellulose acetate succinate (HPMCAS). Solubilized bile acid dosage form.   6. The primary water-solubilized bile acid dosage form according to claim 5, wherein the primary water-solubilized bile acid dosage form further comprises a pharmaceutically effective amount of at least one pharmaceutical compound. . The pharmaceutical compounds include octreotide, sildinafil citrate, calcitriol, dihydrotaxosterol, apomorphine, yohimbine, trazadone, acyclovir, cidofovir, delavirdine mesylate, didanosine, famciclovir, foscarnet sodium, Fluorouracil, ganciclovir sodium, idoxuridine, interferon-α, interferon-β, interferon-γ, lamivudine, nevirapine, penciclovir, ribavirin, stavudine, trifluridine, valacyclovir / HCl, zalcitabine, zidovudine, indinavir / H ₂ SO ₄ , ritonavir, nelfinavir _· CH 3 _SO 3 H, saquinavir _· CH ₃ SO ₃ H, d- Penishira Min, chloroquine, hydroxychloroquine, aurothioglucose, sodium gold thiomalate, auranofin levamisole, DTC, isoprinosine, methylinosine monophosphate, muramyl dipeptide, diazoxide, hydralazine / HCl, minoxidil, dipyridamole, isoxpurine / HCl , Niacin, nyridrin · HCl, phentolamine, doxazosin · CH ₃ SO ₃ H, prazosin · HCl, terazosin · HCl, clonidine · HCl, nifedipine, molsidomine, amiodarone, acetylsalicylic acid, verapamil, diltiazem, nisoldipine, isradidine, bepridil, isosorbide Dinitrate, pentaerythritol tetranitrate, nitroglycerin, cimetidine, famot Emissions, nizatidine, ranitidine, lansoprazole, omeprazole, misoprostol, sucralfate, metoclopramide · HCl, erythromycin, alprostadil, albuterol, pirbuterol, terbutaline _· H 2 SO _4, salmeterol, aminophylline, dyphylline, ephedrine, ethylnorepinephrine, isoetharine, isoproterenol Terenol, metaproterenol, n-docromil, oxtriphyrin, theophylline, vitorterol, fenoterol, budesonide, flunisolide, beclomethasone dipropionate, fluticasone propionate, codeine, codeine sulfate, codeine phosphate, dextromethorphan HBr, triamcinolone Acetonide, montelukast sodium, zafirlukast Zileuton, sodium cromoglycate, ipratropium bromide, nedocromil sodium benzoate, diphenhydramine / HCl, hydrocodone / tartrate, methadone / HCl, morphine sulfate, acetylcysteine, guaifenesin, ammonium carbonate, ammonium chloride, potassium antimony tartrate, glycerin, Terpine hydrate, corfosseryl palmitate, atorvastatin calcium, cerivastatin sodium, fluvastatin sodium, lovastatin, pravastatin sodium, simvastatin, piclorizacroa (Piclorrhazia kruroa), andrography spanicurata, moringa oleifera, albizzarez i lebeck), Adhatoda Bashika, Rukuma Longa, Mormorica charantia, Gymnema sylvestre, Terminaria arjuna, Azadelacchia indica, Tinosporia cordior clotrimazole, fluconazole, haloprogin, ketoconazole, griseofulvin, itraconazole, terbinafine · HCl, econazole · HNO _3, miconazole, nystatin, oxiconazole · HNO _3, sulconazole · HNO _3, cetirizine · 2HCl, dexamethasone, hydrocortisone, prednisolone, Cortisone, mosquito Tequine and its derivatives, glycyrrhizin, glycyrrhizic acid, betamethasone, ludocortisone acetate, flunisolide, fluticasone propionate, methylprednisolone, somatostatin, lispro, glucagon, acarbose, chlorpropamide, glipizide, glyburide, metformin HCl, repaglinide, tolbutamide , Colchicine, sulfinpyrazone, allopurinol, piroxicam, tolmetine sodium, indomethacin, ibuprofen, diflunisal, mefenamic acid, naproxen, trientine, sulindac, sulindac sulfone, selenium compounds, insulin, heparin, ampicillin, amantadine, rimantadine, proinsulin, Celecoxib, budesonide, salicylic acid and its derivatives, vitamins , Vitamin C, superoxide dismutase (SOD), N-acetylcysteine, lazaloids, 21-aminosteroids such as U74389F and U74006F, catalase (CAT), putrescine-modified catalase (PUT-CAT), estrogen, alpha-lipoic acid , Selegiline, desferrioxamine, d, l-penicillamine, alpha and beta-carotene, retinol, selenium, gingko biloba, riluzole, flupirtine, pifithrin-alpha, CGP3466B, TGP3466B 26. The method of claim 25, selected from the group consisting of CPI-1189, CEP-1347, and Coenteam Q10. The primary water-solubilizing bile acid dosage form 燥 form.   The primary water-solubilized bile acid dosage form according to claim 5, further comprising an additive.   28. The primary water-solubilized bile acid dosage form according to claim 27, wherein the additive is selected from the group consisting of diluents, lubricants, binders, fillers and combinations thereof. A method for producing a primary water-solubilized bile acid dosage form in a dry form, comprising:
A first substance selected from the group consisting of bile acids, water-soluble derivatives of bile acids, bile salts, bile acids conjugated by amine and amide bonds, and combinations thereof;
A second substance selected from the group consisting of water-soluble starch conversion products, non-starch polysaccharides and combinations thereof,
Preparing a primary water-solubilized bile acid dosage form in which the first substance and the second substance are both in solution for all pH values of the solution within the selected pH value range;
The primary water-solubilized bile acid dosage form to wet granulation method, fluidized bed granulation method, dry granulation method, spheronization method, spray drying method, evaporation method, freeze drying method and combinations thereof A method for producing a primary water-solubilized bile acid dosage form in a dry form, comprising: removing water by a granulation method selected from:   30. The method of claim 29, further comprising sonicating the primary water solubilized bile acid dosage form.   30. The method of claim 29, wherein the dry form comprises granules.   32. The method of claim 31, further comprising coating a granule having an enteric polymer.   The enteric polymer is cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), methacrylic acid-methacylic acid ester copolymer, cellulose acetate trimellitate (CAT), carboxymethyl ethyl cellulose (CMEC). 33. The method of claim 32, wherein the method is selected from the group consisting of: and hydroxypropyl methylcellulose acetate succinate (HPMCAS).   30. The method of claim 29, further comprising forming a film comprising a polymer and a plasticizer on the dry form.   35. The method of claim 34, wherein the polymer is selected from the group consisting of hydroxypropyl methylcellulose ether, methylcellulose ether, methacrylate copolymer and methyl methacrylate copolymer.   35. The method of claim 34, wherein the plasticizer is selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, triacetin, acetylated monoglyceride, triethyl citrate and dithyl phthalate.   30. The method of claim 29, wherein the removal of water is by spheronization and a spherical pellet is formed.   30. The method of claim 29, wherein the primary water solubilized bile acid dosage form further comprises sodium bicarbonate and a sour agent.   40. The method of claim 38, wherein the amount of sodium bicarbonate is about 10 times the amount of the first material.   40. The method of claim 38, wherein the primary water solubilized bile acid dosage form comprises about 20% by weight of acidulant from sodium bicarbonate.   40. The method of claim 38, wherein the sour agent is selected from the group consisting of tartaric acid and citric acid.   30. The method of claim 29, further comprising completely dissolving the solid form in water in a neutral or weakly acidic reaction.

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