Modern aspects of the treatment of nonspecific ulcerative colitis in children. Aminosalicylic acid Indications for the use of aminosalicylates

The nature of the diet for Crohn's disease depends on the location and extent of intestinal damage, the phase of the disease, as well as the patient's tolerance to certain foods. During the period of exacerbation, fractional meals are prescribed 5-6 times a day. The protein content in the diet, especially with persistent diarrhea, should be increased to 1.3-2 g/kg per day. In the acute phase, the diet should be mechanically and chemically gentle with a high content of protein, vitamins, exclusion of milk if it is intolerant, and a limited amount of coarse plant fiber, especially when areas of the intestine are narrowed. These conditions correspond to diet No. 4, then No. 46 (see chapter “Treatment of chronic enteritis”).

In case of extensive damage to the small intestine during an exacerbation period, enteral elementary balanced mono-diets are recommended (see chapter “Treatment of malabsorption and digestion syndromes”) containing hydrolyzed protein, fats, carbohydrates with the exception of lactose and fiber. In case of significant exhaustion of patients and persistent diarrhea, parenteral nutrition is indicated; it is also necessary in the treatment of intestinal lesions such as fistulas, obstructive processes, short bowel syndrome, as well as in preparing patients for surgery with underweight and metabolic disorders.

2. Treatment of malabsorption syndrome

Treatment of malabsorption syndrome, correction of metabolic disorders, imbalance of vitamins, microelements and intestinal oxalaturia is extremely important in the complex therapy of Crohn's disease and allows for faster remission.

This direction of the treatment program is carried out in the same way as described in Chapter. "Treatment of chronic enteritis" and "Treatment of malabsorption and digestion syndromes."

3. Basic pathogenetic therapy

Basic drugs influence the pathogenetic factors of Crohn's disease and are the basis for its treatment.

3.1. Treatment with drugs containing 5-aminosalicylic acid (5-asc)

These drugs include sulfasalazine, salazopyridazine, as well as 5-ASA in the form of salofalk, mesalazine, mesacol, etc.

The mechanism of action of these agents is described in detail in Chapter. "Treatment of nonspecific ulcerative colitis." The most important aspect is the inhibition of the lipoxygenase pathway for the conversion of arachidonic acid, the metabolic products of which serve as mediators of inflammatory

process in the intestine, as well as an immunomodulatory effect (these effects are due to 5-ASA).

Treatment sulfasolosin A.R. Zlatkina (1994) recommends starting with a dose of 0.5 g 4 times a day, after 2-3 days the dose is doubled, and after a week it is increased to 2 g 4 times a day, in severe cases - up to 2 g 5 times a day. within 2-3 weeks. The daily dose of sulfasalazine in some cases may be 4-6 t. The duration of treatment with sulfasalazine is not strictly regulated, it is determined by the dynamics of the disease and can be from 3-4 weeks to 3-4 months or more.

The literature contains data on treatment with drugs containing 5-ASA for a year or even longer (Plame K., 1980). The effectiveness of treatment with sulfasalazine for terminal ileitis is lower than for Crohn's disease of the colon. This is explained by the fact that the breakdown of sulfasalazine into 5-ASA and sulfapyridine occurs under the influence of colon microflora.

A drug salazopyridazine use 2 g per day for 4 weeks, and the next 3-4 weeks - 1.5 g per day.

5-Amshusalicylic acid(salofalk, mesalazine) is prescribed 3 g per day. The effectiveness of the drug is higher and its tolerability is better than sulfasalazine and salazopyridazine.

Side effects of drugs containing 5-ASA are manifested by dyspeptic disorders, skin rashes, leukopenia, agranulocytosis (sulfasalazine, salazopyridazine), so it is necessary to check the analysis blood Once every 10 days.

The present invention relates to 5-amino-2-(-D-galactopyranosyloxy)benzoic acid or 5-amino-2-(-D-galactopyranosyloxy)benzoic acid, which are described by the general formula:

or a pharmaceutically acceptable salt thereof, a pharmaceutical composition having a therapeutic effect for ulcerative colitis, based on these compounds, as well as a therapeutic agent for use in ulcerative colitis, including 5-amino-2-(-D-galactopyranosyloxy)benzoic acid as an active ingredient acid, 5-amino-2-(-D-galactopyranosyloxy)benzoic acid or 5-amino-2-(-D-glucopyranosyloxy)benzoic acid or a pharmaceutically acceptable salt thereof. The compound of the present invention can be effectively delivered to the colon as its site of action, subject to decomposition by intestinal bacterial flora, so that 5-aminosalicylic acid as the active ingredient is produced in the colon. 3 n.p. f-ly, 1 table., 9 ill.

Drawings for RF patent 2341529

Field of technology

The present invention relates to 5-amino-2-(-D-galactopyranosyloxy)benzoic acid (hereinafter referred to as "compound", described by the general formula , or 5-amino-2-(-D-galactopyranosyloxy)benzoic acid (hereinafter referred to as "compound" described by the general formula, or a pharmaceutically acceptable salt thereof

In addition, the present invention relates to a therapeutic agent for use in ulcerative colitis, comprising as an active ingredient the compound or a pharmaceutically acceptable salt thereof.

State of the art

5-Aminosalicylic acid (hereinafter referred to as “5-ASA”) has free radical scavenging (DPPHL) activity, hydrogen peroxide scavenging, hypochlorite ion scavenging, lipid peroxidation inhibition and leukotriene B4 biosynthesis, and is therefore used as a therapeutic agent for ulcerative colitis (UC) and Crohn's disease (CD), generally classified as inflammatory bowel diseases (IBD), which are inflammatory diseases that are difficult to treat, requiring long courses of therapy, during which periods of remission and exacerbation may alternate (See, for example, non-patent document 1).

However, it is known that orally administered 5-ASA, as such, is rapidly and completely absorbed in the upper part of the small intestine and only a small amount of 5-ASA, which exerts its effect by local action on the site of inflammation, is delivered to the colon area at the site of injury ( see, for example, non-patent document 3).

In this regard, for the purpose of delivering 5-ASA to the desired target site in the colon, a drug delivery system (hereinafter referred to as DDS) for 5-ASA and 5-ASA prodrugs has been studied (see, for example, Non-Patent Documents 1, 2 and 4).

There is a 5-ASA SLD drug, trade name Pentase (registered trademark), manufactured by Nisshin Kyorin Pharmaceutical Co., Ltd., which is formulated to achieve gradual release of 5-ASA in an area extending from small intestine to colon by coating 5-ASA with a porous film of ethylcellulose (see, for example, non-patent documents 1 and 2). However, it is known that a significant amount of 5-ASA is transferred into the plasma after oral administration of Pentaza to an adult in the fasted state at a dose of 1000 mg as 5-ASA, although the plasma concentration of unchanged drug substance decreases at a minimum point to the level of one fourteenth (C max = 1448.6±586.4 ng/ml) compared to the oral administration of 5-ASA alone (see, for example, Non-Patent Document 5).

Further, there is the drug salazosulfapyridine, which is a prodrug of 5-ASA (hereinafter referred to as “SASP”) (trade name: salazopyrine (registered trademark), manufactured by Pfizer Inc.), in which the amino group of 5-ASA is nitrided (see, for example , non-patent document 3). This compound is metabolized to 5-ASA by intestinal bacteria present in the colon, which contain an enzyme that reduces the azo group. Although SASP has been found to be effective in ulcerative colitis, there are problems associated with various adverse reactions, such as hypersensitivity to the drug, male infertility, nausea and headache, which are caused by sulfapyridine (SP), formed after the degradation of SASP by intestinal bacteria (see ., for example, a non-patent document 3).

Additionally, methyl 5-amino-2-(-D-glucopyranosyloxy)benzoate and methyl 2-acetoxy-5-(-D-glucopyranosylamino)benzoate, which are glucose glycosides of methyl 5-aminosalicylate, are known as other prodrugs. having high water solubility (see, for example, Non-Patent Documents 6 and 7). Although the safety of these compounds has been established, their therapeutic effect in ulcerative colitis has not been fully studied.

Additionally, it is reported that, in addition to 5-ASA, a therapeutic agent such as dexamethasone or prednisolone glycoside with glucose or the like is used as a prodrug of a steroid compound in the treatment of ulcerative colitis (see, for example, Non-Patent Document 1). The purpose of using this compound is to obtain a specific drug delivered to the colon. However, it has been reported that after intragastric administration to rats, only 60% of the glucose derivative of dexamethasone is delivered to the cecum and only 15% or less of the glucose derivative of prednisolone is delivered to the cecum.

As stated above, there are currently no known drugs for the treatment of ulcerative colitis that are safe, can be administered over an extended period of time, and that can effectively deliver 5-ASA, a therapeutic agent for ulcerative colitis, to the colon. to the site of the lesion, with little or no absorption or metabolization in the stomach or upper small intestine.

[Patent Document 1] JP-B-60-501105

[Non-Patent Document 1] Folia Pharmacol. Jpn. 104, pp. 447-457 (1994)

[Non-Patent Document 2] Folia Pharmacol. Jpn. 104, pp. 303-311 (1994)

[Non-Patent Document 3] Scandinavian Journal of Gastroenterology, 23, pp. 107-112 (1988)

[Non-Patent Document 4] Advanced Drug Delivery Reviews, 7, pp. 143-199 (1991)

[Non-Patent Document 5] Yakuri To Chiryo, 22 (Suppl. 10), pp. S2467-2495 (1994)

[Non-Patent Document 6] Magyar Kemiai Folyoirat, 97 (4), pp. 143-148 (1991)

[Non-Patent Document 7] Archiv der Pharmazie An International Journal Pharmaceutical and Medicinal Chemistry, 332(9), pp. 321-326 (1999)

Disclosure of the Invention

Problems that the invention solves

The aim of the present invention is to develop a therapeutic agent for the treatment of ulcerative colitis, with which it is possible to deliver 5-ASA, used as a therapeutic agent for ulcerative colitis, to the colon, to the site of the lesion, without its absorption or metabolization in the stomach or upper small intestine. intestines, and which can be safely administered over a long period of time.

Tools to solve existing problems

As a result of extensive research, the inventors of the present invention have found a compound with which the above objectives can be achieved, which is the subject of the present invention.

The present invention may include compound , or compound , or a pharmaceutically acceptable salt thereof.

Further, the present invention may include a pharmaceutical composition containing the compound , or the compound , or a pharmaceutically acceptable salt thereof as an active ingredient, as well as a therapeutic agent for the treatment of ulcerative colitis, including the compound , the compound or the compound (for convenience, hereinafter all of them will be referred to as be referred to collectively as “the compound of the present invention”) or a pharmaceutically acceptable salt thereof as the active ingredient.

Since the compound of the present invention is metabolized to 5-ASA by intestinal bacterial flora, when using the compound of the present invention, systemic side effects can be reduced and long-term administration of a relatively high dose becomes possible.

The following is a definition of the terms used in the present invention.

The term "ulcerative colitis" refers to an erosive nonspecific inflammation of the colon of unknown etiology, which mainly affects the mucous membrane and often leads to the formation of erosions and ulcers.

Below the present description is described in more detail.

The compound of the present invention can be prepared, for example, according to the following method from a known compound or an intermediate that can be easily prepared. When preparing a compound of the present invention, if the starting material contains a substituent that may affect the reaction, according to the general strategy, the reaction is carried out after protecting the starting material with an appropriate protecting group according to a known procedure. Further, after completion of the reaction, said protecting group can be removed by a known procedure.

Obtaining method 1

(In the above formulas, R 1 is a linear or branched alkyl containing from 1 to 6 carbon atoms; R 2 is D-glucopyranosyl or D-galactopyranosyl (each hydroxyl group in R 2 may be protected by a protecting group such as acetyl); and X means a halogen atom such as fluorine, chlorine, bromine and iodine).

Stage 1

This step is the esterification of a known compound and can be carried out according to a known procedure (see non-patent document 7). The reaction temperature is maintained within an acceptable range of 20°C to 200°C. In general, the solvent used in the reaction may vary depending on the type of carboxylic acid ester produced, and examples thereof may include alcohols such as methanol and ethanol. Examples of the acid may include inorganic acids such as hydrochloric acid and sulfuric acid. The reaction time varies depending on the type of starting material used, the reaction temperature, and generally ranges from 1 hour to 72 hours.

Stage 2

This step is the condensation of a compound with a compound obtained by halogenation of glucose or galactose at an anomeric position, which can be carried out by a known method per se (see Non-Patent Document 7). This reaction occurs by inversion of configuration in the presence of a catalyst. Examples of catalyst for this reaction may include silver(I) oxide, mercury(II) oxide and AgOCOR 3 (R 3 denotes linear or branched alkyl containing 1 to 6 carbon atoms). In general, the solvent used in the reaction is not particularly limited as long as it does not participate in the reaction, and quinoline can be mentioned as an example thereof. The reaction temperature is maintained within an acceptable range of 0°C to 100°C. The reaction time may vary depending on the type of starting material used, the reaction temperature, etc., and ranges from 1 hour to 72 hours. Further, if desired, the protecting group for each hydroxyl group in R 2 of the resulting compound can be removed by known techniques.

Additionally, although the starting material compound is commercially available, it can also be prepared, for example, by the following procedure. This reaction is a halogenation reaction at the anomeric position of a sugar such as glucose or galactose, and can be carried out by known methods per se. Examples of the halogenating agent may include generally hydrogen bromide in acetic acid, phosphorus oxybromide, phosphorus oxychloride and the like. In general, the solvent used in the reaction is not particularly limited as long as it does not participate in the reaction, and examples thereof may include halogen-containing solvents such as methylene chloride, chloroform and 1,2-dichloroethane. The reaction temperature is maintained within an acceptable range of 0°C to 100°C. The reaction time may vary depending on the type of starting material used or the reaction temperature and ranges from 1 hour to 72 hours.

Stage 3

This step is the hydrogenation of the compound and can be carried out by known techniques per se (see non-patent document 7). This reaction can be carried out, for example, in the presence of a metal catalyst in a suitable solvent, generally in a hydrogen atmosphere at a pressure of from 1 to 10 atm and at a temperature of from 0°C to 100°C. Examples of the metal catalyst may generally include palladium on carbon, palladium black, platinum dioxide, platinum on carbon and the like. The choice of solvent used in this reaction is not particularly limited as long as it is not involved in the reaction, and examples of suitable solvent may include ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, alcohols such such as methanol and ethanol, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, hydrocarbons such as benzene, toluene and xylene, and mixtures of these solvents. The reaction time may vary depending on the type of starting material used in the reaction, the reaction temperature, and generally ranges from 1 hour to 48 hours.

Additionally, if desired, in the resulting compound, the protecting group for each hydroxyl group in R 2 can be removed in accordance with known techniques.

Stage 4

This step is the hydrolysis of the carboxylic acid ester of the compound and can be carried out according to known techniques per se. The reaction temperature is maintained in an appropriate range from 0°C to 100°C. The solvent used in this reaction is not particularly limited as long as it is not involved in the reaction, and examples of a suitable solvent may include alcohols such as methanol and ethanol. Examples of the base may include inorganic bases such as sodium hydroxide and potassium hydroxide. The reaction time may vary depending on the type of starting material used in the reaction or the reaction temperature, and generally ranges from 1 hour to 72 hours.

Additionally, as an example of another method used to prepare the compound , another procedure is described below.

[In the given formulas, R 1 and R 2 are described above. X 1 represents a halogen atom such as a fluorine, chlorine, bromine or iodine atom].

Stage 1

This step is an esterification reaction of a known compound and can be carried out according to a known procedure (see Non-Patent Document 7). The reaction temperature is maintained in an appropriate range from 20°C to 200°C. The solvent generally used in the reaction may vary depending on the type of carboxylic acid ester produced, and examples thereof may include alcohols such as methanol and ethanol. Examples of the acid may include inorganic acids such as hydrochloric acid and sulfuric acid. The reaction time may vary depending on the type of starting material used in the reaction or the reaction temperature and generally ranges from 1 hour to 72 hours.

Stage 2

This stage is a condensation reaction of a compound with a glucose or galactose derivative and can be carried out according to a known procedure per se. In this reaction, since the configuration of the anomeric position cannot be controlled, it is necessary to separate and purify the individual diastereomer by silica gel chromatography or the like. By using this separation procedure, compounds with both anomeric position configurations (β-form and β-form) can be obtained. Examples of the base used in this reaction include 1,5-diazabicyclo-5-nonene, 1,4-diazabicyclooctane and 1,8-diazabicyclo-7-undecene. In general, the solvent used in the reaction is not particularly limited as long as it is not involved in the reaction, and examples thereof include acetonitrile and dimethyl sulfoxide. The reaction temperature is maintained in an appropriate range from 0°C to 100°C. The reaction time may vary depending on the type of starting material used in the reaction, the reaction temperature, etc., and is generally from 1 hour to 72 hours. Further, if desired, in the resulting compound, the protecting group for each hydroxyl group in R 2 can be removed in accordance with known techniques.

The compound of the present invention obtained by the described method can be isolated and purified using known techniques per se, such as concentration, solvent exchange, phase transfer, solvent extraction, crystallization, recrystallization, fractional distillation or chromatography.

The compound of the present invention can be used as a drug as received or can be converted into a pharmaceutically acceptable salt thereof by a known method.

The term "salt" of a compound of the present invention as used herein may include a pharmaceutically acceptable salt, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid and hydrobromic acid, salts of organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid and camphorsulfonic acid, as well as salts of alkali or alkaline earth metals such as like sodium, potassium and calcium. Preferred is the hydrochloric acid salt (hydrochloride).

The hydrochloride of the present invention can be obtained by treating the compound of the present invention with an alcoholic solution of hydrogen chloride or a solution thereof in diethyl ether, and then obtaining precipitated crystals by filtration or, in the case where crystals do not precipitate, by concentrating the solution, thereby causing the crystals to precipitate , and then obtaining crystals, for example, by filtration.

As will be shown later in the experimental examples, the compound of the present invention has one remarkable property that it is difficult to transfer into plasma, which currently available 5-ASA-based products do not have, and due to which 5-ASA, being the active ingredient, it is effectively delivered after administration to the affected areas, i.e. into the cecum, and into the colon, into the proximal and distal parts of the intestine, and into the rectum when administered orally. In this regard, the compound of the present invention is useful as a therapeutic agent for ulcerative colitis, which is safe and can be administered for a long period of time. In particular, the compound has a pronounced effect.

In a rat model of trinitrobenzenesulfonic acid (TNBS)-induced colitis, as will be described in the relevant Examples below, the compound of the present invention significantly suppresses lesion scores and reduces colon wet weight, indicating its potential as an excellent therapeutic agent. remedies for ulcerative colitis.

With regard to the administration of the compound of the present invention as a drug, the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to mammals, including humans, in the form of the compound itself or in the form of a pharmaceutical composition thereof containing the compound in a pharmaceutically acceptable non-toxic and inactive carrier, in an amount, for example, from 0.1% to 99.5%, preferably from 0.5% to 90%.

The pharmaceutically acceptable carrier may include diluents and excipients in the form of solid, semi-solid or liquid or other additives used in the formulation of the compositions, and at least one of these is used. The pharmaceutical composition is preferably administered in dosage form. The pharmaceutical composition may be administered orally or parenterally (eg, by transrectal administration, etc.). And, of course, for administration, a dosage form suitable for the given routes of administration is used. For example, oral administration is preferred.

The dosage of the compound of the present invention may preferably be adjusted based on the condition of the patient, taking into account factors such as age, body weight, nature and severity of the disease, and route of administration, and generally the effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof is between 10 mg per adult up to 10 g per adult, preferably 1 g to 4 g per adult per day, when administered orally. In some cases, a dosage less than the stated dosage range may be sufficient, or a dosage greater than the stated range may be required. Typically, the daily dose is administered once a day or several times, divided into several servings.

For oral administration, a solid or liquid dosage form may be used, such as a particulate preparation, powder, tablet, sugar-coated tablet, capsule, granule, suspension, liquid, syrup, drops, sublingual tablet, or other dosage forms.

The particulate preparation can be prepared by nebulizing a compound of the present invention or a pharmaceutically acceptable salt thereof to an appropriate particle size.

The powder can be obtained by atomizing the compound of the present invention or a pharmaceutical salt thereof to an appropriate particle size and then mixing it with a pharmaceutical carrier such as a dietary carbohydrate such as starch or mannitol or the like. Fragrances, preservatives, dispersants, dyes, flavors or the like may be used for mixing, if required.

The capsule may be prepared by introducing into a capsule shell, such as a gelatin capsule, to fill it with particles or powder that have been produced by spraying, as described above, or by granulating, which will be described in relation to tablets in the appropriate section. A lubricant or flow aid such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol may be added to the powder and a filling procedure may then be carried out. In the case of adding a disintegrant or solubilizer, for example, carboxymethylcellulose, calcium-carboxymethylcellulose, low-substituted hydroxypropylcellulose, sodium cross-carmellose, sodium carboxymethylstarch, calcium carbonate or sodium carbonate, the effectiveness of the drug product for which the capsule form is selected will vary. may be increased.

A tablet can be prepared by preparing a powder mixture with an excipient, granulating or clumping it, adding a disintegrant or lubricant to it, and then compressing it into tablets. The powder mixture can be obtained by mixing the appropriately sprayed material with the above diluent or base and, if necessary, in combination with them a binder (for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone or polyvinyl alcohol) can be used. , dissolution retardant (eg, paraffin), reabsorbent (eg, quaternary salt), or adsorbent (eg, bentonite, kaolin, dicalcium phosphate). The powder mixture may be first wetted with a binder such as syrup, starch glue, gum arabic, cellulose solution and polymer solution, followed by mixing, drying and grinding. Instead of the above-described powder granulation procedure, after processing in a tablet compression machine, the resulting semi-finished lumps are ground to obtain granules. The granules thus formed are prevented from sticking together by adding stearic acid, stearate salt, talc, mineral oil or other lubricant. The mixture treated with lubricant is further subjected to tabletting. The resulting uncoated tablets can be subjected to a film-coating or sugar-coating procedure.

In addition, the compound of the present invention or a pharmaceutically acceptable salt thereof can be directly compressed into tablets after mixing with a liquid inactive carrier, without introducing the granulation and lump forming steps described above. A transparent or translucent protective film can also be used, such as a shellac protective film, a sugar polymer film, or a glossy wax film. Other orally administered forms, such as solution, syrup and elixir, can be formulated into a unit dosage form such that a given amount contains a corresponding amount of drug. A syrup can be prepared by dissolving a compound of the present invention or a pharmaceutically acceptable salt thereof in an aqueous solution with appropriate flavoring agents, and the elixir can be prepared using a non-toxic alcoholic carrier.

If necessary, the oral dosage unit may be microencapsulated. Longer duration and prolonged release of the active ingredient may also be achieved by coating the composition or by immersing it in a polymer, wax or the like.

For parenteral administration, a suppository or similar form may be used. For transrectal administration, a suppository prepared by dissolving or suspending a compound of the present invention or a pharmaceutically acceptable salt thereof in a water-soluble or water-insoluble low melting point solid such as polyethylene glycol, cocoa butter, semi-synthetic oil and fat (for example, Witepsol) may be used. Witepsol (registered trademark)), higher esters (eg myristyl palmitate) or a mixture thereof.

Brief description of drawings

[Figure 1] Figure 1 shows the change in plasma 5-ASA concentration. The vertical axis denotes plasma 5-ASA concentration (ng/mL) and the horizontal axis denotes time (hour). Black circles, white diamonds, white triangles, and white circles indicate the change in 5-ASA concentration after administration of compound , compound , compound , and Pentase (registered trademark), respectively.

[Figure 2] Figure 2 shows the change in the amount of 5-ASA in the contents of the cecum. The vertical axis shows the amount of 5-ASA (% of dose) present in the rat cecal contents, and the horizontal axis represents time (hour). Black circles, white circles and black triangles show the change in the amount of 5-ASA after administration of the compound, Pentase (registered trademark) and 5-ASA, respectively.

[Figure 3] Figure 3 shows the change in the amount of 5-ASA in the contents of the proximal intestine. The vertical axis shows the amount of 5-ASA (% of dose) present in the rat proximal intestinal contents, and the horizontal axis represents time (hour). Black circles, white circles and black triangles show the change in the amount of 5-ASA after administration of the compound, Pentase (registered trademark) and 5-ASA, respectively.

[Figure 4] Figure 4 shows the change in the amount of 5-ASA in the contents of the distal intestine. The vertical axis represents the amount of 5-ASA (% of dose) present in the rat distal intestinal contents, and the horizontal axis represents time (hour). Black circles, white circles and black triangles show the change in the amount of 5-ASA after administration of the compound, Pentase (registered trademark) and 5-ASA, respectively.

[Figure 5] Figure 5 shows the change in the amount of 5-ASA in the rectal contents. The vertical axis shows the amount of 5-ASA (% of dose) present in the rat rectal contents, and the horizontal axis represents time (hour). Black circles, white circles and black triangles show the change in the amount of 5-ASA after administration of the compound, Pentase (registered trademark) and 5-ASA, respectively.

[Figure 6] Figure 6 shows the change in the concentration of 5-ASA in colon tissue. The vertical axis denotes the plasma 5-ASA concentration (μg/g) present in 1 g of rat colon, and the horizontal axis denotes time (hour). White diamonds and white circles indicate the change in 5-ASA concentration after administration of the compound and Pentase (registered trademark), respectively.

[Figure 7] Figure 7 shows the change in the concentration of 5-ASA in rectal tissue. The vertical axis denotes the concentration of 5-ASA (µg/g) available in 1 g of rat rectum, and the horizontal axis denotes time (hour). White diamonds and white circles indicate the change in 5-ASA concentration after administration of the compound and Pentase (registered trademark), respectively.

[FIG. 8] FIG. 8 illustrates the therapeutic effect of Pentase (registered trademark) and the compound in rats with TNBS-induced colitis using the lesion development score. The vertical axis shows the severity of the lesion, in points, and the horizontal axis shows the dose of each of the studied drugs (mg/kg/per single administration).

[Figure 9] Figure 9 illustrates the therapeutic effect of Pentase (registered trademark) and the compound in rats with TNBS-induced colitis, assessed by wet weight of tissue relevant to the development of colitis. The vertical axis shows colonic wet weight (u) and the horizontal axis shows the dose of each study drug (mg/kg/per dose).

Best Mode for Carrying Out the Invention

The present invention is explained in more detail below with the help of illustrative examples, test examples and composition examples, but the invention is not limited to these embodiments.

Example 1: 5-amino-2-(-D-galactopyranosyloxy)benzoic acid

Concentrated sulfuric acid is added dropwise to a solution of 30 g of 5-nitrosalicylic acid in 500 ml of anhydrous methanol and the mixture is refluxed for 2 days. The reaction solution was concentrated under reduced pressure and diluted with 500 ml of ethyl acetate, and then another 500 ml of water was added. Then, while cooling with ice, saturated sodium bicarbonate solution is slowly added to the reaction mixture until the reaction is alkaline (pH 9). The resulting yellow precipitate was filtered off and the aqueous layer of the filtrate was extracted with ethyl acetate. The combined organic layer was washed with water and brine, then dried over anhydrous magnesium sulfate and then filtered. The solvent is then concentrated to obtain 31.26 g of methyl 5-nitrosalicylate.

Step 2-1: 2",3",4",6"-tetra-O-acetyl--D-galactopyranosyl bromide

A solution of 1",2",3",4",6"-penta-O-acetyl-β-D-galactopyranose in 500 ml of methylene chloride is cooled with ice and 177.5 g of a 30% solution of hydrogen bromide in acetic acid is added dropwise. The reaction mixture was stirred at room temperature for 14 hours and then poured into saturated sodium bicarbonate solution containing ice. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate and filtered. Thereafter, the solvent was concentrated to obtain 68.7 g of 2", 3",4",6"-tetra-O-acetyl-β-D-galactopyranosyl bromide.

Step 2-2: Methyl 5-nitro-2-(2",3",4",6"-tetra-O-acetyl-α-D-galactopyranosyloxy)benzoate

To a solution of 30.55 g of methyl 5-nitrosalicylate obtained in step 1 and 63.7 g of 2,3,4,6"-tetra-O-acetyl-β-D-galactopyranosyl bromide obtained in step 2- 1, 35.92 g of silver oxide was added to 250 ml of quinoline and the mixture was stirred at room temperature in the dark for 62 hours. The reaction mixture is diluted with 1000 ml of ethyl acetate and then filtered through celite. The ethyl acetate layer is washed twice with 1000 ml of 2N. hydrochloric acid, followed by double extraction with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, water and brine, dried over sodium sulfate and then filtered. The solvent is then concentrated to obtain 71.7 g of methyl 5-nitro-2-(2",3",4",6"-tetra-O-acetyl-β-D-galactopyranosyloxy)benzoate.

Step 2-3: Methyl 5-nitro-2-(-D-galactopyranosyloxy)benzoate

The methanol solution containing 10.55 g of methyl 5-nitro-2-(2",3",4",6"-tetra-O-acetyl-β-D-galactopyranosyloxy)benzoate obtained in step 2-2 is stirred at a temperature of 60°C and sodium methoxide is added to it. The mixture is stirred for 30 minutes, after which 5.0 g of Amberlite IRC-50 is added to neutralize. The organic layer obtained after filtration was concentrated to obtain 4.90 g of methyl 5-nitro-2-(α-D-galactopyranosyloxy)benzoate.

Step 3: Methyl 5-amino-2-(-D-galactopyranosyloxy)benzoate

To a solution of 4.90 g of methyl 5-nitro-2-(-D-galactopyranosyloxy)benzoate obtained in stage 2-3 in 100 ml of methanol, add 0.49 g of 10% palladium on carbon and carry out catalytic reduction at room temperature in a hydrogen atmosphere under a pressure of 1 atm. After 20 hours, the reaction solution was filtered to remove the catalyst and the organic layer was concentrated to obtain 4.18 g of methyl 5-amino-2-(α-D-galactopyranosyloxy)benzoate.

To a suspension of 4.18 g of methyl 5-amino-2-(-D-galactopyranosyloxy)benzoate obtained in step 2-4 in 120 ml of anhydrous methanol, add dropwise 12.7 ml of 1N. sodium hydroxide solution. The mixture is stirred at reflux for 16 hours. The reaction solution is concentrated under reduced pressure and the residue is diluted with distilled water. Then the solution is neutralized by adding 6.4 ml of 2N. hydrochloric acid solution. The mixture is then concentrated to obtain 3.41 g of the desired compound.

Colorless powder

MS (EI): m/z = 338 +

Rotation: D 20 = -19.84 (C = 1.28, H 2 O)

Elemental analysis (C 13 H 17 NO 8)

Calculation (in%): C - 49.52; N - 5.43; N - 4.44;

Found (in%): C - 49.12; N - 5.37; N - 4.38

1H NMR (D2O): 3.74-4.01 (m, 6H, H-2 to 6), 5.04 (d, 1H, J 1.2 = 7.4 Hz, H-1) , 7.30-7.39 (m, 3H, Ph)

Example 2: 5-amino-2-(-D-galactopyranosyloxy)benzoic acid

Stage 1: Methyl 2-fluoro-5-nitrobenzoate

A solution containing 12.0 g of 2-fluoro-5-nitrobenzoic acid, 60 ml of anhydrous tetrahydrofuran and 60 μl of dimethylformamide was cooled with ice and 9.05 g of oxalyl chloride was added dropwise. After the drops have been added, the mixture is stirred at room temperature for 5 hours. 30 ml of anhydrous tetrahydrofuran and 30 ml of methanol solution were added dropwise to the reaction solution, after which the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure and diluted with 240 ml of ethyl acetate. The diluted solution was then washed with 5% aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and filtered. The solvent is then concentrated, and 24 ml of isopropyl ether is added to the concentrated residue to dissolve the residue. Next, the solution is cooled to 5°C to precipitate crystals. The precipitated crystals were filtered off under reduced pressure and dried at room temperature and under reduced pressure to obtain 10.5 g of methyl 2-fluoro-5-nitrobenzoate.

Step 2: Methyl 5-nitro-2-(2",3",4",6"-tetra-O-acetyl--D-galactopyranosyloxy)benzoate

To a solution of 7.13 g of methyl 2-fluoro-5-nitrobenzoate obtained in step 1 and 12.50 g of 2,3,4,6"-tetra-O-acetyl-D-galactopyranose in 70 ml of acetonitrile, 4.95 g of DBU was added dropwise and the mixture was stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure, diluted with 300 ml of ethyl acetate, washed with 150 ml of 1N. hydrochloric acid, 150 ml of 5% aqueous sodium bicarbonate and 150 ml of brine, dried over anhydrous magnesium sulfate and filtered. The solvent is then concentrated. The concentrate is purified by column chromatography (Wako Gel (Registered Trademark) C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), n-hexane:ethyl acetate = 4 to 1.5) to obtain 7.51 g of methyl-5 -nitro-2-(2",3",4",6"-tetra-O-acetyl--D-galactopyranosyloxy)benzoate and 7.92 g of methyl-5-nitro-2-(2",3", 4",6"-tetra-O-acetyl--D-galactopyranosyloxy)benzoate.

Step 3-1: Methyl 5-amino-2-(2",3",4",6"-tetra-O-acetyl-α-D-galactopyranosyloxy)benzoate

To a solution of 7.00 g of methyl 5-nitro-2-(2",3",4",6"-tetra-O-acetyl-β-D-galactopyranosyloxy)benzoate obtained in step 2-1 in 210 ml methanol, add 0.70 g of 10% palladium on carbon and carry out catalytic reduction at room temperature in a hydrogen atmosphere under a pressure of 1 atm. After 18 hours, the reaction solution was filtered to remove the catalyst, and the organic layer was concentrated. The concentrate was purified by column chromatography (Wako Gel (Registered Trademark) C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), n-hexane:ethyl acetate = 3:1 - 3:2) to obtain 5.73 g of methyl 5-amino-2-(2",3",4",6"-tetra-O-acetyl-β-D-galactopyranosyloxy)benzoate.

Step 3-2: Methyl 5-amino-2-(-D-galactopyranosyloxy)benzoate

To 5.52 g of methyl 5-amino-2-(2",3",4",6"-tetra-O-acetyl-β-D-galactopyranosyloxy)benzoate obtained in step 3-1 in 100 ml of anhydrous tetrahydrofuran and anhydrous methanol (1:1), 307 mg of potassium carbonate was added and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the concentrate was purified by column chromatography (Wako gel (registered trademark) C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), chloroform:methanol = 10:1 - 5:1) to obtain 2 .71 g methyl 5-amino-2-(-D-galactopyranosyloxy)benzoate.

Step 4: 5-amino-2-(-D-galactopyranosyloxy)benzoic acid

To a suspension of 2.00 g of methyl 5-amino-2-(-D-galactopyranosyloxy)benzoate obtained in step 3-2 in 40 ml of water, add dropwise 6.07 ml of 1N. aqueous sodium hydroxide solution and the mixture was stirred at 50°C for 2 hours. The reaction solution is filtered to remove insoluble substances, and the filtrate is neutralized by adding 6.07 ml of 1N. hydrochloric acid. The reaction solution was concentrated under reduced pressure to obtain 1.34 g of the desired compound.

Slightly yellow powder

MS (FAB): m/z = 338 +

Rotation: D 20 = 79.37 (C = 1.28, H 2 O)

Elemental analysis (C 13 H 17 NO 8 0.8 H 2 O))

Calculation (in%): C - 47.36; N - 5.69; N - 4.22;

Found (in%): C - 47.20; N - 5.48; N - 4.22

1H NMR (D2O): 3.70-4.10 (m, 6H, H-2 to 6), 5.76 (d, 1H, J 1.2 = 3.6 Hz, H-1) , 7.37-7.40 (m, 3H, Ph)

Reference Example 1: 5-Amino-2-(-D-glucopyranosyloxy)benzoic acid

Stage 1: Methyl 5-nitrosalicylate

The synthesis is carried out according to the procedure described in relation to stage 1 of example 1.

Step 2: Methyl 5-nitro-2-(2",3",4",6"-tetra-O-acetyl-β-D-glucopyranosyloxy)benzoate

To a solution of 6.0 g of methyl 5-nitrosalicylate obtained in stage 1 and 18.8 g of 2,3,4,6"-tetra-O-acetyl-β-D-glucopyranosyl bromide in 60 ml of quinoline 10.5 g of silver oxide and the solution are stirred vigorously at room temperature for 1 hour. The reaction solution is diluted with 300 ml of ethyl acetate and then filtered through celite. The ethyl acetate layer is washed twice with 2 ml of 2N. hydrochloric acid and then carry out double extraction of the aqueous layer using 300 ml of ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, water and brine, dried over sodium sulfate and then filtered. The solvent is then concentrated to obtain 15.63 g of methyl 5-nitro-2-(2",3",4",6"-tetra-O-acetyl-β-D-glucopyranosyloxy)benzoate.

Step 3-1: Methyl 5-amino-2-(2",3",4",6"-tetra-O-acetyl-α-D-glucopyranosyloxy)benzoate

To a suspension of 12.0 g of methyl 5-nitro-2-(2",3",4",6"-tetra-O-acetyl-β-D-glucopyranosyloxy)benzoate obtained in step 2 in 400 ml of methanol is added 2.4 g of 10% palladium on carbon and catalytic reduction is carried out at 30°C in a hydrogen atmosphere under a pressure of 3 atm. After 3 hours, filter through Celite. The solvent is concentrated to give 11.2 g of methyl 5-amino-2-(2",3",4",6"-tetra-O-acetyl-β-D-glucopyranosyloxy)benzoate.

Step 3-2: Methyl 5-amino-2-(-D-glucopyranosyloxy)benzoate

To 16 ml of a solution of anhydrous tetrahydrofuran and methanol (1:1) containing 0.68 g of methyl-5-amino-2-(2",3",4",6"-tetra-O-acetyl-β-D-glucopyranosyloxy )benzoate obtained in step 3-1, 37.8 mg of potassium carbonate is added and the mixture is stirred overnight at room temperature. 0.14 ml of 4N is added dropwise to the reaction solution. hydrogen chloride/ethyl acetate solution and concentrate the solvent. The resulting crude product was purified using silica gel column chromatography (Wako Gel (Registered Trademark) C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), methylene chloride:methanol = 10:1 to 8:1 and up to 5: 1), yielding 332 mg of methyl 5-amino-2-(-D-glucopyranosyloxy)benzoate.

Step 4: 5-amino-2-(-D-glucopyranosyloxy)benzoic acid

To a suspension of 100 mg of methyl 5-amino-2-(-D-glucopyranosyloxy)benzoate obtained in step 3-2 in 3 ml of methanol, add dropwise 0.3 ml of 1N. aqueous sodium hydroxide solution and the mixture is stirred at a temperature of 50°C. After 5 hours, the temperature is brought back to room temperature and the solvent is distilled off under reduced pressure. The resulting oily residue is dissolved in 1 ml of water and 0.3 ml of 1N is added dropwise to it. hydrochloric acid, with stirring and cooling with ice. This solution is further concentrated to approximately 1/3 of its original volume and the precipitated material is separated by filtration to obtain 93 mg of the desired compound.

Elemental analysis (C 13 H 17 NO 8 0.2H 2 O)

Calculation (in%) C - 48.97; N - 5.50; N - 4.39

Found (in%): C - 48.80; N - 5.35; N - 4.31

Test example 1: Determination of 5-ASA concentration in plasma

7-week-old male SD rats were administered intravenously 5-ASA as the study drug and were orally administered Compound , Compound , Compound or Pentaza at a dose of 50 mg/kg as 5-ASA. Plasma concentrations of 5-ASA are determined using high performance liquid chromatography (HPLC). In the case of Pentaza (registered trademark), granules obtained by spraying Pentaza (registered trademark) tablets are used.

The results obtained are shown in the table.

Table Pharmacokinetic parameter values ​​based on 5-ASA levels in rat plasma
Compound	Method of administration	Dose (50 mg/kg)	Time achieving maximum plasma concentration (Tmax) (hour)	Maximum plasma concentration (Cmax) (ng/ml)	Area under the concentration curve (AUC) (ng h/ml)	Bioavailability 1) (DB) (in%)
5-ASK	IV	1	-	-	1417	-
Pentasa	Orally	50	2	4958	10441	15
Compound	Orally	50	0,5	435	1504	2
Compound	Orally	50	8	160	571	0,8
Compound	Orally	50	1	1962	4235	6
n = 2-3 1) (AUC after oral administration of each test compound / AUC after intravenous administration of 5-ASA) × (amount of intravenous 5-ASA administered / amount of orally administered each test compound) × 100

From the above data it is clear that 5-ASA is detected in plasma at a relatively high concentration after oral administration of Pentaza (registered trademark) (see Fig. 1), which implies that 5-ASA is released from the part of the administered Pentaza in the upper part small intestine at the site of absorption.

On the other hand, the plasma concentrations of 5-ASA after oral administration of Compound , Compound and Compound , each a 5-ASA glycoside, remain low compared to the concentration of Pentaza (registered trademark) (see FIG. 1). In addition, in the case of administration of the compound or compound, the concentrations of 5-ASA in plasma remain low in comparison with the administration of the compound when low concentrations of 5-ASA are detected (see Fig. 1). The bioavailability of 5-ASA (see table) after oral administration of compound , compound , compound and Pentase (registered trademark) was calculated to be 2, 0.8, 6 and 15%, respectively. Namely, compound , compound and compound were found to have a lower rate of absorption from the gastrointestinal tract compared to Pentase. Thus, compound , compound and compound are shown to have relatively low bioavailability values.

The likely reason for this is that the compound and the compound cannot be easily hydrolyzed in the stomach and small intestine, unlike the compound and, in this regard, they do not lead to the formation of 5-ASA in the stomach and upper small intestine.

Test example 2: Change in the concentration of 5-ASA in the contents of the gastrointestinal tract

7-week-old male SD rats are orally administered the compound, Pentaza (registered trademark) at a dose of 50 mg/kg as 5-ASA and then the contents of the cecum, proximal colon, distal colon and rectum are homogenized and centrifuged. Next, the amount of 5-ASA in appropriate locations in the colon is determined using high performance liquid chromatography (HPLC). For Pentaza (registered trademark), granules obtained by spraying Pentaza (registered trademark) tablets are used for the analysis.

The results obtained are illustrated in Fig.2 - Fig.5.

Next, the compound and Pentaza (registered trademark) at a dose of 50 mg/kg as 5-ASA are administered orally and the colon and rectum are homogenized and centrifuged. The concentrations of 5-ASA in colon and rectal tissue are then determined using high performance liquid chromatography (HPLC). For Pentaza (registered trademark), granules obtained by spraying Pentaza (registered trademark) tablets are used for the analysis.

The results obtained are illustrated in Fig.6 and Fig.7.

In the case of administration of the compound, the concentrations of 5-ASA in colon tissue and in rectal tissue were also higher than in the variant of administration of Pentaza (registered trademark) (see Fig. 6 and Fig. 7).

The results of Test Example 1 confirm that the compound and compound do not undergo rapid hydrolysis in the stomach and small intestine, do not form 5-ASA in the stomach and upper small intestine, and are absorbed in small amounts from the gastrointestinal tract.

It also appears from the results of Test Example 2 that the compound and compound are delivered to the lesion site in the colon and are metabolized to 5-ASA by intestinal bacteria. In particular, in the case of the compound, 5-ASA, which is effective in ulcerative colitis, is found in high concentrations in relevant areas of the colon.

Test Example 3: Study on the Effect of the Compound on Trinitrobenzenesulfonic Acid-Induced Colitis in Rats (hereinafter abbreviated as TNBS)

In female SD rats, after a 24-hour fast, an aqueous solution of TNBS/50% ethanol (30 mg/0.25 ml/rat) was injected into the colon at a distance of 8 cm from the anus using an oral gavage under pentobarbital anesthesia to induce colitis to induce colitis. 3 days after the administration of TNBS, the colon is cut out and the weight of the colon in its raw state is determined by weighing at a distance of 8 cm from the anus. The degree of development of colitis is assessed using a scoring system according to the method of Wallas et al. (Wallace et al., Gastroenterology, 96, 29-36 (1989)). The test compounds were administered orally twice daily: Pentaza (registered trademark) at doses of 30 mg/kg and 100 mg/kg and compound at doses of 61.8 mg/kg and 205.9 mg/kg (calculated to correspond to 30 mg/kg and 100 mg/kg 5-ASA) (on the day of TNBS administration, administered once a day 4 hours before TNBS administration). Pentase (registered trademark) is administered in the form of granules obtained by spraying Pentase (registered trademark) tablets.

The results obtained are illustrated in Fig.8 and Fig.9.

The compound significantly reduces the degree of damage (according to the scoring system) when used at a dose of 61.8 mg/kg (which corresponds to 30 mg/kg 5-ASA) and significantly inhibits the increase in wet weight of the colon at a dose of 205.9 mg/kg kg (corresponding to 100 mg/kg 5-ASA) (see Figs. 8 and 9). Whereas Pentaza (registered trademark) does not show a clear effect on either the severity of the lesion (as assessed) or the level of increase in wet weight of the colon.

Example of preparation of composition 1: Powder form of the drug (for internal use)

250 mg of compound , 63.5 g of corn starch and 17.5 g of crystalline cellulose are introduced into the fluidized bed of a granulator/dryer and sprayed with 175 ml of a 10% aqueous solution of polyvinyl alcohol for granulation. Magnesium stearate (0.4% v/v) is then added to this layer to obtain a 700 mg powder preparation containing 500 mg of this compound.

Example of preparation of composition 2: Tablet (preparation for internal use)

A powder mixture of 400 g of compound, 153 g of corn starch and 42 g of crystalline cellulose is pressed using a dry granulator and sprayed into granules. Magnesium stearate (0.8% v/v) is then added to the mixture and the mixture is formed into tablets weighing 600 mg and having a diameter of 11 mm, thereby obtaining tablets each containing 400 mg of this compound.

Preparation example of composition 3: Capsule (for internal use)

A powder mixture of 250 g of compound, 222.5 g of anhydrous calcium hydrogen sulfate and 25 g of croscarmellose sodium is pressed using a dry granulator and sprayed into granules. Magnesium stearate (0.5% v/v) is then added to the said mixture and 500 mg of the mixture is filled into hard capsule No. 0, thereby obtaining a capsule containing 250 mg of this compound.

Preparation example of composition 4: Cylindrical granules (preparation for internal use)

375 g of the compound, 85 g of corn starch and 25 g of crystalline cellulose are introduced into a kneader and 125 ml of a 12% aqueous solution of polyvinyl alcohol are added and the mixture is mixed. The kneaded material is then extruded through a molding extruder equipped with a sieve having 0.7 mm diameter holes. The extruded material is dried and sieved to obtain pellets weighing 1000 mg, each containing 750 mg of this compound.

Preparation example of composition 5: Spherical coated granules (preparation for internal use)

200 mg of nonpareil (24-32 mesh) is introduced into a fluid bed granulation coater equipped with a centrifuge, and while spraying an 8% aqueous solution of hydroxypropyl cellulose (in 50% ethanol), slowly add a powder mixture of 500 g of compound, 170 g of corn starch and 40 g of low-substituted hydroxypropylcellulose for granulation and the resulting granules are dried to form approximately 900 g of spherical granule base.

Then, 400 g of the said spherical bead base is introduced into the fluidized bed of the granulator/dryer and 250 ml of an aqueous solution containing 12.5 g of hydroxypropyl methylcellulose, 2.5 g of propylene glycol and 1.7 g of titanium oxide is sprayed to obtain a shell-coated spherical bead weighing 1000 mg. , each containing 500 mg of this compound.

Industrial applicability

The compound of the present invention has certain properties to effectively deliver 5-ASA, used as a therapeutic agent for ulcerative colitis, directly to the colon, its site of action, without allowing transfer of 5-ASA into the plasma. In other words, in this case it is possible to reduce systemic side effects and, accordingly, increase the dose required to obtain the maximum therapeutic effect.

CLAIM

1. 5-Amino-2-(-D-galactopyranosyloxy)benzoic acid or 5-amino-2-(-D-galactopyranosyloxy)benzoic acid or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition having a therapeutic effect for ulcerative colitis, comprising as an active ingredient 5-amino-2-(-D-galactopyranosyloxy)benzoic acid or 5-amino-2-(-D-galactopyranosyloxy)benzoic acid or pharmaceutically acceptable thereof salt and a pharmaceutically acceptable carrier.

3. A therapeutic agent for use in ulcerative colitis, comprising as an active ingredient 5-amino-2-(-D-galactopyranosyloxy)benzoic acid, 5-amino-2-(-D-galactopyranosyloxy)benzoic acid or 5-amino-2 -(-D-glucopyranosyloxy)benzoic acid or a pharmaceutically acceptable salt thereof.

10.21518/2079-701X-2017-15-44-50

M.V. SHAPINA, Ph.D., I.L. KHALIFA, MD, professor

State Scientific Center of Coloproctology named after. A.N. Ryzhikh Ministry of Health of Russia, Moscow

USE OF 5-AMINOSALICYLIC ACID DRUGS FOR THE TREATMENT OF ULCERATIVE COLITIS

IN DIFFERENT DOSING MODES

5-ASA drugs are the mainstay of treatment for ulcerative colitis. Today on the market of 5-ASA drugs available for the treatment of ulcerative colitis, there are many dosage forms that differ in the shell, the method of delivery of the active substance and the dosage regimens of the drug. The purpose of this review is to compare these forms according to the main parameters: effectiveness, safety and adherence to treatment.

Key words: ulcerative colitis, 5-aminosalicylic acid, dosage regimen, mesalazine. M.V. SHAPINA, PhD in medicine, I.L. KHALIF, MD, Prof.

State scientific center of Coloproctology them. A. N. Redheads Ministry Of Health Of Russia, Moscow USE OF 5-AMINOSALICYLIC ACID FOR TREATMENT OF ULCERATIVE COLITIS IN DIFFERENT DOSAGE MODES Preparations of 5-ASA are the first line treatment of ulcerative colitis (UC). Today, in the market of drugs 5-ASA available for the treatment of UC, there are many dosage forms, varying in the coating, method of delivery of active substance and dosing regimens of the drug. The aim of this review is to compare these dosage forms by the main parameters: efficiency, safety and adherence to treatment.

Keywords: ulcerative colitis, 5-aminosalicylic acid, dosage regimen, mesalazine.

5-ASA DRUGS IN HISTORICAL PERSPECTIVE

In historical perspective, attempts to treat inflammatory bowel diseases have been made for a long time. But the era of successful treatment for ulcerative colitis (UC) began with the advent of sulfasalazine, developed by Nana Schwartz in 1942. Sulfasalazine consists of 5-aminosalicylic acid (5-ASA) linked to sulfapyridine through a diazo bond. This bond is readily cleaved by bacterial azoreductases in the colon to produce two components. Mesalazine has been found to be the therapeutically active component, whereas sulfapyridine, which is primarily absorbed into the blood, is thought to function solely as a carrier molecule.

Giving patients 5-ASA, uncoated or unbound to a carrier molecule, has shown that mesalazine is readily absorbed in the upper small intestine and cannot reach the colon at therapeutic concentrations. The binding to the sulfapyridine molecule largely resists premature absorption and can therefore serve as a delivery system that delivers 5-ASA to affected areas of the colon. Despite the fact that the use of corticosteroids has a more pronounced clinical effect compared to 5-ASA, the use of hormonal drugs is limited in time due to the development of severe side effects. It was precisely this problem that the appearance of

the introduction of 5-ASA drugs, which have proven effective in clinical trials not only for inducing remission, but also, more importantly, for maintaining it for a long time.

However, despite a significant breakthrough in the treatment of UC, about 30% of patients receiving sulfasalazine experienced adverse events such as leukopenia with agranulocytosis, toxic-allergic skin lesions, renal dysfunction, pancreatitis, infertility in men, etc. The main cause of a large number of adverse events was the sulfapyridine molecule, the toxicity of which had already been proven previously. At the same time, some of the adverse events turned out to be dependent on the dose of the drug, which significantly limited the therapeutic options. More than 10 years of research were required to find and improve alternative delivery systems for 5-ASA.

The toxicity problem was solved by creating 5-ASA preparations without sulfapyridine in the mesalazine molecule. Like sulfasalazine, these drugs are poorly absorbed in the upper gastrointestinal (GI) tract but are easily metabolized by intestinal flora in the lower intestine. The effectiveness and safety of 5-ASA preparations have been evaluated in numerous clinical studies, which have proven the clinical effectiveness and safety of mesalazine, despite the fact that a number of studies did not have sufficient statistical power to draw definitive conclusions. Systematic reviews have shown that oral

5-ASA at doses of 2 g per day or higher is more effective than placebo. Thus, they are as effective as sulfasalazine, and perhaps superior to it, but without its side effects.

VARIETY OF DRUG FORMS 5-ASA

There are different forms of 5-ASA preparations - for systemic therapy (drugs taken orally) and for topical therapy (drugs that are administered directly into the colon). Among the 5-ASA preparations for local therapy are suppositories (their effect extends only to the rectum), foam (to treat inflammation in the rectum and sigmoid colon) and microenemas (reach the left flexure of the colon). All local therapy drugs are prescribed for lesions of the distal colon or left-sided lesions. Systemic therapy with 5-ASA drugs is carried out in patients with widespread lesions of the colon (first line of therapy for total and left-sided UC, second line of therapy for proctitis). Currently, there are various oral forms of delivery of mesalazine to the colon: delayed (extended) and immediate (non-extended) release of 5-ASA; enteric-coated and semi-permeable membrane-coated (time-dependent release of 5-ASA). The main task of oral forms is to deliver the maximum amount of the active substance to the inflamed areas of the colon, because UC remission directly depends on the concentration of 5-ASA in the colon mucosa (COTC) (Fig. 1).

Non-extended forms of 5-ASA include Salofalk, Asacol and Mesacol tablets. To avoid loss of mesalazine in the upper gastrointestinal tract, these drugs are enteric coated, which dissolves at different pH levels. Salofalk tablets are coated with a coating consisting of EuCgadi L - a resin that dissolves at a pH above 6.0. The shell of the drug Asakol consists of EuSgadk S, a resin that dissolves at a pH above 7.0. The composition of the Mesacol drug shell includes both EuSgadk S and EuSgadk L.

Figure 1. UC remission is directly dependent on concentration

5-ASK in SOTC

80 70 60 50 -40 -30 -20 10

Patients with endoscopic remission of UC (n = 48)

Patients without endoscopic remission of UC (n = 25)

Figure 2. Drugs with pH-dependent release

provide the highest concentration of 5-ASA in the area of ​​inflammation in UC

pH dependent release -2.4 g/day (n=73)

Prodrugs - Delayed release sulfasalazine - 3.0 g/day (n=18) pH independent -3.0 g/day (n=11)

In search of the maximum therapeutic effect in the lumen of the colon, mesalazine preparations have continuously evolved, new dosage forms have appeared that provide a constant increase in the effectiveness of UC therapy. The most modern forms of prolonged release of mesalazine are considered. These include Pentasa, tablets and granules, Salofalk, granules, Mezavant, tablets.

Pentasa consists of microgranules of 5-ASA, into which, after oral administration, both tablets and granules of the drug disintegrate. The microbeads are coated with a semi-permeable ethylcellulose membrane designed for controlled release that begins in the duodenum and continues to affected areas of the distal intestine. However, with the early release of 5-ASA in the small intestine, the risk of a decrease in its concentration in the SOT increases. Thus, due to the early onset of release, about 30-50% of the administered dose of Pentasa is absorbed in the small intestine. pH-dependent release formulations have been shown to provide higher concentrations of mesalazine in the colon mucosa compared to other forms of 5-ASA (Figure 2).

Therefore, an alternative to conventional forms of mesalazine is the use of drugs that can provide significant levels of 5-ASA in the distal colon. New forms of mesalazine have been shown to be highly effective - 5-ASA granules and MMX mesalazine (Mezavant), which are superior to conventional 5-ASA in distal UC.

Salofalk, granules, is a slow-release 5-ASA preparation coated with Eudragit L. . Mesalazine MMX (Mezavant) uses MuLti Matrix System (MMX®) technology (a registered trademark of Cosmo Technologies Limited) to slow the release of mesalazine and ensure delivery of the active ingredient to the colon. While other oral drugs

5-ASA parasites release mesalazine into the lumen of the colon, the Mezavant multi-matrix system has an adhesion effect, due to which 5-ASA “sticks” to the wall of the colon, which makes it possible to create a high concentration of mesalazine in the colon throughout the colon, including the rectum (Fig. .3) .

5-ASA drugs are the basic therapy that is necessary for all patients with UC. Since complete cure of patients with UC is achieved only by removing the substrate of the disease (colproctectomy), upon achieving remission, the non-operated patient should remain on constant maintenance (anti-relapse) therapy, the basis of which, as a rule, is 5-ASA. These drugs are used both for induction and maintenance of remission.

INDUCTION OF YAC REMISSION

The goal of UC therapy is to achieve and maintain steroid-free remission (stop taking corticosteroids within 12 weeks after the start of therapy), prevent complications of UC, prevent surgery, and if the process progresses, as well as the development of life-threatening complications, timely prescription of surgical treatment.

According to the European consensus ECCO and Russian clinical guidelines for the diagnosis and treatment of ulcerative colitis, indications for systemic therapy with 5-ASA drugs are left-sided or total lesions of the colon of mild to moderate severity. To induce remission, 2.4-4.8 g of mesalazine (depending on endoscopic activity) per day orally is prescribed in combination with local therapy with 5-ASA drugs or topical glucocorticosteroids for at least 37-45 days according to the ECCO consensus. Russian experts recommend continuing therapy for up to 6-8 weeks if a positive response is achieved after 2 weeks.

The goal of treatment is to achieve clinical and endoscopic remission of UC. You should switch to maintenance therapy after achieving endoscopic remission, which must be monitored (Fig. 4). During patient management, it is possible to non-invasively assess the healing of the mucous membrane (endoscopic remission, adequacy of maintenance therapy) - study the concentration of fecal calprotectin at least once every 3 months.

MAINTAINING YAC REMISSION

5-ASA drugs are the first line of maintenance therapy in patients who have responded to mesalazine or steroids (oral or rectal).

For patients who have achieved remission of ulcerative colitis during therapy with 5-ASA drugs, the oral dose of the drug, after obtaining a clinical response, can be reduced to a maintenance dose of £2.0 g per day. For rectal administration - 3 g per week in divided doses. According to Russian clinical guidelines, for maintenance therapy mesalazine (5-ASA) is prescribed orally 1.2-2.4 g per day. Additionally, rectal administration of mesalazine 1-2 g three times a week is recommended. However, doses can be adjusted individually, since in some cases higher maintenance doses of 5-ASA are necessary.

According to the European ECCO consensus, prescribing dosages of oral 5-ASA less than 2.0 g per day to maintain remission is not advisable, even if lower dosages of 5-ASA are indicated in the instructions for medical use of the drugs. Prescribing 5-ASA in doses lower than recommended or voluntarily reducing them by the patient with a high degree of probability can lead to failure of clinical remission.

The polymer shell, resistant to the stomach environment, begins to dissolve at pH 6.8 in the terminal ileum

The hydrophilic matrix interacts with the intestinal contents and forms a viscous gel-like mass, ensuring a prolonged uniform distribution of 5-ASA throughout the colon

The lipophilic matrix ensures the adhesion of mesalazine to the intestinal mucosa, maintaining

high concentration of 5-ASA throughout the colon, including the rectum

Figure 4. Endoscopic picture of UC

Endoscopic picture of UC, moderate degree of activity of the inflammatory process

Endoscopic picture of UC,

minimal degree of inflammatory process activity

Endoscopic picture of previous inflammation

Endoscopic remission of UC

Photos are the property of the Federal State Budgetary Institution "GNTsK im. A.N. Ryzhikh" of the Ministry of Health of Russia

In cases where remission is achieved during treatment with 5-ASA drugs at a dose of 4.0-4.8 g per day, and an exacerbation of the disease occurs when switching to maintenance therapy at lower doses, it is recommended to carry out continuous maintenance therapy with 5-ASA drugs in therapeutic dose 4.0-4.8 g per day.

5-ASA drugs to maintain remission are also prescribed when remission is achieved with the help of glucocorticosteroids (GCS). In this case, 5-ASA drugs are prescribed against the background of reducing the dose of systemic

corticosteroids, when their daily dose reaches 40-45 mg, equivalent to prednisolone. It should be especially noted that GCS cannot be used as maintenance therapy, therefore, after 3 months of therapy, the use of GCS should be discontinued while maintaining basic 5-ASA therapy.

5-ASA preparations are prescribed for daily use, dividing the daily dose into several doses or taking once a day (as for the drug Mezavant with the MMX® mesalazine delivery system). According to current recommendations, the use of 5-ASA once a day is preferable for maintenance therapy in patients with UC.

It is advisable to carry out maintenance therapy of left-sided and total UC with a combination of oral and rectal forms of 5-ASA. In some cases, it is possible to carry out monotherapy with a multi-matrix form of mesalazine (the drug Mezavant), when used, a sufficient concentration of 5-ASA is observed throughout the colon, including the rectum (Fig. 5). It has been proven that long-term continuous use of mesalazine MMX as monotherapy is comparable in clinical effectiveness to the use of combination therapy (a combination of oral and rectal forms of 5-ASA) for the treatment of distal forms of UC. In some patients with severe inflammation of the distal parts, an insufficient response may be observed, therefore, to increase the concentration of 5-ASA in the rectal mucosa, a rectal form of 5-ASA should be added to this oral form. It is important to exclude that the reduced response to monotherapy was not due to non-adherence to therapy.

Patients with ulcerative colitis should receive ongoing supportive care throughout their lives (as an alternative to colproctectomy). With adequate anti-relapse therapy, exacerbations can be avoided in half of the patients for 5 years, and in 20% of patients for 10 years.

Figure 5. MMX® ensures uniform distribution of mesalazine throughout the colon

(SoZD Etomacfl

Rectum -- Sigmoid Colon

Gamma scintigraphy 1 tablet Mezavant 1.2 g

COMPARISON OF DIFFERENT DOSING REGIMENS OF 5-ASA DRUGS FOR INDUCTION OF REMISSION

Efficiency

Two studies compared the effectiveness of single-dose and multiple-dose mesalazine regimens for inducing remission of UC.

According to the first study, which included 380 patients with active UC, 79.1% of patients in the single-dose group (n = 191) and 75.7% in the three-dose group (n = 189) achieved clinical remission (p = 0.001) for non-superiority). Thus, 3 g mesalazine once daily was found to be as effective as 1 g mesalazine 3 times daily for inducing UC. Due to higher adherence, the single dose regimen should be preferred.

According to the second study, in which patients (n = 206) were randomized to 2 treatment groups with mesalazine (4 g per day, 8 weeks), taken once a day or twice a day, morning and evening. Patients also received rectal mesalazine 1 g daily for 4 weeks. The study met the primary endpoint of non-superiority of the double dosing regimen over the single dose regimen in clinical and endoscopic remission at week 8 (41.8% vs. 52.1%, respectively, 95% confidence interval, p = 0.14). Improvement on the iC^A scale! (92% vs. 79%; p = 0.01) and mucosal healing (87.5% vs. 71.1%; p = 0.007) were higher in the single-dose group, the time to achieve remission was significantly shorter (26 vs. 28 days; p = 0.04).

Safety

There was no statistically significant difference in the incidence of side effects between single and traditional dosing.

Table. Dosage regimen for oral forms of 5-ASA

Drug Dose Frequency of dosing for exacerbation of UC Frequency of dosing for maintenance therapy of UC

Sulfasalazine (tab.) 500 mg 8 tablets per day for 4 divided doses 4 tablets per day for 4 divided doses

Mesacol (tab.) 400 mg 10 tablets per day for 3-4 doses 5 tablets per day for 3-4 doses

Asacol (tab.) 400 mg 800 mg 10 tablets per day for 3-4 doses 5 tablets per day for 3-4 doses 5 tablets per day for 3 doses 3 tablets per day for 3 doses

Pentasa (tab.) 500 mg 8 tablets per day for 2-4 divided doses 4 tablets per day for 2-4 divided doses

Pentasa (granules) 1 g 2 g 4 sachets per day for 2 doses 2 sachets per day for 2 doses 2 sachets per day for 2 doses 1 sachet per day

Salofalk (tab.) 250 mg 500 mg 16 tablets per day for 4 doses 8 tablets per day for 4 doses 8 tablets per day for 4 doses 4 tablets per day for 4 doses

Salofalk (granules) 500 mg 1 g 8 sachets per day for 1-3 doses 4 sachets per day for 1-3 doses 4 sachets per day for 1-3 doses 2 sachets per day for 1-2 doses

Mezavant (Tab. MMX) 1.2 g 4 tablets 1 r/day 2 tablets 1 r/day

*In terms of maximum dosages in accordance with clinical recommendations (4.0-4.8 g - to induce remission of UC; 2.0-2.4 g - to maintain remission of UC).

COMPARISON OF DIFFERENT DOSING REGIMENS OF 5-ASA DRUGS FOR MAINTAINING REMISSION

Efficiency

Three studies (1,871 patients) reported the effectiveness of maintenance treatment in terms of the number of patients remaining in clinical and endoscopic remission at six months. Among patients receiving the drug once, 19% of patients experienced disease relapse within 6 months of therapy compared with 18% of patients receiving the drug as standard (OR 1.02, 95% CI 0.85 to 1.23). This comparison did not reveal any statistically significant differences (p = 0.76, 12 = 0%). When comparing subgroups by drug form, no differences in effectiveness were identified between single administration and usual dosing.

Eight studies (3,127 patients) showed results of maintaining clinical and endoscopic remission after 12 months. There were no statistically significant differences in relapse rates at 12 months. In the groups of patients receiving the drug once a day, the proportion of patients with a relapse was 29%, while in the group of patients receiving the drug in a standard dosage regimen, 31% ^ - 0.91, 95% CI 0.82 to 1. 01). This comparison revealed no statistically significant differences (p = 0.26, 12 = 22%). Since the effectiveness of taking mesalazine for maintaining remission in a single and multiple doses does not differ, preference should be given to taking the drug once a day due to higher patient adherence and, accordingly, better treatment results.

Safety

Six studies (2,714 patients) reported the proportion of patients who reported at least one adverse event.

There were no statistically significant differences in the frequency of adverse events. Approximately 45% of patients in the once daily dosing group and the standard dosing group each reported at least one adverse event (OR 1.00, 95% CI 0.92 to 1.08). With this comparison, no statistically significant differences were obtained (p = 0.43; 12 = 0%). Seven studies (3,737 patients) reported the proportion of patients who were withdrawn from studies due to adverse events. Differences in groups with different dosage regimens of the drug were not recorded.

The most common side effects reported in the studies were: dyspepsia, abdominal pain, diarrhea, headache, nasopharyngitis, upper respiratory tract inflammation, gastroenteritis and worsening ulcerative colitis.

ADDITION TO TREATMENT

Patients with UC face the need to take a large number of medications per day. Many patients do not adhere to standard multiple-dose regimens (two or three times daily), which may result in decreased effectiveness and increased risk of relapse in patients in remission and a worse long-term prognosis. Poor adherence to treatment may be especially pronounced in patients in remission, since patients do not have persistent symptoms that motivate them to take medications. Many factors influence the adherence of patients with ulcerative colitis to therapy: disease activity and duration, cost of treatment, fear of adverse events, individual psychosocial characteristics and the patient-physician relationship. Although multiple factors influence adherence to drug therapy in patients with UC, large pill counts and multiple-dose regimens are thought to be the main determinants.

dividing factors of insufficient adherence. Thus, an online survey conducted among IBD patients in the United States, involving 1,595 patients with ulcerative colitis taking 5-ASA, showed that 65% (944) of patients admitted that they were not adherent to therapy. At the same time, 90% of them noted non-compliance with the dosage regimen as the main reason - “I simply forgot” to take the drug. Additionally, the reasons were indicated - frequent intake per day and a large number of tablets, rectal use, inconvenience of administration. Summarizing the survey data, it should be concluded that the use of oral forms of mesalazine taken

Once a day, preferably for patients. Also, in a large open-label study of real-life clinical practice, based on the analysis of data of approximately

In 2 thousand patients with UC, it was confirmed that the drug Mezavant (mesalazine MMX) with a once-daily dosing regimen showed the greatest adherence compared to drugs taken two or more times a day.

Thus, mesalazine formulations that include once daily dosing may improve adherence and treatment outcomes (Table).

CONCLUSION

The emergence of 5-ASA drugs has significantly changed the approach to the treatment of UC. This class for 45 years

remains the basic therapy for this disease both for induction and maintenance of remission. Mesalazine is highly effective for the treatment of mild and moderate forms of UC, as well as a good safety profile.

Since non-operated patients after achieving remission should remain on constant maintenance (anti-relapse) therapy with 5-ASA, it is important

choose a therapy to which patients will adhere for a long time.

The emergence of new forms of mesalazine, which make it possible to increase the concentration of 5-ASA in the distal parts of the colon and reduce the dosage regimen to once a day, has led to increased patient adherence to treatment, which, in turn, is a prognosis for long-term maintenance of remission in patients with UC. f

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Pharmacotherapy

Place and purposes of using aminosalicylates in ulcerative colitis

Summary

Various aspects of the use of 5-aminosalicylic acid (5-ASA) drugs in ulcerative colitis are considered. The mechanisms of action of this group and their points of application in the inflammatory cascade in this disease are analyzed in detail. The general characteristics of different 5-ASA preparations are given, as well as the features of their pharmacodynamics, which determine the advisability of their use in different clinical situations. Indications for use are listed, indicating treatment regimens and the duration of their use during exacerbation and remission of ulcerative colitis. The treatment of distal forms of the disease using different dosage forms of 5-ASA is discussed in detail. Emphasis is placed on the duration of maintenance therapy depending on the goal - prevention of relapse of the disease or colon cancer. The mechanisms of the anticarcinogenic effect of aminosalicylates and the advisability of their use as a means of preventing cancer in ulcerative colitis are described with reference to controlled studies.

Keywords: 5-ASA, sulfasalazine, mesalazine, ulcerative colitis, colon cancer

Since 1946, 5-aminosalicylic acid (5-ASA) preparations have become firmly established in the arsenal of therapeutic agents for ulcerative colitis (UC). Aminosalicylates (sulfasalazine and mesalazine) are traditionally used as first-line drugs for mild and moderate forms of the disease to stop an attack and induce remission, to maintain remission.

Mechanism of action of aminosalicylates

The mechanism of action of 5-ASA is due to the inhibition of inflammatory mediators (arachidonic acid derivatives and proinflammatory cytokines) involved in the implementation of intercellular interactions and the development of inflammation in inflammatory bowel diseases (IBD). Unlike salicylic acid derivatives (aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs]), which block the cyclooxygenase pathway of the arachidonic acid cascade and selectively inhibit prostaglandin synthesis, aminosalicylates have a multidirectional effect on the synthesis of arachidonic acid metabolites (Fig. 1). Thus, high doses of 5-ASA and sulfasalazine suppress the production of prostaglandins, while low doses can stimulate it. This is a fundamentally important point, since prostaglandins in IBD play the same protective role for the intestinal mucosa as for the gastric mucosa in peptic ulcer disease. Their deficiency reduces the protective functions of the mucous membrane. The main point of application of 5-ASA in the arachidonic cascade is the enzyme 5-lipoxygenase, which results in the formation of eicosanoid peroxides and hydroperoxides of fatty acids and leukotrienes. The latter, primarily leukotriene B4, play a major role in the development of inflammation (Fig. 1). 5-ASA also suppresses the synthesis of pro-inflammatory cytokines of macrophage origin: interleukins (IL) - IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor (TNF-α), the production of antibodies by B lymphocytes, neutralizes free oxygen radicals (Fig. 2). In addition, it has been shown that 5-ASA is able to suppress the nuclear factor NFkb, which is responsible for the synthesis of proinflammatory cytokines.

Characteristics of 5-ASA preparations

Sulfasalazine, synthesized in 1946, it is 5-ASA linked by a nitrogen bond to a sulfanilamide (sulfapyridine). Sulfapyridine is an inert part of the molecule, prevents the absorption of the drug in the jejunum and, in fact, serves as a carrier of 5-ASA to the colon. The bond between 5-ASA and sulfapyridine is cleaved in the ileum and colon under the influence of bacterial enzymes (azoreductases) and the released 5-ASA exerts its anti-inflammatory effect by blocking the synthesis of mediators in the colon mucosa (COTC). Free 5-ASA is only 20-30% absorbed from the colon, so its systemic effect is very insignificant. The main part of the drug remains in the intestinal lumen and in the intestinal epithelium in a partially acetylated form. Thus, 5-ASA released from sulfasalazine has a mainly local effect. A therapeutic dose of sulfasalazine is prescribed until clinical and endoscopic remission is achieved (within 4-8 weeks), after which it is recommended to take a maintenance dose to prevent relapse for an average of 1.5 years after the UC attack subsides. However, the duration of anti-relapse therapy can vary widely (from 6 months to 2 years) depending on the individual nature of the disease and the frequency of relapse.

Despite its more than 50-year history, sulfasalazine has not lost its clinical significance, although it has significant drawbacks that limit the possibility of increasing doses and duration of administration. Sulfasalazine is toxic and has a wide range of adverse reactions, including: leukopenia with agranulocytosis, toxic-allergic skin manifestations, impaired renal function, pancreatitis, infertility in men, etc. These reactions occur in 15-20% of patients. The development of side effects is associated with the sulfonamide part of the drug, since sulfapyridine is almost completely absorbed from the colon and metabolized in the liver.

Mesalazine. The toxicity problem was solved by the creation of 5-ASA preparations without sulfopyridine in the molecule (mesalazine, olsalazine, balsalazide). These drugs are not inferior to sulfasalazine in effectiveness, and perhaps even superior to it, but are devoid of its side effects. The most widespread both abroad and in Russia mesalazine (mesalamine). Tablet mesalazine preparations produced in different countries are similar in action and effectiveness and are 5-ASA in a protective coating. They differ in the nature of the enteric coating (eudragit, acrylic or ethylcellulose) and, accordingly, the location and rate of release of 5-ASA in the intestine. There is a clear correlation between the intraluminal concentration of 5-ASA and clinical efficacy, so the location of the lesion must be taken into account when prescribing 5-ASA drugs. The dissolution of the enteric eudragit coating of most mesalazine preparations (salofalk, azacol, samesil claversal, mezacol, etc.) and the release of 5-ASA depends on the pH in the intestinal lumen and is destroyed at its certain values ​​(pH > 6-7) in the terminal ileum and in the colon, where the maximum therapeutic concentration of 5-ASA is achieved. It follows from this that mesalazine is optimal for the treatment of UC and terminal ileitis in Crohn's disease. Long-term studies indicate its high effectiveness in the specified localization of the pathological process. In Russia, many years of experience in the use of mesalazine has been acquired based on work with the drug Salofalk , which is used for the treatment and prevention of relapses of IBD and has a minimum of side effects associated with individual intolerance to the drug.

Indications for the use of aminosalicylates

Treatment goals for UC include suppression of inflammatory activity and induction of remission, maintenance of remission, prevention of complications, and improvement of patients' quality of life. The use of 5-ASA for UC fully meets these goals, however, this only applies to mild and moderate forms of the disease. In severe cases, these drugs are not effective.

Ulcerative colitis with widespread lesions in the acute stage

Aminosalicylates are used as basic agents for oral administration during the period of UC attack. When taken orally, the maximum concentration of 5-ASA is achieved mainly in the ileum and cecum and in the ascending, and to a lesser extent, transverse, sections of the colon. In the left half of the colon, the concentration of 5-ASA is significantly lower, and in the sigmoid and rectum it is minimal; here the drug is practically absent. Therefore, oral administration of aminosalicylates is effective for widespread UC (total, subtotal and, to a lesser extent, left-sided). For mild UC, it is usually sufficient to prescribe 5-ASA drugs - sulfasalazine at a dose of 3-4 g/day or mesalazine 3 g/day. As a rule, there is no need to use hormonal drugs, excluding rare cases refractory to 5-ASA. For moderate UC, sulfasalazine 4-6 g/day or mesalazine 4–4.8 g/day are used. If there is no effect, corticosteroids are prescribed after 2-3 weeks.

Ulcerative colitis in remission

In UC, long-term anti-relapse therapy is a mandatory rule in the absence of contraindications. Refusal of maintenance treatment in most cases quickly leads to exacerbation. In the case of induction and achievement of remission by aminosalicylates, these same drugs are, of course, the main means for maintenance treatment. For common forms of UC, the drug of choice for long-term therapy is mesalazine. Sulfasalazine, due to its high toxicity, is not recommended for long-term use. Prevention of relapse of UC requires prolonged therapy for 1.5-2 years after the attack subsides and remission is achieved. The dose of mesalazine is 1.5 g per day, sulfasalazine 2 g per day.

5-ASA drugs are not effective for maintenance therapy of UC in cases of steroid-dependent or steroid-resistant disease. In these cases, azathioprine is used.

Distal ulcerative colitis

For distal forms of UC (proctitis, proctosigmoiditis), and, in some cases, for left-sided colitis, local treatment is recommended. For this purpose, there are dosage forms of mesalazine in the form of enemas, foams, gels and suppositories.

Rectal forms of 5-ASA are considered effective as first-line drugs (they have priority over steroids) for achieving both clinical and endoscopic remission. In the treatment of proctosigmoiditis, enemas with mesalazine (salofalk) are used, 2 and 4 g per day, depending on the degree of activity. Some studies indicate that the use of 1, 2 or 4 g of mesalazine rectally has the same effectiveness, however, the clinical experience of most gastroenterologists around the world shows that the daily dose of drugs for rectal administration in active inflammatory process is the same as for oral administration of 3-4 g/day. day. This dose allows you to quickly achieve remission if the course of the disease is favorable, but if necessary, use continues for up to 30 weeks without reducing the dose. To treat ulcerative proctitis, mesalazine is prescribed in suppositories. The daily dose is 1-2 g per day once or in 2 divided doses. In children, lower dosages are used in suppositories of 250 mg 2 - 3 times a day.

Doses, schedule and duration of treatment of distal UC with aminosalicylates are similar to those for common forms of the disease. Patients require mandatory prolonged anti-relapse treatment with locally active drugs for a long time. The maintenance dose can be 1 g/day of mesalazine rectally daily, every other day, or at least 2 times a week. Economic analysis has shown that even with the high cost of mesalazine drugs for local administration, prolonged therapy is more beneficial for the patient, and the total cost of treatment per year is lower, since spending on long-term maintenance doses is less than spending on high doses of drugs for relapses.

The question of the advisability of combined treatment with oral and rectal aminosalicylates is being debated. The effectiveness of such combinations for ulcerative proctitis is questionable; for proctosigmoiditis it has not been proven, but for left-sided colitis it may be optimal.

Recently created new rectal forms of drugs in the form of foam for the treatment of active UC with distal or left-sided lesions have a more pronounced effect and better tolerability due to uniform spraying and long contact with the mucous membrane compared with the same enemas and suppositories, especially in those patients who due to active inflammation, it is not able to retain even minimal volumes of fluid in the rectum. If there is no response to treatment with aminosalicylates within 2-4 weeks, it is recommended to switch to local administration of hormonal agents (budesonide, hydrocortisone, etc.). If further failure occurs, topical treatment with 5-ASA or steroids may be combined with oral mesalazine or sulfasalazine.

Typically, the clinical effect of local treatment develops quickly, however, in some cases, distal forms of UC are more persistent and refractory to treatment. In accordance with the provisions developed at an international workshop (1991), distal UC is considered resistant to treatment if remission is not achieved within 6-8 weeks with rectal use of aminosalicylates and corticosteroids or with a combination of local treatment and oral mesalazine.

If resistance is established and there is no effect from local treatment, they resort to systemic administration of prednisolone in medium doses - pomg/day until improvement is achieved, then they should again switch to rectal administration of 5-ASA drugs (Table 1). These recommendations are purely empirical and not supported by controlled studies.

Ulcerative colitis and colon cancer

It is well known that UC is associated with an increased risk of developing colon cancer (CC). This risk is believed to be 7-8 times higher in patients with UC than in the general population. A meta-analysis based on the results of 194 studies showed that the incidence of cancer among patients with UC ranges from 3-6/1000 per year. In Russia, the incidence of RTC in UC is, according to various authors, from 1.6 to 6.1%. In this regard, the issue of preventing RTC in this category of patients is urgent. As numerous studies have shown, aminosalicylates, used as basic drugs for the treatment of UC, also have an anticarcinogenic effect. The possibility of inhibiting tumor growth has already been discussed for aspirin and NSAIDs. The similarity of the structure and mechanisms of action of salicylates and aminosalicylates allowed us to assume the possibility of anticarcinogenic effects in the latter. This was confirmed in a retrospective study in which RTC was detected in 3% of UC patients regularly taking 5-ASA drugs, while cancer developed in 31% of patients not taking these drugs. A large population-based study conducted in Sweden, which included more than 3000 UC patients with follow-up for 10 years, showed a significant reduction in the relative risk of developing CC for patients who systematically took aminosalicylates compared with those who took the drugs occasionally. In particular, in patients receiving sulfasalazine, the risk decreased to 0.38 when compared with patients of the same age and sex with the same duration and severity of the disease, but who did not receive maintenance therapy. Long-term regular use of 5-ASA has also been demonstrated to reduce the risk of CC by 75-81% compared with controls, with mesalazine showing significantly higher efficacy than sulfasalazine. The mechanism of action of aminosalicylates on tumors is due to their ability to inhibit proliferation and enhance apoptosis of colon epithelial cells. The use of mesalazine (salofalk) in therapeutic doses for 4 weeks in patients with UC is accompanied by a decrease in the proliferation index of epithelial cells in the colon mucosa by 2-6 times compared with the initial values.

Since long-term use of sulfasalazine is limited by its side effects, the drug of choice not only for the prevention of relapse, but also for the prevention of RTC in UC is mesalazine. It should be assumed that the use of mesalazine as an anticarcinogenic drug should be longer than its use for the prevention of relapse, possibly lifelong. Such prolonged use helps to reduce the proliferative activity of the epithelium and reduces the likelihood of developing CC in risk groups. According to general recommendations, the maintenance dose, regardless of the main task, is 2 g for both mesalazine and sulfasalazine. At the same time, the feasibility of using higher doses for maintenance therapy, almost equal to therapeutic ones (3-4 g of mesalazine), is being discussed. This is due to the fact that it is not yet known which dose has the optimal anticarcinogenic effect and is indicated for cancer prevention.

Thus, there is clinical and experimental evidence of the anticarcinogenic effect of 5-ASA drugs. However, expanded clinical studies are required to determine the minimum required dose of drugs and the optimal timing of its administration.

Literature

Crohn's disease and ulcerative colitis. M.: Geotar-Med, 2001. Belousova colitis and Crohn’s disease. M.: Triad, 2002. Sandborn W. J. Medical management of ulcerative colitis. In: Targan S., Shanahan S., Karp L., editors. Inflammatory dowel disease-from bench to bedside. 2nd ed. London: Kluwer Academic publishers, 2002. pp. 605-630 Egan L. J., Sandborn W. J. Clinical pharmacology in inflammatory bowel disease: optimizing current medical therapy. In: Targan S., Shanahan S., Karp L., editors. Inflammatory bowel disease-from bench to bedside. 2nd ed. London: Kluwer Academic publishers, 2002. pp. 495-522. Donovitz M. Arachidic acid metabolites and there role in inflammatory bowel disease. An update requiring addition in a pathway. Gastroenterology 1985;88:580-7. Zimmerman M., Jewel D. Cytokins and mechanism of action of glucocorticoids and aminosalicylates in the treatment of ulcerative colitis and Crohn’s disease. Aliment Pharmacol Ther 1996;10(Suppl. 2):93-8. Hanauer S. B. Review article: aminosalicylates in inflammatory bowel disease. Aliment Pharmacol Ther 2004;20(Suppl. 4):60-5. Frieri G., Pimpo M. T., Palumbo G. C., Onori L., et al. Rectal and colonic mesalazine concentration in ulcerative colitis oral vs oral plus topical treatment. Aliment Pharmacol Ther 1999;13:1413-1417. Sandborn W. J. Marion J. F. Medical management of ulcerative colitis. In: Targan S., Shanahan S., Karp L., editors. Inflammatory dowel disease-from bench to bedside. 2nd ed. London: Kluwer Academic publishers, 2002. pp. 605-629. Cohen R. D., Woseth D. M., Thisted R. A., Hanauer S. B. A meta-analysis and overview of the literature on treatment options for left-side ulcerative colitis and ulcerative proctitis. Am J Gastroenterol 2000;95:1263-76. Marshall J. K., Irvine E. J. Rectal corticosteroids versus alternative treatment in ulcerative colitis: a meta analysis. Gut 1997;40:775-81. Ardizzone S., Doldo P., Ranzi T., Sturniolo G. C., et al. Mesalasine foam (Salofalk foam) in the treatment of active distal ulcerative colitis. A comparative trial vs. Salofalk enema. The SAF-3 study group. Ital J Gastroenterol Hepatol 1999;31:677-684. Pokrotnieks J., Marlicz K., Paradowski L., Margus B., et al. Efficacy and tolerability of mesalazine foam enema (Salofalk foam) for distal ulcerative colitis: a double-blind, randomized, placebo-controlled study. Aliment Pharmacol Ther 2000;14:1191-1198. Rufle W., Fruhmorgen P., Huber W., Kimmig J. M. Budesonide foam as a new therapeutic concept in the therapy of distal ulcerative colitis in comparision to mesalazine enemas. An open, controlled, randomized and prospective multicenter pilot study. Z Gastroenterol 2000;38:287-93. Jarnerot G., Lennard-Jones J., Brynskov J. Working team report: Medical treatment of refractory distal ulcerative colitis. Gastroenterol Int 1991;4:93-8. Bernstein C. N., Blanchard J. F., Kliever E., Wajda A. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 2001;91:854-62. Eaden J., Abrams K., Mayberry J. F. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001;48:526-35. Ekbom A., Helmick C., Zack M., Adami H. O. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 1990;323:1228-33. , Belousova colitis and colon cancer. Formation of risk groups, screening and prevention. Pharmatheca 2004;(13):39-44. , etc. Colon cancer in patients with ulcerative colitis. Klin Med 1988;(9):108-13. Hixson L. J., Alberts D. S., Krutzsch M., et al. Antiproliferative effect of nonsteroidal antiinflammatory drugs against human colon cancer cells. Cancer Epidemiol Biomarkers Prev 1994;3:433-8. Moody G. A., Jayanthi V., Probert C. S. J., Mac Kay H., Mayberry J. F. Long-term therapy with sulphasalazine protects against colorectal cancer risk and compliance with treatment in Leicestershire. Eur J Gastroenterol Hepatol 1996;8(12):1179-83. Brown W. A., Farmer K. S., Skinner S. A., et al. 5-aminosalicylic acid and olsalazine inhibit tumor growth in a rodent model of colorectal cancer. Dig Dis Sci 2000;45:1578-84. Bus P. J., Nagtegaal I. D., Verspaget H. W., Lamers C. B., et al. Mesalazine-induced apoptosis of colorectal cancer: on the verge of a new chemopreventive era? Aliment Pharmacol Ther 1999;13:1397-402. Ekbom A., Kornfeld lphasalazine use as a preventive factor for colorectal cancer in ulcerative colitis patients - a review (Clinical review). Inflammatory Bowel Disease 1996;2(4):276-8. Eaden J., Abrams K., Ekbom A., et al. Colorectal cancer prevention in ulcerative colitis: a case-control study. Aliment Pharmacol Ther 2000;14:145-53. Reinacher-Schick A., Seidensticker F., Petrasch S., et al. Mesalazine changes apoptosis and proliferation in normal mucosa of patients with sporadic polyps of the large bowel. Endoscopy 2000;32(3):245-54. , Isakov activity of the colonic epithelium in ulcerative colitis. Materials of the scientific session of TsNIIG. M, 1998. Velayos F. S., Loftus E. V., Jess T. et al. Predictive and protective factors associated with colorectal cancer in ulcerative colitis: a case-control study. Gastroenterology 2006;130:1941-9. Munkholm P., Loftus EV., Reinacher-Schick A. et al. Prevention of colorectal cancer in inflammatory bowel disease: value of screening and 5-aminosalicylates. Digestion 2006;73:11-9. , Nikitina colorectal cancer: molecular mechanisms of the anticarcinogenic effect of aminosalicylates of non-steroidal anti-inflammatory drugs. Pharmatheca 2005;(14):37-43.

Table 1 Treatment of distal and left-sided ulcerative colitis

_____________________________________________________________________________________________

proctitis mesalazine suppositories 500 mg x 4 r, 4-8 weeks before

1 g x 2 r to achieve remission

500 mg x 2 times, 1.5 years

1 g x 1 r night/night, anti-relapse

minimal therapy

500 mg h/day

proctosigmoiditis mesalazine enemas 2 g x 2 r, 4 g x 1 r 4-8 weeks before

hydrocortisone rectally 125 mg x2 r, achieving remission

drips or enemas 250 mg x 1 r night/night

mesalazine enemas 2 g daily or hourly for 1.5 years

anti-relapse

left-sided colitis mesalazine enemas 2-4 g/day 4-8 weeks before

hydrocortisone rectally 125-250 mg to achieve remission

budesonide enemas 2-4 mg nightly

mesalazine per os 2 g/day

or sulfasalazine 3-4 g/day

mesalazine per os 1.5-2 g/day anti-relapse

or sulfasalazine 2 g/day therapy

refractory prednisolone per os 40-60 mg

distal colitis +

mesalazine or until remission is achieved

steroids rectally

mesalazine enemas

or anti-relapse suppositories

_____________________________________________________________________________________________

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Rice. 2. Scheme of intercellular interactions in the lesion and points of application of drugs in IBD

T-lymphocytes, Th1 - type 1 helper cells, Tcyt - cytotoxic cells, APC - antigen-presenting cell, IF-interferon

» Medicines for ulcerative colitis - review

Attention: the information is not intended for self-medication. We do not guarantee its accuracy, reliability or relevance to your situation (although we strive to do so). Treatment must be prescribed by a medical specialist.

There are no magic drugs that can completely get rid of ulcerative colitis, but the choice of drugs that can achieve sustainable remission in IBD is quite wide.

Let's consider some features of drug therapy for this disease (other methods of combating UC - surgery, a gentle diet - are discussed).

How is UC treated?

As noted by S.R. Abdulkhakov and R.A. Abdulkhakov in the article “UC: modern approaches to diagnosis and treatment”, there are two basic groups of drugs used in the fight against ulcerative colitis:

• 5-ASA (aminosalicylates);
• GCS (glucocorticosteroids).

Treatment of ulcerative colitis: 5-ASA drugs

5-aminosalicylic acid agents increase the local concentration of prostaglandins that have a cytoprotective effect (i.e., increasing the protective capabilities of the intestinal mucosa).

The group includes, first of all, such well-known drugs as sulfasalazine and mesalazine.

Sulfasalazine- an old drug, it has been used for more than half a century. Its disadvantage is a variety of side effects, from nausea to headaches. Side effects occur in about a quarter of cases. The negative effect is explained by the influence of sulfapyridine, which is formed during the breakdown of the drug and does not provide its own anti-inflammatory effect.

Mesalazine(preparations with 5-ASA in a purer form) are a more modern development. The list of medications based on mesalazine includes salofalk, mesacol, pentasa, tidokol. So far these are the best remedies for NIBD. They have relatively few side effects and are sometimes recommended even for children, as well as pregnant and lactating women.

The group's drugs are available in various dosage forms - not only in tablets, but also in rectal suppositories and microenemas. Suppositories and microenemas are used very widely in the treatment of UC, since with this type of IBD, the distal (lower) parts of the large intestine are primarily affected.

The period of use of aminosalicylates can be quite long - months, or even years. Correct and timely cessation of therapy helps prevent relapse of the disease.

Glucocorticosteroids for ulcerative colitis

Known corticosteroids that are prescribed for nonspecific ulcerative colitis are:

• budesonide;
• hydrocortisone;
• prednisolone and its analogues.

Glucocorticosteroids are administered preorally, rectally, and intravenously.

They have anti-inflammatory, desensitizing, immunosuppressive and antitoxic effects.

Possible negative effects of long-term use of GCS drugs are increased blood pressure, excess growth of terminal hair, acne. In the worst cases, the development of steroid osteoporosis and neurological pathologies cannot be excluded.

If UC is mild, glucocorticosteroids are not necessary; treatment is often limited to a course of aminosalicylates.

Other medicines

What drugs are used in the fight against ulcerative colitis besides GCS and 5-ASA?

In case of resistance to steroids (it is detected in approximately 16% of patients) or, on the contrary, steroid dependence, immunosuppressants are included in the treatment regimen - cyclosporine, azathioprine.

In situations where UC is detected simultaneously with an intestinal infection, it is necessary to turn to broad-spectrum antibiotics (gentamicin, kanamycin, etc.). Antibacterial drugs are also required if there is a threat of sepsis or toxic megacolon.