Preparation of transparent aqueous solution of therapeutical forms with bile acids

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention deals with creating pharmaceutical compositions containing bile acids and methods of treatment using these compositions. For this purpose, invention provides transparent aqueous solution containing bile acid or its compounds, polysaccharide, and water. Amounts of the two formers are selected so that they remain in solution at all values within selected pH range. Administration of such a composition increases level of enterohepatic bile acid in body, including blood, and also increases absorption of bile acid. Addition of various drug to composition allows effective treatment of corresponding diseases.

EFFECT: improved transportation to body tissues of bile acids both as individual therapeutic agents and as drug forms.

47 cl, 11 dwg, 16 tbl, 18 ex

 

BACKGROUND of INVENTION

Salts of bile acids, which are organic acids formed from cholesterol, are natural ionic detergents, which play a major role in the absorption, transport and secretion of lipids. In the chemistry of bile acids steroid ring salts of bile acids is a ring perhydrothioxanthene common to all targetrotation. Distinctive features of bile acids include saturated ring of the Sterol with 19 carbon atoms, beta-oriented hydrogen in position 5, branched, saturated side chain of 5 carbon atoms, containing a terminal carboxylic acid group, and an alpha-oriented hydroxyl group at position 3. The only Deputy, available at most natural bile acids, is a hydroxyl group. Most mammals hydroxyl groups are in positions 3, 6, 7, or 12.

Normal bile acids differ mainly by the number and orientation of hydroxyl groups on the ring of the Sterol. The term primary bile acids refers to bile acids synthesized de novo in the liver. In humans, the primary bile acids include cholic acid (3α,7α,12α-trihydroxy-5β-Holloway acid) ("CA") and chenodeoxycholic acid (3α,7α-dihydr the XI-5β -Holloway acid) ("CDCA"). When degidroksilirovanie these bile acids by intestinal bacteria formed more hydrophobic secondary bile acids, desoxycholic acid (3α,12α-dihydroxy-5β-Galanova acid) ("DCA) and lithocholic acid (3α-hydroxy-5β-Galanova acid) ("LCA"). These four bile acids, CA, CDCA, DCA and LCA, usually account for more than 99 percent of the pool of bile salts in humans. Secondary bile acids were metabolized by the liver, sometimes referred to as tertiary bile acids.

Ketogulonic acid is formed additionally in the human body as a result of subsequent oxidation of hydroxyl groups of bile acids, especially the 7-hydroxyl group, the bacteria of the colon. However ketogulonic acid quickly restored by the liver into the appropriate αor β-hydroxyzine acid. For example, the corresponding ketogulonic acid CDCA is a 7-catalytically acid and one of its products recovery with the appropriate β-hydroxysuccinic acid is ursodeoxycholic acid (3α,7β-dihydroxy-5β-Galanova acid) ("UDCA"), tertiary cholic acid.

UDCA, the main component of bile acids, used for the treatment and protection against many types of liver disease for slightly more than 70 years in which the quality of the basic pharmaceutical agent. Its medicinal uses include the dissolution of radiolucent gallstones, treatment of biliary dyspepsia, primary biliary cirrhosis, primary sclerosing cholangitis, chronic active hepatitis and hepatitis C. In other species of mammals bile acids containing 6β-hydroxyl group, which detect in rats and mice, known as morifolia acid; 6α-hydroxyzine acid produced in the body of pigs, called geoholiday acid and hyodesoxycholic acids. 23-Hydroxyzine acid aquatic mammals known as vozehova and facedetection acid.

In typical cases, more than 99 percent of naturally occurring salts of bile acids secreted in human bile, are conjugated. The conjugates are bile acids, in which the second organic substituent (for example, glycine, taurine, glucuronate, sulfate or rarely other deputies) attached to the carboxylic acid side chain or to one of the hydroxyl groups of the ring through the connection of ester, a simple ester or amide. Therefore, the ionization properties of conjugated bile acids with glycine or taurine determined by the acidity of glycine or touringwagon Deputy.

The monomers of free, unconjugated bile acids which have values PK andapproximately 5,0. However, the magnitude of the PKandconjugated with glycine bile acids averaged 3.9 and PKandbile acids conjugated with taurine, less than 1.0. Therefore, the conjugation is to reduce the value of the PKandbile acids, so that a large part of it is ionized at any given pH value. Because the shape of the ionized salt more soluble in water than the protonated form of the acid, the conjugation increases the solubility at low pH value. Salt free bile acids are precipitated from aqueous solution at pH 6.5 to 7. In contrast, the deposition conjugated with glycine bile acids occurs only at pH less than 5. Conjugated with taurine bile acids remain in the aqueous solution at a very strongly acidic conditions (less than pH 1). However, when gastric pH range, some bile acids, such as UDCA and CDCA no longer dissolve.

The side chain conjugation of bile acids with glycine or taurine has little effect on hydrophobic activity fully ionized salts of bile acids. More hydrophobic bile salts have a higher solubilities ability to phospholipid and cholesterol and, therefore, are the best detergents. More hydrophobic Sol the bile acids are also more harmful to various membranes in vivo and in vitro.

The natural pools of bile salts is constantly contain a lot of salts of bile acids. A mixture of two or more salts of bile acids with different hydrophobic activity can behave like one salt of bile acid with an average hydrophobic activity. As a result of this detergent properties and toxicity of mixtures of two salts of bile acids with different hydrophobic activity are often intermediate between those of the individual components. Biological functions and biological properties of bile acids, resulting from their amphiphilic properties are as follows:

1. Ursodeoxycholic acid can be used as immunomoduliruushimi agent.

2. Ursodeoxycholic acid inhibits induced by deoxycholic acid apoptosis through the modulation of the production of mitochondrial transmembrane potential and reactive forms of oxygen.

3. Ursodeoxycholic acid inhibits induction synthase nitric oxide (NOS) in intestinal epithelial human cells and in vivo.

4. The hydrophilic nature of ursodeoxycholic acid provides casasito when necroinflammatory liver disease.

5. Ursodeoxycholic acid significantly increases the level of transaminases and cholestatic enzymatic indices of liver damage in chronic is Apatite.

6. Bile acids significantly inhibit the growth of N. pylori.

7. Ursodeoxycholic acid is the most potent inhibitor of pepsin among bile acids.

8. High levels of bile acids exceptionally strongly inhibit the proliferation of hepatitis C.

9. Ursodeoxycholic acid has properties stabilize cell membranes.

10. Ursodeoxycholic acid alleviates alcoholic fatty infiltration of the liver.

11. Ursodeoxycholic acid has a vasodilator effect on the systemic vascular bed, but it doesn't change the pulmonary vascular function or cardiac functions.

12. Synthesis of bile acids from cholesterol is one of the two main ways to remove cholesterol from the body.

13. Bile flow is generated by the flow of bile salts by passing through the liver. The formation of bile is an important route solubilization and excretion of organic compounds, such as bilirubin, an endogenous metabolites, such as amphipatic derivatives of steroid hormones, and various drugs and other xenobiotics.

14. Secretion of bile salts into bile is associated with the secretion of two other biliary lipids, phosphatidylcholine (lecithin) and cholesterol. Linking output of bile salts with the conclusion of lecithin and cholesterol ensuring the em main path of removal of hepatic cholesterol.

15. Bile salts together with lecithin solubilizing cholesterol in bile in the form of mixed micelles and vesicles. The lack of bile salts and, therefore, decreased the solubility of cholesterol in bile may play a role in the pathogenesis of cholesterol gallstones.

16. It is believed that bile salts are a factor in the regulation of cholesterol synthesis. Currently, it is not known to regulate whether they are the synthesis of cholesterol directly effect on hydroxymethylglutaryl And(HMO-COA)-reductase or indirectly by modulation of cholesterol absorption in the intestine.

17. It is believed that salts of bile acids in enterobacteraceae circulation regulate the synthesis of bile acids by suppressing or derepression activity of cholesterol 7-hydroxylase, which is the limiting velocity of the enzyme in the biosynthesis pathway of bile acids.

18. Bile acids may play a role in the regulation of receptor hepatic lipoprotein (Aro VE) and, therefore, can modulate the rate of uptake of lipoprotein cholesterol by the liver.

19. Intestinal bile salts in the form of mixed micelles participate in interporous solubilization, the transfer and absorption of cholesterol, fat-soluble vitamins and other lipids.

20. Bile salts can participate in is erinose calcium and iron from the intestinal canal to the brush border.

Recent research on the delivery of medicines relating to the characteristics and biofunction existing in nature bile acid in the adjuvant and/or carrier, focused on derivatives and analogs of bile acids and the bile acids as new systems of drug delivery to the intestine and liver. These systems use an active transport mechanism for the delivery of target molecules of the drug to a specific target tissue by oral administration or introduction into the gallbladder. Thus, if the bile acids or derivatives of bile acids quickly and efficiently absorbed in the liver and, therefore, are exposed enterobacteria cycle, assumed many potential therapeutic applications, including the following: improving oral absorption of the biologically active in the body, but is poorly absorbed by the hydrophilic and hydrophobic drugs; directed to the liver delivery of drugs to achieve high therapeutic concentrations in the diseased liver with a minimization of the total toxic reactions elsewhere in the body and delivery systems in the gallbladder holetsistograficskie agents and means to accelerate the dissolution of cholesterol gallstones. As an example, in 1985 Drs. Gordon and Moseset al. showed that therapeutically useful amount of insulin absorbed by the nasal mucosa of a person when introduced into the nose in the form of a spray with the usual salts of bile acids, such as DCA, UDCA, CDCA, CA, TUDCA, TCDCA. Cm. Moses, Alan S., et al., Diabetes, vol. 32 (November 1983) 1040-1047; Gordon, G.S., et al., Proc. NAT'l Acad. Sci. USA, vol. 82 (November 1985) 7419-7423. In their experiment, the bile acids caused a marked increase in the concentration of insulin in serum and approximately 50% reduction of the concentration of glucose in the blood. However, this revolutionary dosage form in the form of a solution to spray in the nose with bile acids (salts) as adjuvant could not continue to grow and commercialservices, because the solution to spray in the nose had to be prepared immediately prior to use due to the deposition of the salts of the bile acids and instability of insulin at pH levels between 7.4 and 7.8 for. In addition, as indicated in this description, ursodeoxycholic acid as adjuvant could not be used due to its insolubility at pH between 7.4 and 7.8 for.

Thus, it appears that the salts of bile acids and insulin are chemically and physically compatible. The pH of the commercial injectable insulin are between 2.5 and 3.5 for acidified dosage forms and between 7.00 and 7.4 for neutral dosage forms. The dosage form is Olga bile acids, received conventional methods, were unfit to overcome the problems of deposition of bile acids at these pH levels, and insulin is unstable at pH 7.4 or above. Therefore, safe and effective drugs of any dosage forms of insulin with bile acid (salt) in the form of solutions are not commercially available at the present time.

Heparin, the most potent anticoagulant widely used in the treatment and prevention of thromboembolism. However, treatment with heparin is usually limited to hospitalized patients, since this medicinal product is administered only by injection. Alternative ways that have been tested, are intra-lungs spray, suppositories and enema. In accordance with numerous publications to facilitate absorption of heparin through the mucous membrane of the gastrointestinal tract drugs must be in acidic conditions. In accordance with Dr. Ziv, Dr. Eldor et al. heparin was absorbed through the mucous membrane of the rectum rodents and primates, only when it was administered in solutions containing Holt sodium or sodium deoxycholate. Cm. Ziy E. et al., Biochemical Pharmacology, vol. 32, No. 5, pp. 773-776 (1983). However, heparin is stable only in acidic conditions. Bile acids are particularly insoluble in acidic conditions. Therefore, because of their Messiah. sovmestimyh characteristics of commercial dosage forms of bile acids with heparin are currently unavailable.

System drug delivery, including bile acids, can provide piecinstalaceja "targeted" delivery of a medicinal product that is the main interest for drug development, since the standard pharmacological approaches to liver disease were unsatisfactory due to inadequate delivery of active agents in liver cells and nonspecific toxicity in relation to other organs. For example, piecinstalaceja shipping medicines necessary for inhibitors of collagen synthesis in the treatment of liver fibrosis, in order to avoid nonspecific and unwanted side effects in extraeconomic tissues. In addition, for the treatment of cancer of the bile system high levels of drug should be achieved in the liver and biliary system, whereas in extraeconomic tissues desirable low concentrations of drugs to minimize the cytotoxicity of cytotoxic agents for the normal, non-neoplastic cells. Dr.Kramer, Dr.Wess et al. showed that a hybrid molecule formed by the covalent binding of drugs with a modified bile acid molecule can be detected Na+-dependent systems the absorption of bile acids in the liver and ileum. Cm. patent school is No. 5641767. Even if salts of bile acids and their derivatives act as shuttles for specific delivery of drugs to the liver, as already indicated above, there are huge risks when developing derivatives of bile acids or salts of bile acids as carriers, as new derivatives of bile acids or bile salts, formed by covalent binding of drugs with bile acid, you have to experience on their pharmacology, toxicity and clinical efficacy. Therefore, development of drugs that the drug may be absorbed with bile acids or salts of bile acids from places that contain excess bile acids in the intestine, is much easier and much more useful task than the development of new derivatives of bile acids, because it requires fewer tests.

Despite an extremely useful therapeutic activity and long historical medical use of bile acids as therapeutically active agents and as carriers and/or adjuvants, based on the already mentioned biological properties and functions of bile acids, introduction bile acids for commercial uses limited to pharmaceutical drugs with the solid form of bile acids, are tablets, capsules and suspensions. This is due to the insolubility of bile acids in the aqueous medium at a pH of approximately from 1 to 8. It is also the result of a particularly bitter taste of bile and touch the same bitter taste in the next few hours. It is noted that ursodeoxycholic acid, chenodeoxycholic acid and lithocholic acid is practically insoluble in water. Desoxycholic acid and cholic acid have solubility 0.24 g/l and 0.2 g/l, respectively. Tauroursodeoxycholic acid, taurochenodeoxycholate acid and human beings need it to acid is not soluble in the solution chlorotoluron acid. Few water dosage forms that are available, are unstable and have very limited use because of the problems of management and conservation of pH values. In addition, it was found that some commercial pharmaceutical dosage forms of bile acids have poor bioavailability, as described in European Journal of Clinical Investigation (1985), 15, 171-178. Bile acid, especially ursodeoxycholic acid is poorly soluble in the contents of the stomach-duodenum-jejunum-hungry entities. From 21% to 50% of swallowed doses were isolated in solid form due to unpredictable changes very slowly progressyou the th solubilize solid ursodeoxycholic acid in the gastrointestinal tract. Bile acids, especially ursodeoxycholic acid, desoxycholic acid, chenodesoxycholic acid, cholic acid, hyodesoxycholic acid, 7-katolikova acid, tauroursodeoxycholic acid and taurochenodeoxycholate acid, other acids are particularly insoluble in gastric juice and in aqueous solution chlorotoluron acid. However, the solubility of bile acids increases with increasing pH in the intestine very slowly and incompletely and ultimately bile acids become soluble at pH between 8 and 9.5.

To overcome this slow and inefficient process of absorption in the intestine due to incomplete and slow solubilization of bile acids were many newly developed pharmaceutical finished formulation forms such as pharmaceutical form prolonged action (slow release of the active ingredient) with water-soluble solid bile acids, which are often highly alkaline. These newly developed pharmaceutical dosage formulation are intersolubility-gastrorresistente. These intersolubility-gastrorresistente dosage forms remain intact in the gastric juice of the stomach, but dissolve and release the alkaline soluble solid salts of bile acids is the courthouse square in area, which is the target, within a limited period of time after they reach the small intestine.

These types of dosage forms, of course, have a better bioavailability than the ones in the present dosage forms as described in U.S. patent No. 5380533. However, it is extremely difficult and very expensive is getting dosage forms with exact slow release, which can release therapeutically active components by disintegration, dissolution and diffusion in the target area within a limited period of time. In accordance with U.S. patent No. 5302398 test on human absorption gastroresistant intersolubility dosage forms of bile acids, especially ursodeoxycholic acid, shows that the absorbance increases in the amount of approximately 40 percent compared with the introduction of the same amount adopted in the present commercial dosage forms. Its maximum gemicheskie concentration on average three times higher and achieved faster than commercial ready preparative forms. Any dosage form bile acids must be able to release bile acids are known and constant, after the introduction of the patient. Both the rate and extent of release is important and should be displayed is adimi. In the ideal case, the degree of liberation should be approximately 100%, whereas the rate of release should reflect the desired properties of the dosage form.

A well-known fact that the dosage forms of drugs in the form of solutions show a significantly increased rate and extent of absorption compared with the same drug, made in the form of tablets, capsules or suspension. This is because of the dosage form in the form of solutions are chemically and physically homogeneous solutions of two or more substances. In addition, specially designed dosage forms in the form of solutions that can save system solutions without failure under all conditions of pH, ready to diffusion in the target areas for the immediate and complete absorption, whereas the tablets, capsules or ready formulation with delayed release of active ingredient should always be subjected to disintegration, dissolution and diffusion in the target region within a limited period of time. Unpredictable variations in the degree and speed of release of bile acids by disintegration, dissolution and diffusion of dosage forms with delayed or immediate release of the active ingredient, having a pH-dependent instability, leading the to the slow and inefficient absorption and low bioavailability of bile acids.

Luminally surface of the stomach is coated with a thin layer of protective mucus. Floor slimy gel maintains the pH gradient from the intraluminal space to the apical membrane and are believed to contribute to the phenomenon of cytotoxity. Infection .pylori occurs on luminale surface of the gastric mucosa in the mucus on the epithelial surface and in the gastric pints. It is believed that bacterial enzymes destroy glycoprotein mesh structure mucus and convert the polymers into monomers (or subzone), so that the mucus can no longer exist in the form of a gel. Furthermore, the reduced mucilagenous and the mucous membrane becomes susceptible to the erosive action of the acid. This condition can lead to gastritis and peptic ulcers.

Compounds of bismuth are becoming of increasing interest in therapeutic treatment of disorders of the stomach and duodenum, and especially when the destruction of the Helicobacter pylori bacteria, which is reputed to be involved in the etiology of the disease. Used many oral preparations of bismuth. It turns out that different preparations vary in clinical efficacy, and pharmacokinetics. Used inorganic salts include basic nitrate, carbonate basic, basic gallate, tartrate, citrate and the main salicylate. Commercial pre is Arata were usually available through sale and often contain other compounds in addition to the salts of bismuth. Commercial preparations used successfully in the treatment of peptic ulcer disease as stomach and duodenal ulcers. These agents are indicated as effective as antagonists of histamine H2 in the treatment of gastric ulcers and duodenal ulcers associated with lower speeds of relapse after cessation of therapy. A lower rate of relapse after primary healing preparations of bismuth was attributed to their ability to destroy .pylori and "soften" gastroduodenitis associated with infection by this organism. Continuous destruction .pylori is more likely when the drug bismuth is administered together with antibiotics or antiseptics (local delivery), such as bile acids.

Different antibiotics and antiseptics have shown good activity against .pylori in vitro. However, when tested as single agents in clinical studies, they have not been successful in eradicating the organism. Failure of therapy and relapse is very common. The reason for this contradiction between in vitro and clinical outcome has not been established. A possible explanation is the poor penetration of the compounds in the mucus of the stomach, destruction by acid pH value, the insolubility in acid environment and their combination. Therefore, the introduction of high doses of antimicrobial agents on aged what avnoj basis, it is necessary to destroy .pylori. The effectiveness of this therapy is hampered by poor compliance of the patient due to negative actions, such as diarrhea, nausea, retching and vomiting and destruction of normal intestinal flora.

Another reason for incomplete destruction may be that the stay of antimicrobial agents in the stomach is so short that effective antimicrobial concentration cannot be achieved in the mucous layer of the stomach or surfaces epitelialnyh cells, where there is .pylori. Hence, the destruction .pylori can be better achieved by therapy, which increases the delivery of antimicrobial agent for local activity and absorbance values for system activity. But not documented tested to destruction in vivo drug forms that prolong the residence time in the stomach for local activity and have a high absorption rate in the gastrointestinal tract. The best results so far have been achieved with a combination of unabsorbed agent with local activity, colloidal compounds bismuth and well-absorbed agent system activity, amoxicillin (Van Caekemberghe and Breyssens, 1987, Antimicrobial Agent and Chemotherapy, pp.1429-1430). But it is clear that therapy against infections N. pylori is still suboptimal.

In addition to the bactericidal action of some compounds of bismuth have the SIL is diversified actions on some pathogenic mechanisms, whereby N. pylori damage the mucous membrane. Compounds of bismuth are potent and specific inhibitors of enzymes. In vitro studies suggest that these compounds can inhibit bacterial enzymes, including lipase, protease and glycosidase synthesized N. pylori. It is believed that the inhibition of enzymes of bacteria and preserve the intact coating in the form of a viscoelastic gel refers to therapeutic effect of the compounds of bismuth-related N. pylori gastritis and peptic ulcers.

Compounds of bismuth block adhesion N. pylori to epithelial cells. Soon after oral administration of these compounds, the organisms were found inside, and not slimy gel. It is believed that this is the result of loss of adhesion to the apical membrane of epithelial cells of the stomach. The bismuth in the form of compounds with electron density, as shown, is deposited on the surface and in bacterial cells. But, unfortunately, the concentration of bacteria within the mucus often drops below the median inhibitory concentration of compounds of bismuth for .pylori due to the effects of dilution with food, long time disintegration-selling tablets at pH<1.1 and deposition of bismuth due to insolubility in acid environment. In addition, .pylori, inactivated under dei is a journey of inhibiting the growth of concentrations of compounds of bismuth, remains viable for several hours and, therefore, is able to restore normal growth, when bismuth is removed.

The inhibitory factor(s) in bile was significantly reduced by acidification followed by centrifugation to remove precipitated complex licencegyezmennyel bile acids and was completely eliminated by application of a blocking bile acid agent cholesterolemia. These results are consistent with the view that the acidic conditions in the bulb of the duodenum can be useful for the deposition inhibiting bile acids (or other inhibiting substances) and growth .pylori in another hostile environment. Reviews D.Y.Graham (Osato et al., 1999, Digestive Diseases and Sciences 44(3): 462-464)related to gastritis reflux can be distributed to the possible assumption of the link between acid secretion and duodenal ulcer. Low pH in the duodenal bulb in patients with duodenal ulcer associated with high acid secretion, rapid gastric emptying and local production of acid can activate the development of gastric metaplasia, and to besiege destroyed complexes licencegyezmennyel bile acids, which allows .pylori to form colonies and thrive.

BRIEF IZLOZENI THE INVENTIONS

The present invention relates to a composition, which includes (1) a bile acid, its derivative, its salt or its conjugate with an amine, (2) water, and (3) a sufficient amount of water-soluble product of the transformation of starch, so that the bile acid and the product of the transformation of starch remained in solution at any pH within a selected pH range.

The invention further relates to a composition, which includes (1) a bile acid, its derivative, its salt or its conjugate with an amine, (2) water, and (3) a sufficient amount of water-soluble non-starch polysaccharide, so that the bile acid and the polysaccharide remained in solution at any pH within a selected pH range.

The invention further relates to a pharmaceutical composition, which comprises (1) a bile acid, its salt or its conjugate with an amine, (2) water, (3) the pharmaceutical compound in a pharmaceutically suitable number and (4) a sufficient number of water-soluble product of the transformation of starch or water-soluble non-starch polysaccharide, so that the bile acid, the pharmaceutical compound and carbohydrate remain in solution at any pH within a selected pH range.

The invention further relates to dosage forms in the form of solutions of the compositions of bile acids. The benefits of these dosage forms in the form of solutions in luchot increased bioavailability and absorption ability of bile acids. Additional benefits of dosage forms in the form of solutions include increased bioavailability and absorption capacity of pharmaceutical compounds.

In some implementations of the invention proposed composition, which comprises (1) a bile acid, its derivative, its salt or its conjugate with an amine, (2) water, and (3) a sufficient amount of carbohydrate, so that the component of bile acid and carbohydrate remain in solution at any pH within a selected pH range, where the carbohydrate is a mixture of water-soluble product of the transformation of starch and water-soluble non-starch polysaccharide. In the implementation, containing both soluble necromancy polysaccharide, and having a high molecular weight of the product of the transformation of starch, the amount of each of them are such that when mixed together in the composition, they were sufficient to save a component of bile acids with high molecular weight of the product of the transformation of starch, soluble non-starch polysaccharide and pharmaceutical compounds, if present in solution at any pH within a selected pH range.

In some implementations of the invention proposed composition for combination therapy, which can increase the intensity of reactions to pharmaceutical is connected to the e or the effectiveness of such compounds. This composition may be allowed to input a lower dose of the pharmaceutical compounds to influence complex diseases in different places, to affect the destruction and/or alteration of absorption of pharmaceutical compounds. This composition can lead to reduced toxicity and/or side effects of pharmaceutical compounds or contribute.

The invention further relates to a composition, which includes (1) a bile acid, its salt or its conjugate with an amine, (2) water, 3) a water-soluble compound of bismuth and (4) a sufficient number of water-soluble product of the transformation of starch or water-soluble non-starch polysaccharide, so that bile acid, bismuth and carbohydrate remain in solution at any pH within a selected pH range.

The invention further relates to a method of treatment or prevention of disease in man or animal, comprising introducing the composition of the invention.

A BRIEF DESCRIPTION of GRAPHIC MATERIALS

Figure 1 - graph of the serum according to the concentration of UDCA (squares) and GUDCA (triangles) from the time after the introduction of metered ready preparative forms in accordance with examples II and VI and table 4.

Figure 2 - graph of the serum according to the concentration of UDCA from the time after the introduction of metered ready preparative forms VC is Noah acid in accordance with examples III and VI, and table 4.

Figure 3 - chart of the average value (n=5) group 1 pharmacokinetic parameters of UDCA in humans after oral administration of liquid ready preparative forms of UDCA obtained in accordance with example IX without bismuth.

4 is a chart of the average value (n=5) for group II pharmacokinetic parameters of UDCA in humans after oral administration of liquid ready preparative forms of UDCA obtained in accordance with example IX.

Figa obtained using a transmission electron microscope micrograph .pylori, cultured in the medium of Columbia.

Figv obtained using a transmission electron microscope micrograph .pylori after 48 hours after treatment UDCA and citrate of bismuth, obtained in accordance with example IX.

Figs obtained using a transmission electron microscope micrograph .pylori 72 hours after treatment UDCA and bismuth citrate

6 - NMR data for UDCA in liquid dosed ready preparative form obtained in accordance with example III without preservatives, corrigenda and sweeteners.

Fig.7 - record HPLC for UDCA in liquid dosed ready preparative form obtained in accordance with example III without preservatives, corrigenda and sweeteners.

Fig record HPLC standard is Oh UDCA.

Fig.9 - method of cultivation .Pylori.

Figure 10 - method of cultivation .Pylori.

11 - the Method of cultivation .Pylori.

DETAILED description of the INVENTION

The present invention relates to aqueous solution comprising (i) one or more soluble bile acids, water-soluble derivatives of bile acids, salts of bile acids or bile acid conjugated with an amine (together called "bile acid"), (ii) water and (iii) one or more water-soluble products of transformation of starch or water-soluble non-starch polysaccharide in an amount sufficient to obtain a solution, which does not form a precipitate at any pH value in the desired pH range. In a preferred implementation of the invention bile acid and carbohydrate not precipitate at pH between about pH 1 and about pH 10, more preferably at a pH between about pH 1 and about pH 14, and most preferably at all pH values obtainable in an aqueous system. In some implementations of the invention bile acid remains dissolved in the acid conditions in the form of free bile acids, despite the General insolubility of bile acids in acidic conditions. In some implementations of the invention composition can be used as pharmaceutical finished prep the operational form, where the pharmaceutical compound remains in solution without precipitation at the prevailing pH in the oral cavity, the stomach and intestines. The composition may contain bile acid or its salt, which itself has a pharmaceutical efficiency. Compositions of the invention can act as a carrier, adjuvant or agent increasing the delivery of pharmaceutical material, which remains dissolved in the compositions of the invention over the desired pH range. In some implementations of the invention use a pharmaceutical agent, non-bile acid, though not in solution.

The advantage of this invention is that the bile acid and carbohydrate remain in solution without precipitation at any pH from acid to alkaline. These systems are aqueous solutions of bile acid does not inherently contain sediment or particles. Another advantage of this invention is that the system of aqueous solutions do not exhibit changes in physical appearance such as a change in transparency, color or odor after addition of strong acids or alkalis, even after several months of observation at accelerated storage conditions at 50°C.

In some implementations of the invention system of an aqueous solution of bile acid administered orally, PEFC is what it reaches the intestine through the gastrointestinal tract without deposition of bile acids in the form of solid substances when exposed to acidic gastric juice and alkaline intestinal juice. These ready-made formulations of dissolved bile acids, which demonstrate the intact system solutions in the intestine, can be effectively and completely absorbed and, therefore, undergo enterohepatic cycle. In accordance with the invention, the solubility of bile acids (e.g., sedimentation and changes in physical appearance) does not change regardless of whether there can be side chain carboxylic acid of some bile acids protonated (ionized), ionized or true carboxylic acid.

The state of ionization of the side chain with a carboxylic acid of bile acids has a significant impact on the hydrophobic and hydrophilic bile acids in these systems water solutions. In some implementations of the invention in such a state of ionization is controlled by adjustment of pH to control the toxicity, absorption and amphiphiles bile acids. One or more bile acids can be dissolved in these systems, aqueous solutions as a therapeutically active agent, adjuvant, or carrier drug or agent to increase the solubility of the drug. These systems are aqueous solutions can be obtained for oral administration, enemas, liquids for rinsing the mouth, liquids or Rast the Directors for rinsing of the mouth and throat, nasal preparations, ear medications, injections, drugs for the soul, local skin medications, other local drug and cosmetic compositions which have the desired pH value is without fault, manifested in the deposition or deterioration in physical appearance after long periods of time.

Soluble bile acids are any type of water-soluble bile acids. Salt of the bile acid is any water-soluble salt of bile acid. Soluble derivatives of bile acids of this invention are those derivatives which are soluble or more soluble in aqueous solution than the corresponding bile acid is not converted into a derivative. Derivatives of bile acids include, but are not limited to derivatives formed from hydroxyl groups or carboxylic acid groups bile acids with other functional groups, including, but not limited to, halogen and amino. The water-soluble salts of bile acids can be obtained by the interaction of bile acids described above, and an amine, including, but not limited to, aliphatic available amines, such as trientine, Diethylenetriamine, Tetraethylenepentamine, and basic amino acids, such as arginine, lysine, ornithine and ammonia,and amino sugar, such as D-glucamine, N-alkylguanine, and Quaternary ammonium derivatives, such as choline, heterocyclic amines such as piperazine, N-alkylpiperazine, piperidine, N-alkylpiperazine, morpholine, N-alkylboronic, pyrrolidin, triethanolamine and triethanolamine. In this invention the water-soluble salts of bile acids with metals, the connection of inclusion between bile acid and cyclodextrin and its derivatives and water-soluble O-sulfated bile acids are also included as soluble salts of bile acids. Soluble bile acid may include an aqueous preparation of bile acid in the form of the free acid in combination with one reagent of HCl, acetic acid, ammonia and arginine.

Bile acids used in this invention include, but are not limited to ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, hyodesoxycholic acid, desoxycholic acid, 7-oxometabolite acid, lithocholic acid, iodosuccinimide acid, ikalawa acid, tauroursodeoxycholic acid, taurochenodeoxycholate acid, taurodeoxycholic acid, terroritorial acid, glycosidically acid, human beings need it to acid, glycocholic acid and their derivatives have a hydroxyl or carboxylic acid group on steroidally.

The main advantage of the present invention is that through the delivery of bile acids in solution reach higher levels of bile acids in vivo than in the case of conventional drugs. Consequently, it is possible to achieve a more complete therapeutic potential of bile acids than in the previous cases ready preparative forms. The levels of bile acids in vivo, achievable with existing ready preparative forms in which the bile acid dissolved incompletely, are lower and require higher amounts of bile acids. Because bile acid is completely dissolved in the finished preparative form of this invention, can be achieved in vivo higher levels of bile acids, even if administered lower doses.

In some implementations of the invention in one ready preparative form use several bile acids. A mixture of two or more bile acids with different hydrophobic activity can behave like one salt of bile acid with an average hydrophobic activity. In the detergent properties and toxicity of mixtures of two bile acids with different hydrophobic activity are often average between individual components.

Carbohydrates suitable for use in the invention include water-soluble products of the transformation is ragmala and water-soluble non-starch polysaccharides. For the purposes of the invention water-soluble products of the transformation of starch is defined as follows:

1. You can get them at different pH values of partial or incomplete hydrolysis of starch.

2. Non-limiting examples include maltodextrin, dextrin, liquid glucose, solid corn syrup (dried powder of liquid glucose), soluble starch, preferably maltodextrin or solid corn syrup, most preferably, the solid corn syrup. Especially preferred are MALTRIN® M200, solid corn syrup, and MALTRIN® M700, maltodextrin, both of which are manufactured GPC®, Grain Processing Corporation of Muscatine, Iowa. For the purposes of this invention, the term "corn syrup" includes both corn syrup and liquid glucose.

3. If the connection is a polymer, the polymer has at least one restoring end group and at least one non terminal group. The polymer may be linear or branched.

4. Molecular weight is from about 100 units of mass to more than 106units of mass. Having a high molecular weight water-soluble products of the conversion of starch are products with a molecular weight above 105.

For the purposes of the invention water-soluble necr halnya polysaccharides is determined as follows:

1. You can get them at different pH values of various hydrolytic or synthetic methods.

2. Non-limiting examples include dextran, carob bean gum, pectin, unassimilated soluble fiber.

3. If the connection is a polymer, the polymer has at least one restoring end group and at least one non terminal group. The polymer may be linear or branched.

4. Molecular weight is from about 100 mass units to more than 105mass units. The preferred molecular weight greater than 105mass units.

The amount of the water-soluble product of the transformation of starch with high molecular weight and/or soluble non-starch polysaccharide used in this invention is at least the amount needed to make the selected salt of bile acid, soluble at the desired concentration and the required range of pH values. In the preferred implementation of the invention approximate the minimum number of maltodextrin required to prevent the precipitation of bile acids from the dosage forms in the form of an aqueous solution of the invention is 5 grams for each 0.2 g of ursodeoxycholic acid, 25 g for every 1 g at codesexymovies acid and 50 g for every 2 g of ursodeoxycholic acid in 100 ml of water. In the preferred implementation of the invention the approximate minimum amount of maltodextrin is 30 grams for every 200 mg chenodesoxycholic acid, 12 g for every 200 mg of 7-katolickiej acid, 10 g for every 200 mg holeva acid and 50 g for every 200 mg of deoxycholic acid. In the preferred implementation of the invention, the approximate minimal quantity of liquid glucose (commercial light corn syrup)that is required to prevent the precipitation of bile acids from the dosage forms in the form of an aqueous solution of the invention is 80 g for every 500 mg of ursodeoxycholic acid in 100 ml of water and 80 g for every 500 mg of ursodeoxycholic acid in 200 ml of water. In the preferred implementation of the invention, the approximate minimal quantity of dried powder of liquid glucose (solid corn syrup, for example, MALTRIN® M200)required to prevent the precipitation of bile acids from the dosage forms in the form of aqueous solutions of the invention is 30 grams for every 500 mg of ursodeoxycholic acid in 100 ml of water and approximately 30 g for every 500 mg of ursodeoxycholic acid in 200 ml of water. In the preferred implementation of the invention, the approximate minimal quantity of soluble non-starch polysaccharide (e.g., pectin, gum carob, Aravis the second gum), required to prevent the precipitation of bile acids from the dosage forms in the form of aqueous solutions of the invention, 50 g of gum carob tree for every 500 mg of ursodeoxycholic acid in 100 ml of water and 80 g of pectin for every 500 mg of ursodeoxycholic acid in 100 ml of water. The minimum required number having a high molecular weight water-soluble products of transformation of starch or soluble non-starch polysaccharide is determined mainly by the absolute amount of bile acids in the finished formulations in the form of a solution, not concentration.

In some implementations of the invention ready preparative form may include cyclodextrin.

In some implementations of the invention ready preparative form further includes dietary fiber. Non-limiting examples of dietary fiber include carob bean gum, pectin, psyllium, oat gum, soybean fiber cultural, oat bran, corn bran, cellulose and wheat bran.

In some implementations of the invention ready preparative form further includes emulsifying agents. For the purposes of the invention, the term "emulsifying agent" includes emulsifying agents and suspendresume agents. Neogranichivatsya examples of emulsifying agents include gum carob trees is, pectin, Arabic gum, carrageen, sodium carboxymethyl cellulose, hydroxymethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, povidone, tragacanth gum, xanthan gum and ester sorbitan.

The selected pH range in which ready preparative form will not besiege her bile acid, the product of the transformation of starch, soluble necromancy polysaccharide or its pharmaceutical compound can be any range of pH values, attainable with the water system. This range is preferably between about pH 1 and about pH 14, and more preferably between about pH 1 and about pH 10. Even more preferably the range is any part of the range of pH values obtainable in an aqueous system, sufficient to pharmaceutical composition remained in the solution of the drug, and sufficient for the introduction and absorption in the body in accordance with the method of administration.

The invention considers the use of a wide range of pharmaceutical compounds. Non-limiting examples include hormones, hormone antagonists, analgesics, antipyretics, anti-inflammatory drugs, immunoactive drugs, antineoplastic drugs antibiotics anti-inflammatory drugs, sympathomimetic drugs, antibacterial drugs, antineoplastic agents, and anesthetics. The following limitiruyuschie examples include medicines which are "targeting" or affect the gastrointestinal tract, liver, cardiovascular system and respiratory system. Additional non-limiting examples of pharmaceutical compounds include insulin, heparin, calcitonin, ampicillin, octreotide, sildenafil citrate, calcitriol, dihydrotachysterol, apomorphine, yohimbine, trazodone, acyclovir, amantadine•HCl, rimantadine•HCl, cidofovir, delavirdine•mesilate, didanosine, famciclovir, foscarnet sodium, fluorouracil, ganciclovir sodium, idoxuridine, interferon-α, lamivudine, nevirapine, penciclovir, ribavirin, stavudine, trifluridine, valacyclovir•HCl, zalcitabine, zidovudine, indinavir•N2SO4, ritonavir, nelfinavir•CH3SO3N, saquinavir•CH3SO3N, d-penicillamine, chloroquine, hydroxychloroquine, aurothioglucose, mixed thiomalate of gold and sodium, auranofin levamisole, DTC, isoprinosine, monophosphate of methylinosine, muramyldipeptide, diazoxide, hydralazine•HCl, Minoxidil, dipyridamole, isoxsuprine•HCl, Niacin, nylidrin•HCl, phentolamine, doxazosi the• CH3SO3N, prazosin•HCl, terazosin•HCl, clonidi•HCl, nifedipine, molsidomin, amiodarone, acetylsalicylic acid, verapamil, diltiazem, nisoldipine, isradipine, bepridil, isosorbide•dinitrate treatment, pentaerythritol•TETRANITRATE, nitroglycerin, cimetidine, famotidine, nizatidine, ranitidine, lanzoprazol, omeprazole, misoprostol, sukralfat, metoclopramide•HCl, erythromycin, connection bismuth, alprostadil, albuterol, pirbuterol, terbutaline•N2SO4salmetrol, aminophylline, Tefillin, ephedrine, Ethylmorphine, isoetharine, isoproterenol, metaproterenol, n-dobromil, oxtriphylline, theophylline, bitolterol, fenoterol, budesonide, flunisolide, beclomethasone•dipropionate, fluticasone•propionate, codeine, codeine sulfate, codeine phosphate, dextromethorphan•HBr, triamcinolone•acetonide, montelukast sodium, zafirlukast, zileuton, kromolin sodium, ipratropium bromide, nedocromil sodium benzoate, diphenhydramine•HCl, hydrocodone•bitartrate, methadone•HCl, martinslife, acetylcysteine, guaifenesin, ammonium carbonate, ammonium chloride, tartrate of antimony and potassium, glycerol, Turpin•hydrate, palmitate colfosceril, atorvastatin calcium, cerivastatin-sodium, fluvastatin sodium, lovastatin, pravastatin sodium, simvastatin, picrorrhazia kurrva, andrographis paniculata, moringa oleifera, albizzia lebeck, adhata vasica, curcuma longa, momordic charantia, gymnema sylvestre, terminalia arjuna, azadirachta indica, tinosporia cordifolia, metronidazole, amphotericin b, clotrimazole, fluconazole, haloprogin, ketoconazole, griseofulvin, Itraconazole, terbinafine•HCl, econazole•HNO3, miconazole, nystatin, oxiconazole•HNO3sulconazole•HNO3, cetirizine•2HCl, dexamethasone, hydrocortisone, prednisolone, cortisone, catechin and its derivatives, glycyrrhizin, glycyrrhizinate acid, betamethasone, fludrocortisone•acetate, flunisolide, fluticasone•propionate, methylprednisolone, somatostatin, lispro, glucagon, proinsulin, insoluble insulin, acarbose, hlorpropamid, glipizide, gliburid, Metformin•HCl, Repaglinide, tolbutamide, amino acid, colchicine, sulfinpirazon, allopurinol, piroxicam, tolmetin sodium, indomethacin, ibuprofen, diflunisal, mefenamico acid, naproxen and trientine.

Additional pharmaceutical compounds that can be included in the finished preparative form, are any compounds that remain soluble when added to ready the preparative form. With additional pharmaceutical compound in ready preparative form of bile acid in solution may act as an adjuvant, carrier or agent to increase the solubility of some therapeutically active agents, including, but not limited to, the category is Clennam insulin (pH 7.4-7.8)to, heparin (pH 5-7,5), calcitonin, ampicillin, amantadine, rimantadine, sildenafil, neomycin sulphate (pH 5-7,5), apomorphine, yohimbine, trazodone, ribavirin, paclitaxel and its derivatives, retinol and tretinoin, which are soluble and stable in acid and/or alkali can be added, if necessary, in these dosage forms in the form of aqueous solutions of certain concentrations of bile acids in this invention. Some therapeutically active agents, including but not limited to the listed Metformin•HCl (pH 5-7), ranitidine•HCl, cimetidine, lamivudin, citizen•2HCl (pH 4-5), amantadine, rimantadine, sildenafil, apomorphine, yohimbine, trazodone, ribavirin, and dexamethasone, hydrocortisone, prednisolone, triamcinolone, cortisone, Niacin, taurine, vitamins, natural amino acids, catechin and its derivatives, extract Glycyrrhizal and its main components, such as glycyrrhizin and glycyrrhizin acid, water-soluble compounds of bismuth (for example, bismuth tartrate and sodium), which are soluble and stable in acid and/or alkali can be added, if necessary, in these dosed ready formulation in the form of aqueous solutions of this invention containing ursodeoxycholic acid.

In accordance with the invention, the bismuth compounds include water-soluble product of the mutual the steps between the bismuth ion and chelat forming agent. Non-limiting examples of such chelat forming agents include citric acid, tartaric acid, malic acid, lactic acid and adamowo acid and alkali. Non-limiting examples of the compounds include bismuth ammonium salt chelate complex of bismuth citrate, bismuth gallate, bismuth, bismuth sulfate, basic bismuth nitrate, basic bismuth salicylate, triallylisocyanurate and wamutarika.

The invention considers the use of pH-regulating agents. Non-limiting examples include HCl, H2SO4, HNO3CH3COOH, citric acid, malic acid, tartaric acid, lactic acid, phosphate, adamowo acid and alkali.

In some implementations of the invention prepared formulation can be used for the treatment of diseases of humans and mammals. The invention considers the treatment of gastro-intestinal disorders, liver disease, gallstones and hyperlipidemia. Non-limiting examples of diseases of the liver include alcohol-induced liver disease and not caused by alcohol liver disease. Non-limiting examples of gastrointestinal diseases include chronic gastritis, reflux gastritis and peptic ulcer. Non-limiting examples not caused by alcohol liver disease include primary bilia the hydrated cirrhosis, acute and chronic hepatitis, primary sclerosing cholangitis, chronic active hepatitis and excessive accumulation of fat in the liver. The invention further considers the treatment of viral, bacterial and fungal diseases. In some implementations of the invention ready preparative form is administered for the treatment of diseases and/or destruction of the pathogen Helicobacter pylori. In some implementations of the invention ready preparative form is administered for the treatment of diseases and/or destruction of the pathogen virus infection hepatitis C, influenza a, influenza, parainfluenza 1, sendai, and rubella virus false rabies. In some implementations of the invention ready preparative form is administered for the treatment of acute or chronic inflammatory diseases. Non-limiting examples of inflammatory diseases include bronchitis, chronic pharyngitis and chronic tonsillitis. In some implementations of the invention ready preparative form is administered for the treatment of hypercholesterolemia.

In some implementations of the invention ready preparative modify the form so that it can be introduced in the form of liquid, solid, powder or tablets. In some implementations of the invention composition include syrup, thick syrup or paste. A non-limiting example of a syrup is a solution of mA is Icodextrin, in which the concentration of maltodextrin is less than 1.0 kg/L. of a non-limiting example of a thick syrup is a solution of maltodextrin in which the concentration of maltodextrin is between 1.0 kg/l and 1.2 kg/l inclusive. A non-limiting example of the paste is a solution of maltodextrin in which the concentration of maltodextrin higher than 1.2 kg/liter

EXAMPLES

Stability dosed preparations of the invention was evaluated by measuring the concentration of an acceptable bile acid over time in preparations, including soluble bile acid, a water-soluble product of the transformation of starch with high molecular weight and water at different pH levels and temperatures. The retention time of each bile acid can be adjusted, as required, to allow individual analysis of each bile acid present in complex samples, i.e. the sample that have a lot of bile acids.

Stability studies can be carried out on three different systems of aqueous solutions

1. Bile acid and having a high molecular weight water-soluble product of the transformation of starch were mixed in an aqueous solution in accordance with example 1 with the results shown in tables 1A and 1B.

2. Mixed bile acids and having a high molecular weight water-soluble products is the conversion of starch were mixed in an aqueous solution in accordance with example II with the results shown in table 2.

3. Bile acid having a high molecular weight water-soluble product of the transformation of starch and branched chain amino acids (e.g. leucine, isoleucine, valine, or another amino acid with a branched side chain) was mixed in an aqueous solution in accordance with example IV with the results shown in tables 3A to 3F.

Stability tests were performed using HPLC and microscope at different pH values in normal or accelerated conditions. Accelerated conditions for testing pharmaceutical compositions have been described (Remington, The Science and Practice of Pharmacy, 19thed., p. 640). All these test results on stability were satisfactory in the sense that the concentration of bile acids, as measured by HPLC, was not changed significantly over time at various pH values. Thus, the compositions of the examples are suitable for commercial liquid dosage forms. In particular, all songs in the form of solutions, which contained bile acid, was found excellent results in tests for stability without precipitation and without change in physical appearance during the test period. Some songs remain stable for more than 2 years.

In addition, stability tests concrete is performed on dosage forms in the form of aqueous solutions, comprising a mixture of water-soluble UDCA, branched chain amino acids (leucine, isoleucine, valine) and maltodextrin in accordance with example IV as a typical example of dosage forms in the form of a solution in which is dissolved bile acid as a therapeutically active agent, adjuvant or carrier, pharmaceutically active agent or agent to increase the solubility and high molecular weight, water-soluble products of the conversion of starch or soluble non-starch polysaccharides. In accordance with the test results there is no discoloration, changes in transparency and deposition. In addition, not found detectable impurities formed due to the destruction of UDCA or branched chain amino acids in the analysis of HPLC at different pH values such as pH 1, 3, 5, 7, 9 and 10, under accelerated conditions or during incubation at 50°C.

Dosage forms in the form of aqueous solutions according to this invention did not change either physically or chemically under different conditions of pH and at accelerated conditions, despite adding therapeutically and chemically active agents that are stable and soluble in hydrochloric acid. Therefore, these systems in the form of solutions are very valuable pharmaceutical dozorova the different forms of drugs therapeutically active bile acids and/or preparations for delivery of the medicinal product (pharmaceutical compounds), in which bile acids play the role of adjuvant drugs, media drug or agent to increase the solubility of drugs through the formation of micelles at different pH values without problems of solubility, including precipitation at acid conditions.

To test the stability of the solution for each bile acid used HPLC to measure the concentration of the considered bile acid under the following conditions: solvent for elution of 0.02 M KH2PO4: acetonitrile in the ratio 55:45) pH 3,01, flow rate 0.8 ml/min, the amount of injection of 20 μl, the wavelength for detection was 195 nm. In tables, the concentration of the indicated salts of bile acids for each of the three numbered experiments and the average value it is given on each line. The percentage indicates the relative concentration of salts of bile acids after incubation for a certain period of time in comparison with the initial concentration.

Example I

Dosage forms in the form of solutions, which were obtained in accordance with the following composition found no deposition at any tested pH value.

Soluble bile acid 200 mg (as free acid)

The minimum number of maltodextrin

for CDCA approximately 30 g;

for UDCA app is siteline 5 g;

for 7-katolickiej acid

approximately 12 g;

for holeva acid

approximately 10 g;

for deoxycholic acid

approximately 50 g;

for hyodesoxycholic acid

approximately 3.5 g;

Purified water to obtain 100 ml

Received 100 ml of an aqueous solution in which was dissolved one of the above bile acids. The resulting clear solution was added under stirring at room temperature maltodextrin having a high molecular weight, water-soluble product of the transformation of starch. To regulate the total volume to 100 ml was added to purified water. In accordance with the present invention and all examples purified water is deionized, distilled-deionized-distilled water or has a grade commonly used for pharmaceutical preparations.

On the basis of these compositions were obtained from the dosage form in the form of aqueous solutions of different concentrations of some bile acids (or salts) with their corresponding minimum or more high molecular weight water-soluble products of transformation of starch (for example, maltodextrin, liquid glucose, dried powder of liquid glucose (commercial solid corn syrup), dextran, dextrin, and the solution is constituent of starch or soluble non-starch polysaccharide (for example, gum carob, pectin, Arabic gum).

Example II

Dosage forms in the form of solutions, which were obtained in accordance with the following formulations, found no deposition at any tested pH value.

Soluble cholic acid200 mg (as free acid)
Soluble 7-catalytically acid200 mg (as free acid)
Soluble chenodesoxycholic acid200 mg (as free acid)
The minimum number of maltodextrin40 g
Purified water to obtain100 ml

Received 60 ml of an aqueous solution in which was dissolved soluble cholic acid, soluble 7-catalytically acid and soluble chenodesoxycholic acid. The resulting clear solution was added under stirring at room temperature maltodextrin. To regulate the total volume to 100 ml was added purified water.

Using this composition were tested for stability to aqueous mixtures of different bile acids, which can adjust the hydrophilicity or hydrophobicity.

Table 1A shows the results of the test is stabilnosti over time at pH 7 and 50° With songs SA, 7-katolickiej acid (KLCA), CDCA and DCA in solution with maltodextrin obtained in accordance with example I. the Concentration of bile acids was measured by HPLC and the concentration of bile acids as a percentage of its concentration on day 0 is given in the column marked as a percentage.

Table 1B shows the results of the test of stability over time at pH 10 and 50°With songs SA, 7-katolickiej acid, CDCA and DCA in solution with maltodextrin obtained in accordance with example I.

Table 2 shows the results of the test of stability over time at pH 1 and 50°With songs SA, 7-katolickiej acid, CDCA and DCA in solution with maltodextrin obtained in accordance with example II.

Table 1A
CA
Day#1#2#3AveragePercentage
00,5290,5300,5220,527100,0
40,4600,5240,5240,50295,4
70,5200,525 0,547mean HDI of 0.531100,8
200,5160,5760,5350,542103,0
KLCA
Day#1#2#3AveragePercentage
00,8880,8790,8740,880100,0
40,8710,8870,8880,882100,2
70,8970,8930,8880,893101,4
200,8930,9090,8940,899102,1
CDCA
Day#1#2#3AveragePercentage
00,5720,5390,5300,547100,0
40,5400,5520,5760,556101,6
70,5810,5880,5530,574105,0
20of 0.5650,6080,5600,578105,7
DCA
Day#1#2#3AveragePercentage
00,4990,4910,4890,493100,0
40,5010,5000,4740,49199,6
70,4880,4870,4840,48698,6
200,4780,4760,472value (0.475)96,3

7
Table 1B
CA
Day#1#2#3AveragePercentage
00,5340,5240,4900,516100,0
4 0,5010,5090,5240,511of 99.1
70,5520,518of 0.5330,534103,6
200,5350,5630,5480,549106,4
KLCA
Day#1#2#3AveragePercentage
00,8790,8740,8570,870100,0
40,8700,8730,8800,874100,5
70,8930,8760,8820,884of 101.5
200,8870,8930,8870,889102,2
CDCA
Day#1#2#3AveragePercentage
00,5410,5320,4950,522100,0
40,5110,5190,5380,523100,0
0,5640,5270,5400,544104,1
200,5560,5690,5580,561107,4
DCA
Day#1#2#3AveragePercentage
00,4910,4880,4710,483100,0
40,4930,4870,4720,484100,2
70,4790,4880,4790,48299,7
200,4680,4780,479value (0.475)98,3

Table 2
CA
Day#1#2#3AveragePercentage
00,5160,5090,5030,509100,0
40,4530,4530,4660,45789,8
70,4340,4260,4680,44386,9
200,207-0,2060,20740,6
KLCA
Day#1#2#3AveragePercentage
00,8830,8770,8690,876100,0
40,8700,8660,8470,86198,3
70,848services, 0.8440,8430,84596,4
200,661-0,6510,65674,9
CDCA
Day#1#2#3AveragePercentage
00,5600,5280,5130,534100,0
40,4880,5100,5190,50694,7
70,4600,4690,4630,464of 87.0
200,169-0,1540,16130,2

Example III

Dosage forms in the form of solutions, which were obtained in accordance with the following formulations, found no deposition at any tested pH value.

Soluble UDCA200 mg (100 mg to 2000 mg as free base)
The minimum number of maltodextrinapproximately 5 g
(approximately 1.25 g - 50 g)
Preservativesas needed
Corrigentas needed
Sweeteneras needed
Purified water to100 ml

Received 80 ml of an aqueous solution in which was dissolved soluble UDCA and then the resulting clear solution was added under stirring at room temperature maltodextrin. The resulting clear solution was added sweetener, preservatives and corrigentov in quantities suitable for pharmaceutical compositions. To regulate the total volume to 100 ml was added purified water.

In these studies the dosage form in the solutions containing different concentrations of ursodeoxycholic acid (or its salts) with their corresponding minimum or more water-soluble products of transformation of starch (for example, maltodextrin, liquid glucose, dried powder of liquid glucose (commercial solid corn syrup), dextran, soluble starch).

6 is an NMR spectrum of UDCA, demonstrating that UDCA, when it is in the composition obtained in accordance with example III, is absolutely free UDCA. That is, carboxylic acid UDCA in position C-24 is in the free form (R-COOH) and two hydroxyl groups at positions C-3 and C-7 are in a free form (R-OH).

In addition, the HPLC profile of acid UDCA in the composition obtained in accordance with example III (7), similar to the profile of UDCA, dissolved in methanol (Fig). These data show that there UDCA-complex compounds. There is only free UDCA. Standard UDCA solution was obtained by dissolving 100 mg of UDCA in 100 ml of methanol. As the mobile phase used acetonitrile (51), water (49) and acetic acid (1).

Example IV

Dosage forms in the form of solutions, which were obtained in accordance with the following formulations have not found any precipitation at any pH within a selected, desired range of pH values.

Soluble UDCA0.2 g (1 g-2 g
free acid)
Maltodextrin5 g (35 g 50 g)
Amino acid branched
circuit (for example, leucine, isoleucine,
valine)15 g (5 g-15 g
free base)
Sweeteneras needed
Corrigentas needed
Purified water to100 ml

Received 85 ml of an aqueous solution in which was dissolved soluble UDCA, and then the resulting clear solution was added maltodextrin. The resulting clear solution was added under stirring branched amino acids regulation of pH (4-7) and then added sweetener, preservatives and corrigent. To regulate the total volume to 100 ml was added purified water.

On the basis of these compounds were obtained from the dosage form in the form of aqueous solutions of different concentrations of ursodeoxycholic acid (or its salts) and the corresponding minimum or more maltodextrin, liquid glucose, dried powder of liquid glucose (commercial corn syrup) or dextran with different amounts of branched amino acids (the total number of leucine, isoleucine and valine).

In tables 3A-3F shows resultativity on the stability over time of the composition, derived from amino acids in accordance with example IV. All stability tests were carried out at 50°C. Shows the results of stability testing 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).

Table 3A
The stability of UDCA solution in accordance with example IV at pH 1, 50°
IIe
Day#1#2#3AveragePercentage
00,2610,2360,2490,248100,0
10,2560,2750,2510,261105,0
20,268to 0.2630,251is 0.260104,9
60,295 0,2680,2910,285114,6
70,2490,2540,2670,257103,4
80,2530,2430,2400,24598,8
9to 0.2630,268to 0.2630,265106,6
Day#1#2#3AveragePercentage
00,4850,4280,4700,461100,0
10,4700,4770,4560,468of 101.5
20,4850,4810,460 value (0.475)103,1
60,5530,5100,529mean HDI of 0.531or 115.1
70,4780,4730,5130,488105,8
80,4740,4540,511to 0.480104,0
90,4830,4850,4760,481104,4
Val
Day#1#2#3AveragePercentage
00,5060,4480,4600,471100,0
10,438 0,4580,4710,45696,7
20,4790,4850,5130,492104,5
6worn : 0.5050,5360,5490,530to 112.4
70,4940,4650,4960,485102,9
80,4880,4910,4590,479101,7
90,4790,4960,4900,488103,6
Sol
Day#1#2#3Average Percentage
00,3190,3150,3220,319100,0
1of 0.3320,3440,3510,342107,4
20,3710,3390,4030,371116,4
60,3960,4090,4110,405127,2
70,3650,3510,3810,366to 114.7
80,4090,3650,3310,368115,6
90,3380,3910,3740,368 115,4
UDCA
Day#1#2#3AveragePercentage
00,3880,3870,3890,388100,0
10,3670,3700,3660,36894,8
20,3740,3880,3880,383the 98.9
60,3710,3800,3820,37797,3
70,3780,3760,3790,37897,4
80,3740,3820,3840,38097,9
90,3700,3670,3700,36995,1
Table 3B
The stability of UDCA solution in accordance with example IV, at pH 3, 50°
IIe
Day#1#2#3AveragePercentage
00,2610,2540,2530,256100,0
10,2660,2680,2610,265103,3
20,2730,2430,247 0,25499,3
60,2960,3060,3000,301117,4
70,2470,2650,2570,256100,0
80,2500,2470,2470,24896,7
130,2850,2400,2500,258100,9
Leu
Day#1#2#3AveragePercentage
00,4950,4650,4520,471100,0
10,489 to 0.4800,470to 0.480101,9
20,4950,4720,4810,483102,6
60,5220,5320,5560,537114,0
70,4920,4820,4910,488103,7
80,5430,5150,4950,517109,9
130,5120,4960,5430,517109,8
Val
Day#1#2#3AveragePercentage
0 0,4850,4910,4980,491100,0
10,4670,4810,4460,46594,6
20,5100,4930,5270,510to 103.8
60,5270,4910,5530,524106,6
70,4850,4810,4680,47897,3
80,4900,4910,5440,508103,5
130,5190,4980,5170,511104,1
Sol
D. the ery #1#2#3AveragePercentage
00,3430,3550,3700,356100,0
10,3400,3500,3160,335a 94.2
20,3830,3710,4000,385108,0
60,3780,3410,4160,378106,3
70,3550,3810,3150,35098,4
80,3430,3500,3950,363101,9
130,3770,3820,394to 110.7
UDCA
Day#1#2#3AveragePercentage
00,3950,3960,3930,395100,0
10,3960,4010,3920,396to 100.4
20,4270,4210,4160,421106,8
60,4070,4080,4020,405102,7
70,4120,4090,4110,411104,1
80,415 0,4180,4080,414104,9
130,4150,4120,4160,414105,0
Table 3C
The stability of UDCA solution in accordance with example IV at pH 5, 50°
IIe
Day#1#2#3AveragePercentage
00,2850,2580,2950,279100,0
30,2800,2750,2750,27799,0
60,2850,2730,2700,27698,7
100,2740,2760,2760,27598,4
130,2730,2870,2780,279100,0
170,2780,2760,2700,27598,3
200,2610,2750,2610,26695,0
240,2670,2740,2920,27799,3
Leu
Day#1#2#3AveragePercentage
00,495 0,4670,5350,499100,0
30,5100,4950,4940,500100,1
60,4890,4790,4840,48497,0
100,4860,4900,4990,49298,5
130,4920,5090,5080,503100,8
170,5140,5080,5040,509100,9
200,4990,5000,4990,499101,1
240,4880,5090,5280,508101,9
Val
Day#1#2#3AveragePercentage
00,4830,4980,4810,487100,0
30,4920,4940,5260,504103,4
60,459value (0.475)0,4810,47296,8
100,5000,436to 0.4800,47296,9
130,464 0,4510,4740,46395,0
170,4070,4910,4620,45393,0
200,4710,5120,4770,48799,9
240,4710,4760,4580,46896,1
Sol
Day#1#2#3AveragePercentage
00,3410,3510,3600,351100,0
30,3420,3860,371 0,366104,5
60,3160,3210,3420,326br93.1
100,3410,2990,3350,325of 92.7
130,3550,3260,3500,34498,0
170,3340,3760,3530,354101,0
200,3470,3980,3940,380108,3
240,4160,3530,3780,382109,0
UDCA
Day#1#2#3AveragePercentage
00,4070,4040,4040,405100,0
30,4090,4020,4030,40599,9
60,4100,4030,4090,407100,6
100,4040,4050,4070,405100,1
130,4080,4030,3950,40299,3
170,4110,4020,4040,40600,2
200,4050,3940,3960,39898,4
240,3990,4080,4060,40499,9
Table 3D
The stability of UDCA solution in accordance with example IV at pH 7, 50°
IIe
Day#1#2#3AveragePercentage
00,2960,2890,2810,289100,0
50,3000,2820,281in 0.28899,7
80,2770,282 0,2680,27695,5
120,2730,2780,2780,27795,8
150,2710,2730,2660,27093,5
190,2940,2850,2810,28799,3
Leu
Day#1#2#3AveragePercentage
00,5190,5130,4950,509100,0
50,4990,4990,4980,49897,9
80,4980,513to 0.4800,497 97,7
120,5080,5160,5150,513100,9
150,503worn : 0.5050,4990,50298,7
190,5210,5090,5160,515101,3
Val
Day#1#2#3AveragePercentage
00,4830,5300,5250,513100,0
50,5020,4470,4990,48394,1
80,4880,4980,4930,49396,2
120,4900,4690,4430,46791,2
150,4920,5410,4420,49295,9
190,4580,5000,482to 0.48093,6
Sol
Day#1#2#3AveragePercentage
0of 0.3330,3520,3630,349100,0
50,3440,3090,3490,33495,6
80,3340,379 0,3770,363104,0
120,3450,344MX 0.3170,33596,0
150,2860,4060,3210,33896,7
190,3380,4160,3510,368105,4
UDCA
Day#1#2#3AveragePercentage
00,4270,4160,4280,424100,0
50,4060,4270,4320,42299,4
80,4190,4080,4170,41497,7
120,4140,4180,4190,41798,4
150,4130,4180,4090,41497,5
190,4290,4210,4240,425100,1
Table 3E
The stability of the solution with UDCA accordance with example IV,at pH 9, 50°
IIe
Day#1#2#3AveragePercentage
00,2910,2860,2820,286 100,0
30,2660,2730,2820,27395,6
60,2770,2740,2720,27495,9
100,2430,2450,2950,26191,2
130,2460,2690,2360,25087,4
170,2750,2800,2450,267br93.1
Leu
Day#1#2#3AveragePercentage
0 0,5090,5130,5110,511100,0
30,4850,4870,4920,48895,5
60,4950,4960,4920,49496,8
100,4700,4670,5280,48895,6
130,4610,4910,4500,46791,5
170,4680,5160,5000,49596,9
Val
Day#1#2 #3AveragePercentage
00,5080,4760,4840,489100,0
30,4630,4870,4850,478of 97.8
60,4930,4730,4950,48799,5
100,4410,4280,4710,447for 91.3
130,4670,4830,5370,496101,8
170,4990,4950,5010,498101,8
Sol
Day#1 #2#3AveragePercentage
00,3410,3160,3280,328100,0
30,297MX 0.317MX 0.3170,31094,5
60,3130,2910,3140,30693,2
100,2680,2530,3240,28285,8
130,2700,2660,3340,29088,3
17of 0.3370,329MX 0.3170,32899,8
UDCA
Day #1#2#3AveragePercentage
00,3890,3850,3890,388100,0
30,4050,4000,3940,400103,2
60,4270,4110,4160,418107,9
100,4200,4180,4500,429110,8
130,4650,4340,4410,447115,3
170,4540,4570,4130,441113,9

td align="center"> #3
Table 3F
V. the mobility of UDCA solution in accordance with example IV at pH 10, 50°
IIe
Day#1#2#3AveragePercentage
00,2920,2820,2870,287100,0
20,2530,2370,2390,24384,7
50,2210,2120,2210,21876,0
70,2190,2150,2070,21474,5
90,2060,1920,2070,202to 70.2
Leu
Day#1#2#3AveragePercentage
00,5070,4950,5090,504100,0
20,4620,4420,4420,449of 89.1
50,4290,4280,4270,42885,0
70,4100,4170,4140,41482,1
90,4170,3770,4180,404an 80.2
Val
Day#1#2AveragePercentage
0to 0.4800,5060,4710,486100,0
20,5360,4780,5040,506104,2
50,3710,4450,4000,405to 83.5
70,3840,3840,4240,39781,8
90,3890,3540,3620,36875,8
Sol
Day#1#2#3AveragePercentage
00,3680,3760,3310,358100,0
20,284 0,2570,2660,26975,1
50,0530,2170,1920,15443,0
70,0420,0260,1560,07520,8
90,0330,0190,0230,0257,0
UDCA
Day#1#2#3AveragePercentage
00,4160,4020,4060,408100,0
20,4020,3970,4000,39997,9
50,425 0,4130,4230,420103,0
70,4060,4020,4080,40699,4
90,4240,4260,4210,423to 103.8

Example V

Dosage forms in the form of solutions, which were obtained in accordance with the following compounds do not exhibit any precipitation at any pH within a selected, desired range. This composition is based on the known analytical data for pharmaceutical use bile acids.

Taypo-UDCA7 g
Taypo-CDCA1 g
Glyco-UDCA0.8 g
Glyco-CDCA0.2 g
Soluble UDCA1 g
(or 3 g as free form)
Water-soluble product of the transformation of starch250 g
Sweeteneras needed
Corrigenthow much need is about
Purified waterto 2.0 l

Soluble UDCA is dissolved in water and then add having a high molecular weight water-soluble product of the transformation of starch and water. The resulting clear solution add the Tauro-UDCA, Tauro-CDCA, Glyco-UDCA, Glyco-CDCA, sweetener and corrigent. Purified water is added to regulate the total volume to 2.0 liters

Example VI

Dosage forms in the form of aqueous solutions in accordance with this invention, containing 200 mg of ursodeoxycholic acid (UDCA), obtained by the method described in the above example III, and introduced three healthy men with normal weight after fasting. Levels of UDCA and Glyco-UDCA in the blood were assessed using well-known chemical methods. After the introduction of the buffered serum in column sep-pak methanol eluate was derivateservlet penacerrada at 80°C for 45 minutes. These derivatives penacerrada was dissolved in acetonitrile in preparation for HPLC. Experimental results of absorption, measured over some period of time after the dosed introduction, include the total absorption, expressed as area under the curve concentration in serum-time (AUC: ág/ml×hours), the maximum blood concentration (Cmax; μg/ml), which was received, and the time (Tax ; h), which was obtained the maximum concentration. These results are given in table 4, figures 1 and 2.

Experimental pharmacokinetic testing of dosage forms in the form of aqueous solutions according to this invention, carried out on men, showed significant improvements in AUS, Cmaxand Tmaxcompared with the best results of any pharmaceutical form known to the present time. The maximum concentration in the blood (Cmaxtable 4 shows the average value 8,43±1,69 µg/ml, which is at least two times higher than the maximum concentration specified when using drugs sodium salt of UDCA with intersolubility shell, and four times higher than the maximum concentration obtained using conventional drugs UDCA in the form of tablets. In addition, the time of peak concentration (Tmax), which is closely linked to the speed of absorption of UDCA dosage forms in aqueous solution, 0.25 hour at least three times faster than the fastest previously known Tmax.

In table 4A and table 4B shows the concentration of plasma UDCA and GUDCA, measured in 3 men over time after oral administration containing UDCA and GUDCA ready preparative forms in accordance with example VI, and comparing the results with financial p the tatami used by various other pharmaceutical finished preparative forms of UDCA.

Table 5 shows the pharmacokinetic parameters of UDCA in humans after oral administration of liquid ready preparative forms of UDCA. Shown Cmax.

Taken together, the data in tables 4 and 5 and figures 3 and 4 illustrate the superiority ready preparative forms of the present invention relative to conventional ready preparative forms in relation Withmaxand Tmax. The solutions of the present invention acted without any destruction system solution caused the pH environment in the stomach and intestines. therapeutic potential of bile acids and possibly even added pharmaceuticals can more fully be implemented using ready preparative forms of the invention. When therapeutically active ingredients in the form of aqueous solutions is not deposited in the form of solids under the action of the acid gastric juice in the stomach and under the influence of various alkaline pH of the intestine, the drug overcomes as a natural consequence of insufficient bioavailability resulting from unexpected and unwanted results for the degree and speed of release of disintegration, dissolution and/or diffusion, which must be overcome.

0,772
Table 4A
The concentration of UDCA and GUDCA in plasma after oral administration of the drug of the present invention at the dose of 200 mg three men
UDCAGUDCA
Time (hour)#1#2#3average#1#2#3average
0,255,120210,91719,1598,43±1,690,14190,45490,33280,31±0,09
0,54,452S7,74327,43956,55±1,050,25641,24550,8640,79±0,29
11,69211,5460,21631,15±0,470,21620,69260,21420,37±0,16
1,5 0,52560,2759has 0.1680,32±0,111,15730,19290,47520,61±0,29
20,23490,21760,12270,19±0,030,40130,03120,06570,17±0,12
30,1237N,D0,20740,17±0,040,50850,43030,33150,42±0,05
51,92050,02291,63111,18±0,61
70,53280,47970,910,64±0,14
AUC (ug•h/ml)4,326,65,475,46±0,666,262,224,65of 4.38±1,17
Cmax< / br>
(ág/ml)
to 5.2110,929,168,43±1,691,921,251,631,6
Tmax(h)0,250,250,250,2550,553,5±1,5
Table 4B
Pharmacokinetic parameters of UDCA in humans after oral administration UDCA (M±S.O.)
Withmax(ág/ml)Tmax(h)
Roda et al. (1994)
Gelatin capsule UDCA, 450 mg2,59 the 3.8
Gelatin capsule NaUDC, 475 mg3,422,4
NaUDC with intersolubility shell, 475 mg103,4
Nagamatsu et al. (1997)
UDCA 200 mg1,9±0,251,5±0,4
UDCA 400 mg7,09±1,430,8±0,2
UDCA in this invention, 200 mg8,43±1,690,25
Table 5A
Pharmacokinetic parameter (Cmax) UDCA in humans after oral administration of a liquid solution containing 600 mg of UDCA on the day
Time (min)Individual #1Individual #2Individual #3Individual #4Individual #5averageThe study of the production.
0 0,351,630,400,000,710,6180,619
5of 2.519,791,682,656,264,5783,405
1512,50to 47.46to 8.3411,8421,8320,39415,933
609,726,46to 7.779,8117,2510,2024,183
120of 3.771,711,401,152,812,1681,097
2400,650,930,500,481,300,346
Table 5B
Pharmacokinetic parameter (Cmax) UDCA in humans after oral administration of syrup containing 600 mg of UDCA on the day
Time (min)Individual #1Individual #2Individual #3Individual #4Individual #5AverageThe study of the production.
00,620,580,380,000,410,3980,246
5was 2.762,630,831,422,241,9760,827
157,80of 4.453,545,8514,087,1444,197
6016,08 20,338,7612,0617,7715,0004,605
1203,984,245,097,793,004,8201,820
2400,810,991,471,851,17amount of 1, 2580,411

Example VII

Dosage forms in the form of solutions, which were obtained in accordance with the following compounds do not exhibit any precipitation at any pH within a selected required range.

Soluble UDCA0.2 g (0.05 to 2 g
free acid)
Dried powder of liquid glucose
(commercial solid
corn syrup)20 g (3 g 120 g)
Soluble necromancy polysaccharide
(carob gum is AREVA or
pectin, etc.)0.01 g (0.001 g-0.05 g)
Purified water to obtain100 ml

Received 85 ml of an aqueous solution in which the dissolved soluble UDCA, and then the clear solution was added a mixture of dried powder of liquid glucose, high molecular weight water-soluble product of the transformation of starch and soluble non-starch polysaccharide (carob bean gum, pectin, etc.). Purified water was added to regulate the total volume to 100 ml.

Example VIII: Solution mixture

The compositions of examples VIII, IX and X include bismuth sulfate. In each of these examples of the dosage form in the form of a solution was obtained by adding the quantity of ammonium salt of bismuth sulfate, sufficient to provide a specified number of bismuth.

Dosage forms in the form of solutions, which were obtained in accordance with the following formulations did not show any precipitation at any pH within a selected required range.

UDCA5 g
CDCA5 g
Citrate of bismuth5 g
Solid corn syrup260 g
Citric acidas bhodemon
Purified water to obtain1.0 l

UDCA and CDCA were first dissolved in 1.5 ml 1 n NaOH solution. Then in the resulting clear solution was added bismuth citrate and 150 ml of water. Then portions with vigorous stirring was added solid corn syrup. The resulting solution was titrated with citric acid to pH 4. Purified water was added to establish the total volume of 1.0 L.

Example IX: Syrup UDCA (20 g UDCA/l)

Dosage forms in the form of solutions, which were obtained in accordance with the following formulations did not show any precipitation at any pH within a selected required range.

UDCA20 g
1 N. NaOH60 ml
Maltodextrin700 g
Citrate of bismuth4 g
Citric acid or lactic acidas needed
Purified water to obtain1.0 l

First UDCA was dissolved in 60 ml of 1 n NaOH solution. Then to the resulting clear solution was added bismuth sulfate and 150 ml of water. Then in portions with vigorous stirring was added maltodextrin. The resulting solution was titrated with citric acid to pH 3.5. Cleaned up the Yu water was added to establish the total volume of 1.0 L.

Example X: Syrup UDCA (20 g UDCA/l)

Dosage forms in the form of solutions, which were obtained in accordance with the following formulations did not show any precipitation at any pH within a selected required range.

UDCA20 g
1 N. NaOH60 ml
Solid corn syrup1050 g
Citrate of bismuth4 g
Citric acid or lactic acidas needed
Purified water to obtain1 l

First UDCA was dissolved in 60 ml of 1 n NaOH solution. Then to the resulting transparent solution was added sulfate bismuth and 280 ml of water. Then in portions with vigorous stirring was added 1050 g solids corn syrup. The resulting solution was titrated with citric acid to pH 3.5. Purified water was added to establish the total volume of 1.0 L.

Example XI: Thick syrup UDCA (30 g of UDCA/l)

Dosage forms in the form of solutions, which were obtained in accordance with the following formulations did not show any precipitation at any pH within a selected required range.

UDCA30 g
1H. NaOH90 ml
Maltodextrin1050 g
Citric acid or lactic acid50 g
Purified water to obtain1.0 l

First UDCA was dissolved in 90 ml of 1 n NaOH solution. Then to the resulting clear solution was added bismuth sulfate and 250 ml of water. Then in portions with vigorous stirring was added 1050 g of maltodextrine. The resulting solution was titrated to pH 3 by adding 50 g of citric acid. Purified water was added to establish the total volume of 1.0 L.

Example XII: Thick syrup UDCA (30 g of UDCA/l)

Dosage forms in the form of solutions, which were obtained in accordance with the following recipes, did not show any precipitation at any pH within a selected required range.

UDCA30 g
1 N. NaOH90 ml
Solid corn starch1500 g
Citric acid or lactic acid50 g
Purified water to obtain1.0 l

First UDCA was dissolved in 90 ml of 1 n NaOH solution. Then to the resulting transparent solution was added sulfate bismuth and 230 ml of water. Then in the form of portions when the energy is nom stirring was added 1500 g of solids of corn starch. The resulting solution was titrated to pH 3 by adding 50 g of citric acid. Purified water was added to establish the total volume of 1.0 L.

Example XIII: Pasta UDCA (45 g UDCA/l)

The preparations of examples XIII, XIV, XV and XVI included bismuth citrate. In each of these examples of the dosage form in the form of solutions was obtained by adding the quantity of ammonium salt of bismuth citrate, sufficient to provide a specified number of bismuth citrate.

Dosage forms in the form of solutions, which were obtained in accordance with the following formulations did not show any precipitation at any pH within a selected required range.

UDCA45 g
1 N. NaOH135 ml
Maltodextrin1575
Citrate of bismuth10 g
Citric acid or lactic acidas needed
Purified water to obtain1.0 l

First UDCA was dissolved in 135 ml of 1 n NaOH solution. Then to the resulting transparent solution was added bismuth citrate and 200 ml of water. Then in portions with vigorous stirring was added 1575 g of maltodextrine. The resulting solution was titrated to pH 3 by the addition of citric acid. Cleaned the ode was added to establish the total volume of 1.0 L.

Five people were supplied dosage forms obtained according to this example. The results are shown in tables 5A and 5B and are presented graphically in figure 3 and 4. Comparison of acute peak 3 with a broad peak in figure 4 indicates that by adjusting the dosage form, the practitioner can manipulate with Cmaxand Tmaxbile acids.

.pylori were cultured in the medium Columbia Bood Agar Base (CRAB)containing the product of example IX. Received a Cup with 2 l of CRAB, which consisted of 9.9 g CRAB, and 9.1 g of agar with tripticase soybeans, 50 ml of the blood of sheep, vancomycin, amphotericin b, polymyxin B, 2 ml of the preparation of example IX and 358 ml of distilled water. After microaerophilic cultivation from 48 to 72 hours the bacteria were fixed using the Karnovsky fixative and embedded in Epone. Electron micrographs of cells .pylori shown in Fig. from 5A to 5C.

Example XIV: Pasta UDCA (45 g UDCA/l)

Dosage forms in the form of solutions, which were obtained in accordance with the following formulations did not show any precipitation at any pH within a selected required range.

UDCA45 g
1 N. NaOH135 ml
Solid corn syrup2300 g
Citric acid or lactic acid is 50 g
Purified water to obtain1.0 l

First UDCA was dissolved in 135 ml of 1 n NaOH solution. Then to the resulting transparent solution was added bismuth citrate and 150 ml of water. Then in portions with vigorous stirring was added 2300 g solids corn syrup. The resulting solution was titrated to pH 3 by the addition of citric acid. Purified water was added to establish the total volume of 1.0 L.

Example XV: Solution mixture UDCA (22 g) and CDCA (3 g)

Dosage forms in the form of solutions, which were obtained in accordance with the following formulations did not show any precipitation at any pH within a selected required range.

UDCA22 g
1 N. NaOH75 ml
CDCA3 g
Maltodextrin875
Citrate of bismuth4 g
Citric acid or lactic acidas needed.
Purified water to obtain1.0 l

First was dissolved UDCA and CDCA in 75 ml of 1 n NaOH solution. Then to the resulting transparent solution was added to the citrate of bismuth and 240 ml of water. Then in portions with vigorous stirring, we use the and 875 g of maltodextrine. The resulting solution was titrated to pH 3 by the addition of citric acid. Purified water was added to establish the total volume of 1.0 L.

Example XVI: Solution mixture UDCA (22 g) and CDCA (3 g)

Dosage forms in the form of solutions, which were obtained in accordance with the following formulations did not show any precipitation at any pH within a selected required range.

UDCA22 g
1 N. NaOH75 ml
CDCA3 g
Solid corn syrup1320
Citrate of bismuth4 g
Citric acid or lactic acidas needed
Purified water to obtain1.0 l

First was dissolved UDCA and CDCA in 75 ml of 1 n NaOH solution. Then to the resulting transparent solution was added to the citrate of bismuth and 240 ml of water. Then in portions with vigorous stirring was added 1320 solids corn syrup. The resulting solution was titrated to pH 3 by the addition of citric acid. Purified water was added to establish the total volume of 1.0 L.

Example XVII

Was influenced by the handling of infected .pylori mice dosage form in the form of a solution of this image is etenia. Female mice C57BL/6 age six weeks were infected by feeding food, including 109CFU/ml of strain SS1 .pylori. The mouse ate this food twice with an interval feeding for one week. Then four infected animals were injected with 0.2 ml of the dosage form in the form of a solution in accordance with example VIII once a day for one week. Two dogs were killed one week after the last dose of the solution of the invention. The remaining two dogs were killed four weeks after the last dose of the solution of the invention. All stomachs were washed with saturated salt solution to remove the mucosa and debris. A sample of tissue of the stomach of each animal was tested CLO using the kit for rapid urease test (Delta West, Australia). Each remaining after washing the stomach was fixed with 10% formalin solution and were filled with wax. Histological sections (4 µm thick) were collected on glass slides and were stained with staining solution H&e, and the dye solution Warthin. The fabric was evaluated for pathological condition conventional microscopy.

The results, summarized in table 6, show that the results of the test for urease were negative for mice, which was held one week after termination of the introduction of liquid dosage forms, and .pylori was not detected by the Yong in the analysis Warthin. Of the other two mice, one showed a negative test for urease and was not seen .pylori in the analysis Warthin. Another, however, showed a positive test for urease, although only a few .pylori was seen in the analysis of Warthin.

Table 6
The number of weeks after treatmentAnimalTest for ureaseAnalysis of Warthin
11NegativeThe Absence Of N. pylori
12NegativeThe Absence Of N. pylori
43NegativeThe Absence Of N. pylori
44PositiveSeveral N. pylori

Example XVIII

Conducted analysis of the growth of N. pylori on the medium with UDCA, or citrate of bismuth, or as UDCA, and bismuth citrate. For these analyses used the following environment:

V-1 with pH 4.0 and includes 525 g/l maltodextrin and 15 g/l UDCA.

OSABY having a pH of 3.7 and containing 1 kg/l solids corn syrup and 6 g/l of bismuth citrate.

These analyses were performed to assess the ability of growth N. pylori in the presence of UDCA, bismuth, or both, and pH, concentration and duration were varied.

. Helicobacter pylori suspended in physiological saline to obtain the content of the organisms of about 109per milliliter. 50 μl of this inoculum was transferred into tubes containing 1 ml of citrate-phosphate buffer at pH 3.0, 4.0 and a 4.5. Paired tubes were received from 6 mm urea and without it. After incubation for 30 minutes at room temperature the suspension was perseval on agar plates containing V-1, using 1 µl loop. The cups were incubated in microaerophilic conditions at 37°C for 72 hours. This procedure is illustrated in Fig.9.

As shown in table 7, N. pylori grew poorly on a test environment with pH 3 and pH 4. Table 7 also shows that N. pylori did not grow in the medium with pH 3 and pH 4, containing UDCA. The designation "3 ml", "4 ml and 5 ml" refers to the total environment V-1 per Cup. "PBS is phosphate buffered saline at pH 7.0.

Table 7
Test for urease
CuppHUrea1-210 min2 hours20 h
Control3,0There

No
FO

FO
FO

FO
O

0
< / br>
0
4,0There

No
FO

FO
FO

FO
O

O
O

P
4,5There

No
FP

FO
FP

O
P

FP
P

P
PBSThere

No
O

O
FP

FP
P

P
P

P
V-1 (3 ml)3,0There

No
Y

Y
Y

Y
Y

Y
Y

Y
4,0There

No
Y

Y
Y

Y
FO

Y
O

FO
4,5There

No
FP

FP
FP

FP
P

P
P

P
V-1 (4 ml)3,0There

No
Y

Y
Y

Y
Y

Y
Y

Y
4,0There

No
Y

Y
Y

Y
Y

FO
FO

FO
4,5There

No
FP

FP
FP

FP
P

FP
P

P
V-1 (5 ml)3,0There

No
Y

Y
Y

Y
Y

Y
Y

Y
4,0There

No
Y

Y
Y

Y
FO

Y
FO

Y
4,5There

No
FP

FP
FP

FP
P

P
P

P

Explanation of table 7
YFOOFPP
ColorYellowLight orangeOrangeLight pinkPink
HelicobacterNoVery littleLittleA lot

2. Helicobacter pylori suspended in physiological saline to obtain the content of the organisms of about 109per milliliter. 50 μl of this inoculum was transferred into tubes containing 1 ml of citrate-phosphate buffer at various concentrations environment for Petri dishes, such as 1/10, 1/30, 1/50, 1/100, 1/200, 1/500, 1/800, 1/1000, 1/2000. All test tubes were obtained with 6 ml of urea. After incubation for 30 minutes at room the things the temperature of the suspension was perseval on agar plates using a 1 µl loop. These cups are essentially did not contain bismuth and bile acids. The cups were incubated in microaerophilic conditions at 37°C for 72 hours. This procedure is illustrated in figure 10.

Table 8 shows the results of the urease test after 72 hours of growth N. pylori in products obtained with dilutions UDCA (V-1), or bismuth citrate (OSABY), or as UDCA, and bismuth citrate. Observed poor growth N. pylori on media containing either UDCA or citrate of bismuth (table 8). The Growth Of N. pylori was further weakened when the cultivation was carried out on media containing both UDCA and bismuth citrate (table 8).

Table 8
CupTest for urease
Immediately10 min30 min60 min
W-1
ControlPPPP
1/10YFP PP
1/30YFPPP
1/50YFPPP
1/100YFPPP
1/200YFPPP
1/500YFPPP
1/800FPPPP
1/1000FPPPP
1/2000FPPPP
OSABY
ControlPPPP
1/10YFPPP
1/30YFPPP
1/50YFPPP
1/100FPFPPP
1/200FPFPPP
1/500FPFPPP
1/800FPPP P
1/1000FPPPP
1/2000FPPPP
V-1 + OSABY
ControlPPPP
1/10YFPFPFP
1/50YYYY
1/100YYYY
1/500YFPFPFP
1/1000Y FPPP
Explanation of table 8
YFOOFPP
ColorYellowLight orangeOrangeLight pinkPink
HelicobacterNoVery littleLittleA lot

3. Helicobacter pylori suspended in physiological saline to obtain the content of the organisms of about 109per milliliter. 50 μl of this inoculum was transferred into tubes containing 1 ml of citrate-phosphate buffer at various concentrations, such as 1/2, 1/4 and 1/10, and incubated for 15 minutes, 1/2, 1/4 and 1,10 and incubated for 30 minutes and 1/2, 1.4 and 1/10, and incubated for 45 minutes. Paired tubes were inoculable with 6 mm urea or without it. After incubation for 30 minutes at room temperature the suspension was perseval on cups with agar medium, with the use of 1 µl loop. These cups are essentially did not contain bismuth and bile acids. The Cup cu is Aravali in microaerophilic conditions at 37° With within 72 hours. This procedure is illustrated in figure 11.

The table shows the test results of the urease after 72 hours of growth N. pylori on the environment, obtained by dilution of UDCA (000112B-1), or citrate of bismuth, or as UDCA, and bismuth. As indicated, longer times of exposure caused an increase in the negative effects of solutions on N. pylori.

td align="center"> Y
Table 9
DilutionTime of incubation (min)The urease test (min)
13060120240
000112B-1
ControlPPPPP
1/215YYYYY
30YYYYY
45YYYYY
1/415YFOFPP P
30YYFOFOFO
45YYYYY
1/1015YFOFOFOFO
30YFOFO0P
45YYYFOFO
OSABY
ControlPPPPP
1/215YYYYY
30YYYYY
45YYYYY
1/415YYYYY
30YYYYY
45 YYYYY
1/1015YFOFOFOP
30YYYYY
45YYYYY
V-1 + OSABY
ControlPPPPP
1/215YYYYY
30YYYYY
45YYYYY
1/415YYYYY
30YYYYY
45YYYYY
1/1015YYFOFO
30YFOFOFOP
45YYYYY

1. The way to increase enterohepatic bile acids, including:

(a) the introduction of a transparent aqueous solution containing:

(i) a first material selected from the group consisting of bile acids, water-soluble derivative of a bile acid, salts of bile acids, bile acid conjugated with an amine by an amide bond, and combinations thereof;

(ii) a second material selected from the group consisting of water-soluble product of the transformation of starch and/or water-soluble non-starch polysaccharide, and

(iii) water,

moreover, the number of the first and second material are selected so that they both remain in solution for all values of the selected pH range.

2. The method according to claim 1, characterized in that the transparent aqueous solution selected from the group consisting of syrup and heavy syrup.

3. The method according to claim 1, characterized in that the first material is chosen from the group consisting of ursodeoxycholic acid, chenodeoxycholic acid, holeva acid, hyodesoxycholic acid, toxicology acid, 7-oxalidaceae acid, lithocholic acid, iodetachdevice acid, ikolaos acid, tauroursodeoxycholic acid, taurochenodeoxycholate acid, taurodeoxycholic acid, glycosidically acid, human beings need it to acid, glycocholic acid, their derivatives have a hydroxyl or carboxylic acid group on the steroid ring, their salts or their conjugates with amines.

4. The method according to claim 1, characterized in that the second material is chosen from the group consisting of maltodextrin, dextrin, corn syrup solids corn syrup, soluble starch and dextrans.

5. The method according to claim 1, characterized in that the transparent aqueous solution contains one or more additional bile acids, water-soluble derivatives of bile acids, bile salts and bile acid conjugated with an amine by an amide bond.

6. The method according to claim 1, characterized in that the transparent aqueous solution further comprises polyvinyl alcohol or povidone.

7. The method according to claim 1, characterized in that necromancy polysaccharide selected from the group consisting of gum carob, pectin, Arabic gum, Cartagena, sodium salt of carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, methylcellulose, tragacanth gum, xanthan gum and complex ester is orbitone.

8. The method of increasing the concentration of bile acid in the blood, providing

(a) the introduction of a transparent aqueous solution containing:

(i) a first material selected from the group consisting of bile acids, water-soluble derivative of a bile acid, salts of bile acids, bile acid conjugated with an amine by an amide bond, and combinations thereof;

(ii) a second material selected from the group consisting of water-soluble product of the transformation of starch or water-soluble non-starch polysaccharide, and

(iii) water,

moreover, the number of the first and second material are selected so that they both remain in solution for all values of the selected pH range.

9. The method according to claim 8, characterized in that the transparent aqueous solution selected from the group consisting of syrup and heavy syrup.

10. The method of claim 8, wherein the first material is selected from the group consisting of ursodeoxycholic acid, chenodeoxycholic acid, holeva acid, hyodesoxycholic acid, deoxycholic acid, 7-oxalidaceae acid, lithocholic acid, iodetachdevice acid, ikolaos acid, tauroursodeoxycholic acid, taurochenodeoxycholate acid, taurodeoxycholic acid, glycosidically acid, human beings need it to acid, nicholaou acid, their derivatives have a hydroxyl or carboxylic acid group on the steroid ring, their salts or their conjugates with amines.

11. The method of claim 8, wherein the second material is chosen from the group consisting of maltodextrin, dextrin, corn syrup solids corn syrup, soluble starch and dextrans.

12. The method according to claim 8, characterized in that the transparent aqueous solution contains one or more additional bile acids, water-soluble derivatives of bile acids, bile salts and bile acid conjugated with an amine by an amide bond.

13. The method according to claim 8, characterized in that the transparent aqueous solution further comprises polyvinyl alcohol or povidone.

14. The method according to claim 8, characterized in that necromancy polysaccharide selected from the group consisting of gum carob, pectin, Arabic gum, Cartagena, sodium salt of carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, methylcellulose, tragacanth gum, xanthan gum and complex ester sorbitan.

15. The way to achieve maximum concentration in serum bile acids (Cmax) from 4.5 to 20.4 ág/ml in less than 30 minutes, including:

(a) the introduction of a transparent aqueous solution containing:

(i) a first material selected from a group is s, consisting of bile acids, water-soluble derivative of a bile acid, salts of bile acids, bile acid conjugated with an amine by an amide bond, and combinations thereof;

(ii) a second material selected from the group consisting of water-soluble product of the transformation of starch and/or water-soluble non-starch polysaccharide, and

(iii) water,

moreover, the number of the first and second material are selected so that they both remain in solution for all values of the selected pH range.

16. The method according to item 15, wherein the transparent aqueous solution selected from the group consisting of syrup and heavy syrup.

17. The method according to item 15, wherein the first material is selected from the group consisting of ursodeoxycholic acid, derivatives of ursodeoxycholic acid the hydroxyl or carboxylic acid group on the steroid ring, salts of ursodeoxycholic acid and conjugates of ursodeoxycholic acid with amines.

18. The method according to item 15, wherein the second material is chosen from the group consisting of maltodextrin, dextrin, corn syrup solids corn syrup, soluble starch and dextrans.

19. The method according to item 15, wherein the transparent aqueous solution contains one or more additional bile acids, motorstv the action of derivatives of bile acids, salts of bile acids and bile acid conjugated with an amine by an amide bond.

20. The method according to item 15, wherein the transparent aqueous solution further comprises polyvinyl alcohol or povidone.

21. The method according to item 15, wherein necromancy polysaccharide selected from the group consisting of gum carob, pectin, Arabic gum, Cartagena, sodium salt karboksimetilcelljulozy, hydroxymethylcellulose, hydroxypropylcellulose, methylcellulose, tragacanth gum, xanthan gum and complex ester sorbitan.

22. The method according to item 15, wherein the transparent aqueous solution additionally contains at least one pharmaceutical compound in a pharmaceutically effective amount.

23. The method according to item 22, wherein the drug compound is chosen from the group consisting of octreotide, sildenafil citrate calcitriol, dihydrotachysterol, apomorphine, yohimbine, trazodone, acyclovir, cidofovir, delavirdine-nelfinavir and didanosine, famciclovir, foscarnet sodium, fluorouracil, ganciclovir sodium, idoxuridine, interferon-α,-β,-γ, lamivudine, nevirapine, penciclovir, ribavirin, stavudine, trifluridine, valacyclovir-HCI, zalcitabine, zidovudine, indinavir-H2SO4, ritonavir, nelfinavir-CH3SO3N, saquinavir-CH3 SO3N, d-penitsillamin, chloroquine, of hydroxychloroquine, aurothioglucose, mixed thiomalate of gold and sodium, auranofin of levamisole, dacarbazine, groups, monophosphate of methylinosine, muramyldipeptide, diazoxide, hydralazine-HCl, Minoxidil, dipyridamole, isoxsuprine-HCl, Niacin, nylidrin-HCl, fentolamina, doxazosin-CH3SO3N, prazosin-HCl, terazosin-HCl, clonidine-HCl, nifedipine, molsidomine, amiodarone, acetylsalicylic acid, verapamil, diltiazem, nisoldipine, isradipine, bepridil, isosorbide-dinitrate, pentaerythritol-TETRANITRATE, nitroglycerin, cimetidine, famotidine, nizatidine, ranitidine, lansoprazole, omeprazole, misoprostol, sukralfat, metoclopramide HCl, erythromycin, alprostadil, albuterol, pirbuterol, terbutaline-N1SO4, salmetrol, aminophylline, dyphylline, ephedrine, Ethylmorphine, isoetharine, isoproterenol, metaproterenol, nedocromil, oxtriphylline, theophylline, bitolterol, fenoterola, budezonida, flunisolide, beclomethasone-dipropionate, fluticasone-propionate, codeine, codeine sulfate, codeine phosphate, dextromethorphan NVG, triamcinolone-acetonide, montelukast sodium, zafirlukast, zileuton, kromolin sodium, ipratropium bromide, nedocromil sodium, benzoate, diphenhydramine-HCl, hydrocodone-bitartrate, methadone-HCl, martinslife, acetylcysteine, g is Aventina, of ammonium carbonate, ammonium chloride, mixed tartrate of antimony and potassium, glycerol, Turpin hydrate, colfosceril palmitate, atorvastatin calcium, cerivastatin-sodium, fluvastatin sodium, lovastatin, pravastatin sodium, simvastatin, picrorrhazia kurroa, andrographis paniculata, moringa oleifera, albizzia lebeck, adhatona vasica, curcuma longa, momordica charantia, gymnema sylvestre, terminalia arjuna, azadirachta indica, tinosporia cordifolia, metronidazole, amphotericin b, clotrimazole, fluconazole, haloprogin, ketoconazole, grizeofulvina, Itraconazole, terbinafine-HCl, econazole-HNO3, miconazole, nystatin, oxiconazole-HNO3sulconazole-HNO3, cetirizine-2hcl, dexamethasone, hydrocortisone, prednisolone, cortisone, catechin and its derivatives, glycyrrhizin, glycyrrhizinate acid, betamethasone, fludrocortisone-acetate, flunisolide, fluticasone-propionate, methylprednisolone, somatostatin, lispro, glucagon, acarbose, chlorpropamide, glipizide, gliburida, Metformin-HCl, Repaglinide, tolbutamide, colchicine, sulfinpirazon, allopurinol, piroxicam, tolmetin sodium, indomethacin, ibuprofen, diflunisal, mefenamovoy acid, naproxen, trientine, sulindaka, sulindac sulfone, selenium compounds, insulin, heparin, ampicillin, amantadine, rimantadine, proinsulin, celecoxib, budezonida, salicylic acid and its derivatives.

24. The way to increase the absorption and removal of W is lonoy acid, providing:

(a) the introduction of a transparent aqueous solution containing:

(i) a first material selected from the group consisting of bile acids, water-soluble derivative of a bile acid, salts of bile acids, bile acid conjugated with an amine by an amide bond, and combinations thereof;

(ii) a second material selected from the group consisting of water-soluble product of the transformation of starch and/or water-soluble non-starch polysaccharide, and

(iii) water,

moreover, the number of the first and second material are selected so that they both remain in solution for all values of the selected pH range.

25. The method according to paragraph 24, wherein the transparent aqueous solution selected from the group consisting of syrup and heavy syrup.

26. The method according to paragraph 24, wherein the first material is selected from the group consisting of ursodeoxycholic acid, chenodeoxycholic acid, holeva acid, hyodesoxycholic acid, deoxycholic acid, 7-oxalidaceae acid, lithocholic acid, iodetachdevice acid, ikolaos acid, tauroursodeoxycholic acid, taurochenodeoxycholate acid, taurodeoxycholic acid, glycosidically acid, human beings need it to acid, glycocholic acid, their derivatives have a hydroxyl or g is uppy carboxylic acid of the steroid ring, their salts or their conjugates with amines.

27. The method according to paragraph 24, wherein the second material is chosen from the group consisting of maltodextrin, dextrin, corn syrup solids corn syrup, soluble starch and dextrans.

28. The method according to paragraph 24, wherein the transparent aqueous solution contains one or more additional bile acids, water-soluble derivatives of bile acids, bile salts and bile acid conjugated with an amine by an amide bond.

29. The method according to paragraph 24, wherein the transparent aqueous solution further comprises polyvinyl alcohol or povidone.

30. The method according to paragraph 24, wherein necromancy polysaccharide selected from the group consisting of gum carob, pectin, Arabic gum, Cartagena, sodium salt of carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, methylcellulose, tragacanth gum, xanthan gum and complex ester sorbitan.

31. The method according to paragraph 24, wherein the transparent aqueous solution additionally contains at least one pharmaceutical compound in a pharmaceutically effective amount.

32. The method according to p, wherein the drug compound is chosen from the group consisting of octreotide, sildenafil citrate calcitriol, dihydro who histeria, apomorphine, yohimbine, trazodone, acyclovir, cidofovir, delavirdine-nelfinavir and didanosine, famciclovir, foscarnet sodium, fluorouracil, ganciclovir sodium, idoxuridine, interferon-α,-β,-γ, lamivudine, nevirapine, penciclovir, ribavirin, stavudine, trifluridine, valacyclovir-HCl, zalcitabine, zidovudine, indinavir-H2SO4, ritonavir, nelfinavir-CH3SO3N, saquinavir-CH3SO3N, d-penitsillamin, chloroquine, of hydroxychloroquine, aurothioglucose, mixed thiomalate of gold and sodium, auranofin of levamisole, dacarbazine, groups, monophosphate of methylinosine, muramyldipeptide, diazoxide, hydralazine-HCl, Minoxidil, dipyridamole, isoxsuprine-HCl, Niacin, nylidrin-HCl, fentolamina, doxazosin-CH3SO3N, prazosin-HCl, terazosin-HCl, clonidine-HCl, nifedipine, molsidomine, amiodarone, acetylsalicylic acid, verapamil, diltiazem, nisoldipine, isradipine, bepridil, isosorbide-dinitrate, pentaerythritol-TETRANITRATE, nitroglycerin, cimetidine, famotidine, nizatidine, ranitidine, lansoprazole, omeprazole, misoprostol, sukralfat, metoclopramide-HCl, erythromycin, alprostadil, albuterol, pirbuterol, terbutaline-H2SO4, salmetrol, aminophylline, dyphylline, ephedrine, Ethylmorphine, isoetharine, isoproterenol, metaproterenol, nedocromil, EXT ivilina, theophylline, bitolterol, fenoterola, budezonida, flunisolide, beclomethasone-dipropionate, fluticasone-propionate, codeine, codeine sulfate, codeine phosphate, dextromethorphan HBr, triamcinolone-acetonide, montelukast sodium, zafirlukast, zileuton, kromolin sodium, ipratropium bromide, nedocromil sodium, benzoate, diphenhydramine-HCl, hydrocodone-bitartrate, methadone-HCl, martinslife, acetylcysteine, guaifenesin, ammonium carbonate, ammonium chloride, mixed tartrate of antimony and potassium, glycerol, Turpin hydrate, colfosceril palmitate, atorvastatin calcium, cerivastatin-sodium, fluvastatin-sodium, lovastatin, pravastatin sodium, simvastatin, picrorrhazia kurroa, andrographis paniculata, moringa oleifera, albizzia lebeck, adhatona vasica, curcuma longa, momordica charantia, gymnema sylvestre, terminalia arjuna, azadirachta indica, tinosporia cordifolia, metronidazole, amphotericin b, clotrimazole, fluconazole, haloprogin, ketoconazole, grizeofulvina, Itraconazole, terbinafine-HCl, econazole-HNO3, miconazole, nystatin, oxiconazole-HNO3sulconazole-HNO3, cetirizine-2hcl, dexamethasone, hydrocortisone, prednisolone, cortisone, catechin and its derivatives, glycyrrhizin, glycyrrhizinate acid, betamethasone, fludrocortisone-acetate, flunisolide, fluticasone-propionate, methylprednisolone, somatostatin, lispro, glucagon, acarbose, chlorpropamide, glipizide, gliburida, Metformin-HCl, rap is Glinda, tolbutamide, colchicine, sulfinpirazon, allopurinol, piroxicam, tolmetin, sodium, indomethacin, ibuprofen, diflunisal, mefenamovoy acid, naproxen, trientine, sulindaka, sulindac sulfone, selenium compounds, insulin, heparin, ampicillin, amantadine, rimantadine, proinsulin, celecoxib, budezonida, salicylic acid and its derivatives.

33. Method for the treatment of gastritis and peptic ulcers, including:

(a) the introduction of a transparent aqueous solution containing:

(i) a first material selected from the group consisting of bile acids, water-soluble derivative of a bile acid, salts of bile acids, bile acid conjugated with an amine by an amide bond, and combinations thereof;

(ii) a second material selected from the group consisting of water-soluble product of the transformation of starch and water-soluble non-starch polysaccharide, and

(iii) water,

moreover, the number of the first and second material are selected so that they both remain in solution for all values of the selected pH range.

34. The method according to p, characterized in that the transparent aqueous solution selected from the group consisting of syrup and heavy syrup.

35. The method according to p, characterized in that the transparent aqueous solution additionally contains a compound of bismuth in the pharmacist is Cesky effective amount.

36. The method according to p, characterized in that the compound of bismuth contains a water-soluble product of the reaction between the bismuth ion and chelating agent.

37. The method according to p, wherein the chelating agent is selected from the group consisting of citric acid, tartaric acid, malic acid, lactic acid and agateway acids and alkalis.

38. The method according to clause 37, wherein the compound of bismuth selected from the group consisting of ammonium salts of bismuth sulfate, ammonium salt of bismuth citrate and mixed bismuth tartrate and sodium.

39. The method according to p, wherein the first material is selected from the group consisting of ursodeoxycholic acid, chenodeoxycholic acid, holeva acid, hyodesoxycholic acid, deoxycholic acid, 7-oxalidaceae acid, lithocholic acid, iodetachdevice acid, ikolaos acid, tauroursodeoxycholic acid, taurochenodeoxycholate acid, taurodeoxycholic acid, glycosidically acid, human beings need it to acid, glycocholic acid, their derivatives have a hydroxyl or carboxylic acid group on the steroid ring, their salts or their conjugates with amines.

40. The method according to p, characterized in that the second material is chosen from the group consisting of maltodextrin, dextrin, corn syrup, solids Cyr is PA corn, soluble starch and dextrans.

41. The method according to p, characterized in that the transparent aqueous solution contains one or more additional bile acids, water-soluble derivatives of bile acids, bile salts and bile acids, conjugated amide bond with the amine.

42. The method according to p, characterized in that the transparent aqueous solution further comprises polyvinyl alcohol or povidone.

43. The method according to p, characterized in that necromancy polysaccharide selected from the group consisting of gum carob, pectin, Arabic gum, Cartagena, sodium salt of carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, methylcellulose, tragacanth gum, xanthan gum and complex ester sorbitan.

44. The method according to p, characterized in that the transparent aqueous solution additionally contains at least one drug in a pharmaceutically effective amount.

45. The method according to item 44, wherein the drug is selected from the group consisting of antibiotics, antagonists of N2-receptor and Antiprotozoal drugs.

46. The method according to item 44, wherein the drug is selected from the group consisting of ampicillin, amoxicillin, cefaclor, cephalo-Smoking, azithromycin, clarithromy the ina, demeclocycline HCl, doxycycline, minocycline HCl, tetracycline, oxytetracycline, cimetidine, famotidine, nizatidine, ranitidine, skrapeta, metronidazole, atovaquone and of pentamidine isetionate.

47. Transparent aqueous solution containing:

(a) a first material selected from the group consisting of bile acids, water-soluble derivative of a bile acid, salts of bile acids and bile acid conjugated with an amine by an amide bond;

(b) a polysaccharide having at least one restoring end group and at least one non terminal group, and

(c) water,

moreover, the number of the first material and the polysaccharide pick up so that they both remain in solution for all values of the selected pH range.



 

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13 cl

FIELD: medicine, oncology, biology.

SUBSTANCE: method involves per os administration of the preparation "oligokhit activ" to a cancer carrier in the dose 20-24 mg/kg of weight for 7 days, not less. Method provides elimination of dystrophic changes in hepatocytes caused by metabolic disturbances in body of a cancer carrier, to improve proliferative activity of hepatocytes and to recover microcirculation.

EFFECT: improved correction method.

1 tbl, 1 ex

FIELD: medicine, hepatology.

SUBSTANCE: invention relates to treatment of chronic hepatitis C. Method involves administration in a patient α2A-interferon modified with polyethylene glycol (PEG)(conjugate PEG-IFN-α2A) in combination with ribavirin. Method provides the prolonged clearance of virus that promotes both activity with respect to cells proliferation and effective treatment of disease.

EFFECT: enhanced effectiveness of preparation.

2 cl, 1 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with the ways of extracorporal detoxication and treatment of hepatic failure. The method should be implemented due to introducing albumin-containing solution through a catheter into abdominal cavity at concentration of 30-40 g/l as dialyzing liquid for 2-4 h. This solution should be purified through "Artificial kidney" apparatus, coal sorbent and anion-exchange resin. Perfusion rate of albumin-containing solution in the course of its purification corresponds to 20-30 ml/min. Detoxication cycle with the help of albumin followed by its deligandization should be repeated many times. The innovation provides optimal mode of perfusion and, thus, high rate of toxins elimination through patient's peritoneum and excludes the necessity in applying anticoagulants and expensive "MARS" system.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine.

SUBSTANCE: one should perform the following stages: a) removal of contaminants out of plant; b) plant's reducing; c) treatment of reduced plant with laser radiation; d) suspending the mixture obtained at stage c) in water; e) maceration of suspension obtained at stage d) and f) separation of liquid developed. Composition should be obtained due to this technique. It should be applied at treating hepatitis C as an aqueous extract. It should be applied as aqueous extract as immunostimulant. Pharmaceutical preparation includes aqueous extract as an active constituent.

EFFECT: increased biological activity of the product.

43 cl, 16 ex, 1 tbl

FIELD: medicine, ophthalmology, chemico-pharmaceutical industry.

SUBSTANCE: the suggested pharmaceutical composition is indicated for local application and contains an inhibitor angiotensin converting enzyme as an active substance and target additions, moreover, the content of active substance corresponds to about 1-20 mg/ml. The composition suggested could be designed as eye drops, spay, gels, solution for local injections. As target additions one should apply water that contains a buffer agent, an isotonic mixtures, a conservant and a prolongator. Additionally, this composition contains preparations chosen out of the following groups: antibiotics, macro- and microelements, vitamins, adrenoblocking agents. The innovation provides anti-ischemic action, improves reparative processes and accelerates the processes of healing.

EFFECT: higher efficiency.

3 cl, 7 ex

FIELD: veterinary medicine.

SUBSTANCE: composition comprises solution for per os introducible to animals. The solution contains Phenasal and additives. Phenasal is applied as solution of its salt in aprotonic bipolar hydroxyl-containing solvents and bases.

EFFECT: high therapeutic activity; reduced Phenasal consumption; enhanced effectiveness of treatment.

4 cl, 2 tbl

Haemostatic agent // 2275201

FIELD: pharmaceutical industry, in particular haemostatic agent.

SUBSTANCE: claimed agent represents aqueous solution, containing 2-150 g of zinc polyacrylate, 10-100 g sodium alginate and 1-30 of acetic acid in 1 l of distilled water. Agent of present invention being in contact with blood and tissues provides film formation 30 s.

EFFECT: haemostatic agent of improves quality.

FIELD: pharmaceutical industry, in particular agent for treatment of joint diseases in form of injections.

SUBSTANCE: claimed agent contains glucoseamine salt, preservative, non-ionic surfactant, in particular oleic acid and polyoxyethylated sorbitan monoether, and water.

EFFECT: agent for treatment of joint diseases of improved effectiveness combining chondroprotevtive action with high pharmacokinetic properties and biological availability.

3 cl, 3 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: remedy has saccharides like chondroitin sulfate (0.5-20.0% by mass) and salt of glycosamine (1.0-25.0% by mass), preservative (0.1-2.0% by mass), nonionogenic substance like monoester of oleic acid and polyoxyethylized sorbitan (1.0-5.0% by mass), and water (the rest).

EFFECT: increased active substances bioavailability and diffusion rate into articulation zone.

3 cl, 3 tbl

FIELD: medicine, in particular preparation of quick closing insulin preparations for treatment of diabetus mellitus.

SUBSTANCE: claimed method includes preparation of solutions containing insulin and ancillary substances, blending thereof, sterilizing filtration and bottling into flacks. Previously buffer solution containing 2.35-2.45 mg of disubstituted sodium phosphate; 2.25-3.0 mg m-cresol, and 15-17 mg of glycerol as calculated to 100 U of insulin is prepared, then insulin solution is prepared at 3.1-3.3 and added to buffer solution. Solutions are blended at agitation for 10-20 min, pH is adjusted to 7.2-7.4 and water is added up to finish insulin concentration of 100 IU/ml.

EFFECT: human gene engineered insulin of prolonged storage time without losses of physical, chemical and biological properties.

2 ex, 1 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to therapy of topical suppurative-inflammatory processes. Agent represents an aqueous isoosmotic solution comprising 0.25% of novocaine, 1% of cefazolin sodium salt and 0.77% of sodium chloride. Invention provides the development of optimal conditions for safety mechanical moving of agent in intercellular space under positive hydrodynamic pressure in the permanent state from the injection point in direction to side of deeply localized pathological focus and eliminates the pain component of the inflammatory response.

EFFECT: valuable medicinal properties of agent.

2 ex

FIELD: medicine, transfusion, infusion therapy.

SUBSTANCE: invention proposes antioxidant representing hydroxyethylated starch or pullulan chemically modified with steric-hindranced phenol. Fragment of steric-hindranced phenol represents β-(4-hydroxy-3,5-di-tert.-butylphenyl)-propionyl or β-(4-hydroxy-3,5-di-tert.-butylphenyl)-α-(N-benzoylamino)-acryloyl and its content is from 2 wt.-% up to limit solubility of polymer in water and doesn't exceed 10 wt.-% for modified hydroxyethylated starch and 12 wt.-% for modified pullulan. Plasma substitute showing antioxidant and antiradical activity represents indicated polymeric antioxidant in physiological solution or Ringer-Lock solution in plasma substitute based on the corresponding non-modified polymer. Also, invention describes a method for maintenance the level of arterial pressure and processes of antioxidant protection of body under condition of acute blood loss by using the indicated plasma substitute. As compared with analogs, new plasma substitute shows two kinds of activity: antioxidant and antiradical that are sufficient for operative increase of arterial pressure and its stabilization at the level of physiological norm, and for decreasing amount of free radicals and enhancing antioxidant protection of body in acute massive blood loss.

EFFECT: valuable medicinal properties of agents.

5 cl, 6 tbl, 4 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a medicinal agent representing solution of the compound N-[O-(p-pivaloyloxybenzenesulfonylamino)benzoyl]glycine of the formula (I):

in common with at least one regulator of pH value chosen from the group consisting of trisodium phosphate hydrate, sodium hydroxide and potassium hydroxide in the amount providing pH 7.0-9.0. Proposed medicinal agent represents injection formulation and designated for treatment of state with the proposed compound that is an inhibitor of enzyme elastase and improves the disease state. Also, invention relates to the ready medicinal formulation of this agent representing the injection formulation prepared by drying and freezing out. Invention provides acceptable solubility and stability of the compound (I) in solution and as a component of ready injection medicinal formulations.

EFFECT: improved and valuable pharmaceutical properties of medicinal formulation.

15 cl, 6 tbl, 1 dwg, 6 ex

FIELD: special compositions.

SUBSTANCE: invention relates to active composition for regional effect that comprises active compounds for regional effect and taken in the amount from about 0.001 to about 5 wt.-%, anionic surface-active substance taken in the amount from about 0.1 to about 15 wt.-%, hydrotrop taken in the amount from about 0.5 to about 35 wt.-%, water-soluble hydrogen-containing solvent taken in the amount from about 0.5 to about 25 wt.-%, and from 0 to about 5 wt.-% of secondary surface-active substance, and water. Also, invention relates to a method for surface cleansing and precipitation of active compound for regional effect on indicated surface. The composition provides rapid and effective precipitation of active compound for regional effect in combination with producing effective residual effect.

EFFECT: improved and valuable properties of compositions.

15 cl, 3 tbl, 29 ex

FIELD: medicine, oncology, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions used for inhibition of metastasis or prophylaxis of malignant tumor relapse after the topical therapy. As an active component, compositions contain derivative of polysaccharide comprising polysaccharide with carboxyl group bound with an active substance possessing anti-tumor activity through amino acid or peptide consisting of from 2 to 8 amino acids that are similar or different, or its salt wherein this active anti-tumor substance is represented by derivative of camptothecin of the formula (I) by claim 1 or compound of the formula (II) by claim 1 given in the invention description. The topical therapy involves surgery, radiation therapy, thermotherapy, cryotherapy or laser-burning therapy. Proposed compositions allow providing the high concentration of active substance in tumor metastasis region and prophylaxis of relapses of malignant tumor after carrying out the topical therapy.

EFFECT: valuable medicinal properties of pharmaceutical compositions, improved method of treatment.

9 cl, 1 dwg, 4 tbl, 6 ex

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