RU2709495C1 - Method for intestine cleaning and kit for its implementation - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine and aims at intestinal cleansing. Disclosed is a kit for preparing a laxative medicinal agent consisting of three parts in form of dry forms for mixing with water. First part contains polyethylene glycol 75.0–125.0 g, sodium sulphate 7.0–11.0 g, sodium chloride 1.5–2.5 g, and potassium chloride 0.5–1.5 g; second part contains polyethylene glycol 30.0–50.0 g, sodium chloride 3.0–3.5 g, potassium chloride 1.0–1.5 g, and sodium bicarbonate 16.0–25.0 g; and the third portion contains L-ascorbic acid 40.0–60.0 g. In the intestinal cleaning method, said parts after mixing with water are introduced in the form of a solution orally in two steps, at the first stage, a solution is added, obtained by mixing with water part of 1 laxative medicinal preparation, and at second step, solution obtained by mixing with water parts 2 and 3 of laxative medicinal preparation.

EFFECT: group of inventions improves the taste properties of the preparation and low volume of the liquid taken.

5 cl, 18 tbl, 7 ex

Description

The present invention relates to the field of medicine and pharmacology, and in particular to a kit for implementing a method of bowel cleansing, providing a soluble effervescent laxative drug and a method of bowel cleansing based on it.

Laxative drugs reduce the passage of food through the gastrointestinal tract and are intended for the treatment of constipation and bowel cleansing before radiological and endoscopic examinations, as well as surgical operations and manipulations. According to the mechanism of action, laxatives are divided into several classes, namely, drugs that contribute to the softening of feces, anatomical-therapeutic-chemical classification code (ATX) A06AA; contact laxatives, code ATX A06AB; laxatives that increase the volume of intestinal contents, code ATX A06AC; osmotic laxatives, code ATX A06AD; enema laxatives, code ATX A06AG; and other laxative drugs, code ATX A06AX. In the composition of laxatives with osmotic properties, solutions of polyethylene glycol, other osmolytes, and electrolytes in volumes from 2 to 12 liters are often used to cleanse the intestines. Burke DA et al. Postgrad Med J. 1988, 64 (756): 772-4. Lee TJ et al. Recent advances in colonoscopy. F1000Res. 2016, pii: F1000 Faculty Rev-328. eCollection 2016.

Reducing the volume of solution taken by the patient is the main direction for improving laxative drugs with osmotic properties, as it makes the bowel cleansing procedure faster and more convenient for the patient.

Ascorbic acid (L-ascorbic acid) is an osmotically active substance, the use of which in the composition of laxatives provides a decrease in the volume of injected solution. Therefore, a number of technical solutions in the prior art relates to attempts to create effective compositions based on it and methods for their use.

For example, US Pat. No. 5,274,001 A is known, which discloses a laxative isotonic solution effective when used in an amount of 2-3.5 L and containing 0.25-50 g / L of ascorbic acid or its salt, 30-60 g / L of polyethylene glycol and 0 2-20 g / l sodium sulfate. This source does not apply to dry effervescent laxatives.

Patent RU 2353412 C2 discloses dry colon cleansing compositions and a colon cleansing kit containing a first container and a second container, where the first container contains a first dry composition, which, per liter of solution prepared from it, contains the following components, g:

polyethylene glycol from 90 to 150,

alkali metal or alkaline earth sulfate

metal or a mixture of alkali metal sulfates

or alkaline earth metals from 5 to 10,

sodium chloride 2 to 4 and

potassium chloride from 0.5 to 1.3;

the second container contains a second dry composition containing a mixture of ascorbic acid and its salt in a weight ratio of 2: 8 to 8: 2 in an amount of 5 to 15 g. The composition may optionally contain sodium bicarbonate up to an osmolality of 300-700 mOsmol / kg. The possibility of including this component in the kit is not mentioned and its quantity is not disclosed.

The high content of ascorbic acid in this composition increases the cleaning efficiency, but gives the solution an unpleasant taste and can cause nausea and vomiting in a significant part of patients, which complicates the procedure for cleaning the intestines. The product provides bowel cleansing when taking 1.5-3 l of the solution, however, according to the results of clinical trials, nausea and vomiting were observed in 31-42% and 7-10% of patients taking this drug, respectively. Found on the Internet: https://clinicaltrials.gov/ct2/show/results/NCT01732692.

Patent EA 028866 may be chosen as the closest analogue. The patent discloses a colon cleansing composition for mixing with water, comprising from 150 to 400 mmol of ascorbate anion formed by a mixture of ascorbic acid and at least one salt of ascorbic acid in a molar ratio from 1: 4.5 to 1: 7.0, and from 5 to 100 g of polyethylene glycol (PEG), upon dissolution of which a solution is obtained containing from 300 to 800 mmol of ascorbate anion and from 10 to 200 g of polyethylene glycol per liter of solution. Also disclosed is a kit for preparing a composition for mixing with water in two or more parts containing the components of the solution in dry form. The kit may contain: a) from 150 to 400 mmol of ascorbate anion provided by a mixture of: (i) ascorbic acid and (and) one or more salts of ascorbic acid, while components (i) and (ii) are in a molar ratio of 1 : 4.5 to 1: 7.0; b) from 5 to 100 g of PEG with an average molecular weight of from 3000 to 4000 Da; c) sodium chloride and potassium chloride; d) optionally sodium sulfate; e) optionally one or more flavors; f) optionally one or more sweeteners.

In one embodiment of the kit, it includes: A) a first sachet contains polyethylene glycol and / or sodium sulfate; B1) a second sachet contains one or more components selected from polyethylene glycol, one or more alkali metal sulfates, alkaline earth metal sulfates, or a mixture thereof and electrolytes; and B2) the third sachet contains one of several salts of ascorbic acid and, if appropriate, ascorbic acid itself; however, the contents of the sachets (B1) and (B2) taken together provide the components for the second cleaning solution.

The elimination of the salty taste is achieved by adding flavors such as sucralose, aspartame, and preferably a mixture thereof and tasting thereof.

Thus, there is a need to reduce the unpleasant taste of high concentrations of ascorbic acid when using laxatives with its high content.

The objective of the present invention is to develop an effective way to cleanse the intestines using a laxative preparation based on ascorbic acid, devoid of the disadvantages of known analogues.

The problem is solved by the developed set of dry components to obtain a new effervescent laxative drug, which, after mixing with water, effectively cleanses the intestines. The set consists of three parts with the following content of components in each part, g:

The invention differs from the closest analogue in that the first part of the kit additionally contains sodium chloride and potassium chloride, the second part contains sodium chloride and potassium chloride as electrolytes, and additionally sodium bicarbonate in certain quantities.

The technical result of the present invention is to reduce the unpleasant taste of a solution with a high content of ascorbic acid, prepared by mixing dry components with water, which facilitates the use of the drug by the patient. Also the technical result is the provision of high stability during storage.

The technical result is achieved by dividing the components for cleansing the intestine into three parts, which, after dissolving in water, provide the necessary therapeutic effect of the laxative drug as a whole while reducing the unpleasant taste of a solution with a high content of ascorbic acid.

The first part of the kit does not contain ascorbic acid and is administered to the patient after mixing with water in the first stage to ensure preliminary cleaning of the intestine and to reduce the total volume of the solution that contains ascorbic acid, which is one of the factors for achieving a technical result.

The introduction of the solution obtained by mixing parts 2 and 3 of the kit with water allows the release of carbon dioxide due to the reaction of bicarbonate and L-ascorbic acid at the time of preparation of the solution immediately before its introduction to the patient, which ensures a high concentration of carbon dioxide in the solution at the time of administration to the patient and due to This high concentration of carbon dioxide in the solution reduces the unpleasant taste of the solution with a high content of ascorbic acid.

The separation of L-ascorbic acid, sodium bicarbonate and sodium sulfate in the kit into three separate parts ensures storage stability, including the impossibility of a spontaneous reaction with the release of carbon dioxide, which could occur if they were part one piece.

In general, a medicament obtained from the components of the kit of the present invention relates to so-called effervescent dosage forms that emit carbon dioxide when mixed with water immediately before use. The dissolution of the drug in water during the preparation of the solution is accompanied by the release of carbon dioxide, which reduces the unpleasant taste, which can lead to symptoms of nausea and vomiting and limit the effectiveness of the drug in patients.

Parts can be made in the form of tablets, granules or powder.

The term "polyethylene glycol" means an ethylene glycol polymer with the general chemical formula HO- (CH ₂ -CH2-O) _n -OH, CAS number 25322-68-3. Preferably, the present invention uses polyethylene glycol with a molecular weight of from 2,000 to 8,000 Daltons, of pharmacopoeial quality. In the present invention, the molecular weight of polyethylene glycol is indicated next to the name, for example, "polyethylene glycol 2000" means polyethylene glycol with a molecular weight of 2000 Daltons, "polyethylene glycol 3350" means a polyethylene glycol with a molecular weight of 3350 Daltons, and "polyethylene glycol 8000" means a polyethylene glycol with a molecular weight of 8000 Daltons.

Sodium sulfate or sodium sulfate has the chemical formula Na ₂ SO ₄ , CAS number 7757-82-6. Preferably, the present invention uses sodium sulfate in the form of an anhydrous salt of Na ₂ SO ₄ , of pharmacopoeial quality, but can also be used in the form of crystalline hydrate Na ₂ SO ₄ ⋅ 10H ₂ O. In the latter case, the amount of sodium sulfate in the composition of the drug of the invention is calculated by the amount of anhydrous salt.

Sodium chloride has the chemical formula NaCl, CAS number 7647-14-5. Preferably used in the present invention in the form of an anhydrous salt, pharmacopoeial quality.

Potassium chloride has the chemical formula KCl, CAS number 7447-40-7. Preferably used in the present invention in the form of an anhydrous salt, pharmacopoeial quality.

Sodium bicarbonate has the chemical formula NaHCO ₃ , CAS 144-55-8. Preferably used in the present invention in the form of an anhydrous salt, pharmacopoeial quality.

L-Ascorbic acid, CAS No. 50-81-7, has the chemical formula C ₆ H ₈ O ₆ and the structural formula:

and is used in the present invention as a dry substance of pharmacopoeial quality.

The term "mammal" means any mammal, preferably humans and domestic mammals (dog, cat, and horse), as well as rodents.

The kit of the present invention is made up by methods well known in the art, for example, using procedures well known in the art and described in Remington's pharmaceutical manual. Remington's Pharmaceutical Sciences, seventeenth edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, Pa., Eighteenth edition, 1990.

Preferably, part 1 of the kit is a sachet filled with polyethylene glycol, sodium sulfate, sodium chloride and potassium chloride in the amounts indicated above; part 2 of the kit is a sachet filled with polyethylene glycol, sodium chloride, potassium chloride and sodium bicarbonate in the amounts indicated above; and part 3 of the kit is a sachet bag filled with ascorbic acid in the amount indicated above.

The kit of the present invention is provided with instructions for use.

The kit of the present invention may optionally contain components for improving taste and odor (flavoring). Examples of flavorings include, but are not limited to, extracts from fruits such as apple, cranberry, pear, peach, plum, apricot, nectarine, grape, cherry, currant, raspberry, gooseberry, elderberry, blackberry, blueberry, strawberry, lemon, lime, mandarin , orange, grapefruit, cupuacu, potato, tomato, lettuce, celery, spinach, cabbage, watercress, dandelion, rhubarb, carrot, beetroot, cucumber, pineapple, coconut, pomegranate, kiwi, mango, papaya, banana, watermelon, passion fruit , tangerine, melon, and cola nut; as well as anise, vanilla, vanilla, cocoa, chocolate, menthol, grape, mint, clover, laurel, eucalyptus, cumin, cedar leaf, nutmeg, bitter almond, cinnamon, citrus, lemon, orange, lime, and grapefruit oils. Examples of flavor enhancers include, but are not limited to, sucrose, fructose, glucose, and mixtures thereof, glycyrrhizin, stevia, saccharin, cyclamates, and aspartame.

Further, another object of the present invention is a method of cleansing the intestines, characterized in that the laxative drug of the present invention, obtained after mixing with water, is administered as a solution orally to a mammal in need of cleansing the intestine, in two stages, at the first stage, the solution is administered to the mammal obtained by mixing with 400-600 ml of water of part 1 of the kit, and in the second step the solution obtained by mixing with 400-600 ml of water of parts 2 and 3 of the kit is administered to the same mammal.

Preferably, the drug is administered sequentially in two doses. For this, part 1 of the drug is dissolved in 500 ml of water and administered to the patient for 30 minutes. After a break of 2-12 hours, at the choice of the patient and the doctor, parts 2 and 3 of the drug are dissolved in 500 ml of water and administered to the patient for 30 minutes. After each administration of the drug, at least 500 ml of water is administered to the patient. The introduction of solutions obtained by dissolving part 1 and parts 2 and 3 of the kit can be carried out in one day or for two days, based on the convenience of the patient.

The present invention can also be used for research on experimental models of irritable bowel or colorectal cancer in laboratory animals requiring bowel cleansing before experimental manipulations.

The following examples illustrate the invention.

Example 1

Part 1 of the kit is obtained by mixing the components in the amounts shown in Table 1, after which the resulting dry mixture is placed and hermetically closed in a sachet.

Part 2 of the kit is obtained by mixing the components in the amounts shown in Table 2, after which the resulting dry mixture is placed and hermetically closed in a sachet.

Part 3 of the kit is obtained by mixing the components in the amounts shown in Table 3, after which the resulting dry mixture is placed and hermetically closed in a sachet.

Parts 1, 2, and 3 sets are placed in a common package and provided with instructions for use.

Example 2

Part 1 of the kit is obtained by mixing the components in the amounts indicated in Table 4, after which the resulting dry mixture is placed and hermetically closed in a sachet.

Part 2 of the kit is obtained by mixing the components in the amounts shown in Table 5, after which the resulting dry mixture is placed and hermetically closed in a sachet.

Part 3 of the drug is obtained by mixing the components in the amounts indicated in Table 6, after which the resulting dry mixture is placed and hermetically closed in a sachet.

Parts 1, 2, and 3 sets are placed in a common package and provided with instructions for use.

Example 3

Part 1 of the kit is obtained by mixing the components in the amounts shown in Table 7, after which the resulting dry mixture is placed and hermetically closed in a sachet.

Part 2 of the kit is obtained by mixing the components in the amounts shown in Table 8, after which the resulting dry mixture is placed and hermetically closed in a sachet.

Part 3 of the kit is obtained by mixing the components in the amounts shown in Table 9, after which the resulting dry mixture is placed and hermetically closed in a sachet.

Parts 1, 2, and 3 are placed in a common package and provided with instructions for use.

Example 4

Part 1 of the kit is obtained by mixing the components in the amounts shown in Table 10, after which the resulting dry mixture is placed and hermetically closed in a sachet.

Part 2 of the kit is obtained by mixing the components in the amounts shown in Table 11, after which the resulting dry mixture is placed and hermetically closed in a sachet.

Part 3 of the kit is obtained by mixing the components in the amounts indicated in Table 12, after which the resulting dry mixture is placed and hermetically closed in a sachet.

Parts 1, 2, and 3 are placed in a common package and provided with instructions for use.

Example 5. The study of effectiveness.

The effectiveness of the solutions obtained using the claimed kit was evaluated by the effect on the total transit time of an orally administered label, namely carmine red, through the gastrointestinal tract. Carmine red is not absorbed from the intestinal lumen and is widely used as a marker for estimating the transit time of food masses through the gastrointestinal tract. Kimball ES et al. Am J Physiol Gastrointest Liver Physiol. 2005, 288 (6): G1266-73. C57B1 / 6 male mice weighing 20-22 g had free access to water and food and were randomly assigned to several groups. In group No. 1, animals were injected through a probe into the stomach with 15 ml / kg of distilled water (control), tinted to a bright red color with a 6% carmine red solution suspended in 0.5% methylcellulose. In group No. 2, animals were injected into the stomach through a probe 15 ml / kg of solution (equivalent to introducing 1000 ml of a solution to a person weighing 70 kg), obtained by dissolving parts 1, 2, and 3 sets of example No. 2 in 1 liter of water and stained with the above solution of carmine red . In group No. 3, animals were injected through a probe into the stomach with 15 ml / kg of a solution obtained by dissolving parts 1, 2, and 3 sets of Example No. 3 in 1 liter of water and stained with the above carmine red solution. In group No. 4, animals were injected through a probe into the stomach with 15 ml / kg of a solution obtained by dissolving parts 1, 2, and 3 sets of Example No. 4 in 1 liter of water and stained with the above carmine red solution. In group No. 5, the animals were given a 7.5 ml / kg solution through the tube into the stomach (equivalent to administering 500 ml of the solution to a person weighing 70 kg), obtained by dissolving part 1 of the kit from Example No. 2 in 500 ml of water and stained with the above carmine red solution, and after 30 min, another 7.5 ml / kg of the solution obtained by dissolving parts 2 and 3 of the kit from Example No. 2 was introduced into 500 ml of water. The appearance of feces stained with carmine red was visually controlled, starting from the moment the solution was introduced and then every 10 minutes. The total transit time of the gastrointestinal tract was determined as the interval between the introduction of the stained solution and the time of the first observation of feces with carmine red stain. The results are presented in table 13 as the average value ± the error of the average total time the label passes through the gastrointestinal tract (n = 6 in the group). Differences between groups were evaluated using Student's t-test and were considered significant at p <0.05.

Table 13 shows that the administration to the mammal of a solution obtained by mixing parts of the kit of the present invention with water significantly reduces the total transit time of the gastrointestinal tract as compared with the control, which indicates a strong laxative effect, which is achieved when the solution was administered with a single dose obtained by mixing all three parts 1, 2, and 3 of the drug (groups 2-4), and in the case of sequential administration in two doses, where the first dose is obtained by dissolving part 1 of the kit in water, and the second dose receives by dissolving parts 2 and 3 of the kit in water (group 5).

Example 6. The taste of a solution of a laxative drug.

To assess the taste of the drug solution obtained using the kit of the present invention, several additional control kits were prepared (Tables 14-16), differing from the compositions of the present invention only in that instead of sodium bicarbonate, an equimolecular amount of sodium hydroxide was introduced into their composition, therefore, the solutions obtained by dissolving these components of the control kits in water differed from the solutions obtained by dissolving the components of the kit of the present invention only the absence of carbon dioxide that is released when parts of the kit of the present invention are dissolved in water.

Further, for comparison, pairs of solutions were prepared that differ only in the presence of carbon dioxide. The first pair was obtained by dissolving in one liter of water parts 1, 2, and 3 of the kit from example No. 2 (solution 1) and example No. 6, Table 14 (control 1). The second pair was obtained by dissolving in one liter of water parts 1, 2, and 3 of the kit from example No. 3 (solution 2) and example No. 6, Table 15 (control 2). The third pair was obtained by dissolving in one liter of water parts 1, 2, and 3 of the kit from example No. 4 (solution 3) and example No. 6, Table 16 (control 3). Pairs of solutions were offered for testing to a group of 7 people. A solution from a couple whose taste was recognized as the best during testing received 1 point, and a taste that was recognized as the worst received 0 points. The scores for each solution and control in the group (n = 7) were summarized. The results are presented in Table 17.

Table 17 shows that the average value (± error of the mean) for the solutions obtained according to the present invention was significantly higher than 5.0 ± 0.6 points (p <0.05; Student's t-test) than in control 2.0 ± 0.6 points. Thus, the introduction into the kit of the present invention of individual dosage forms that emit carbon dioxide at the time of preparation of the solution immediately before administration to the patient, improves the unpleasant taste of the solution of the laxative drug of the present invention in the entire range of the claimed quantitative content.

Example 7. The taste of the solution of parts 2 and 3 of the laxative drug Given that the drug is used in two doses, and ascorbic acid is introduced in the second dose, the following pairs of solutions were prepared and tested, differing only in the presence of carbon dioxide. The first pair was obtained by dissolving in 500 ml of water parts 2 and 3 of the kit from example No. 2 (solution 1) and example No. 6, table 14 (control 1). The second pair was obtained by dissolving in 500 ml of water parts 2 and 3 of the kit from example No. 3 (solution 2) and example No. 6, table 15 (control 2). The third pair was obtained by dissolving in 500 ml of water parts 2 and 3 of the kit from example No. 4 (solution 3) and example No. 6, table 16 (control 3). Pairs of solutions were offered for testing to a group of 7 people. A solution from a couple whose taste was recognized as the best received 1 point, and a taste that was recognized as the worst received 0 points. The scores for each solution and control were summarized in the group (n = 7). The results are presented in Table 18.

Table 18 shows that the average value (± the error of the mean) for the solutions of the dosage forms (B) and (C) of the preparation of the present invention was significantly higher than 5.7 ± 0.3 points (p <0.01; Student's t-test), than in the control 1.3 ± 0.3 points. Thus, the introduction into the kit of the present invention of individual dosage forms that emit carbon dioxide in the preparation of the solution immediately before administration to the patient provides an improvement in the unpleasant taste of the ascorbic acid solution in the kit for producing a laxative drug in the entire range of the claimed quantitative content of the components of the dosage forms.

Claims (7)

1. A kit for preparing intestinal cleansing solutions, characterized in that it consists of three parts, each of which includes dry components, with their following content, g:

2. The kit according to claim 1, characterized in that it consists of three parts, with the following components, g:

3. A method of bowel cleansing, characterized in that the mammal in need of bowel cleansing is orally administered in the first stage a solution obtained by mixing with 400-600 ml of water part 1 of the kit according to claim 1 or 2, and in the second stage, the same mammal is administered the solution obtained by mixing with 400-600 ml of water of parts 2 and 3 of the kit according to claim 1 or 2. 4. The method according to p. 3, characterized in that the solution is obtained by mixing with 500 ml of water. 5. The method according to p. 3, characterized in that the second stage is carried out after 2-12 hours.