Laxative tablets and laxatives containing the same

Abstract

The present invention provides a laxative tablet containing an alginate as the main component, which prevents damage to the gastric mucosa due to physical collision between the tablet and the gastric mucosa, while allowing the alginate contained in the tablet to disintegrate quickly, thereby providing a laxative tablet with excellent bowel cleansing effect, and a laxative containing the same. The laxative tablet according to the present invention can exhibit excellent bowel cleansing effect even with a small dose, and medication compliance can be further improved by selectively miniaturizing the tablet or introducing an adhesion-improving coating layer.

Description

Technical Field

[0001] The present invention relates to a colon-cleansing tablet and a colon-cleansing agent containing the same. More specifically, the present invention relates to a colon-cleansing tablet containing a gel-forming coating layer containing alginate as a main component, which prevents gastric mucosal damage and has an excellent colon-cleansing effect, and a colon-cleansing agent containing the same.

Background Art

[0002] In order to improve the efficiency of colonoscopy, colon cleansing is required. Colon cleansing is achieved by dietary adjustment before the examination and taking a colon-cleansing agent.

[0003] Drugs used as colon-cleansing agents are classified into osmotic laxatives, stimulant laxatives, and saline laxatives according to their mechanism of action. Osmotic laxatives are non-absorbable electrolyte solutions that generate an osmotic pressure difference in the intestine after administration to wash away feces. Stimulant laxatives prevent the absorption of water and electrolytes in the large intestine, stimulate the intestinal mucosa to induce muscle contraction of the large intestine, and forcibly cause defecation. Saline laxatives are not absorbed in the intestinal tract, retain water from the small intestine by osmotic action to soften the stool, and at the same time activate peristaltic movement to induce defecation.

[0004] An example of an osmotic laxative is a polyethylene glycol (PEG) solution. Since PEG has little effect on plasma volume and electrolytes, it is suitable for patients with coexisting diseases such as kidney disease, heart disease, and liver disease. However, a large amount of 4 liters of solution must be taken, and it has a rather repulsive taste, so the compliance of taking the medicine is low. There is also a product that shows a cleansing effect with a volume of only 2 liters as a complex of PEG and ascorbic acid, but due to the unpleasant taste peculiar to PEG, the dosage is still at a level that is a burden.

[0005] Examples of stimulant laxatives include sodium picosulfate hydrate, magnesium oxide, and citrate complexes. For adults, this involves taking 170 ml of the solution before 8:00 AM the day before the examination, followed by an additional 170 ml 6-8 hours later. This has the advantage of significantly reducing the dosage compared to PEG preparations. However, to avoid dehydration, it is recommended to drink 250 ml of water per hour after taking the medication, and medication compliance is still not considered excellent.

[0006] Examples of saline laxatives include phosphates and sulfates. While phosphates were reported to be more effective at cleansing the colon at lower doses compared to PEG, they were found to induce side effects such as abdominal distension, pain, and dizziness with similar frequency to PEG, and were particularly known to cause complications such as acute phosphate nephropathy. As a result, the European Society of Gastroenterology restricted the use of oral sodium phosphate in 2013. In contrast, sulfates are considered relatively safer than phosphates. Sulfate preparations mainly consist of sodium sulfate, potassium sulfate, and sodium sulfate combinations.

[0007] Korean Patent Publication No. 10-2015-0089430 discloses a laxative tablet prepared by mixing magnesium sulfate, potassium sulfate, and sodium sulfate, adding PEG as an excipient (not the main component), then adding sodium stearyl fumarate, and compressing the mixture using a tablet press. The document reports that a product composed of these three sulfates is safe and effective, and introduces the development of a product called Suprep Bowel Prep Kit in the United States. Products composed of these three sulfates also exist in Korea, such as Suprep Liquid and Suclear Liquid. However, liquid formulations have the problem of reduced medication compliance due to the salty taste and unpleasant odor characteristic of sulfates. Although excessive amounts of sweeteners and flavorings are sometimes added to eliminate the rotten egg-like odor characteristic of sulfates, the effect of this is limited.

[0008] To address the aforementioned problems with conventional laxatives, the applicant proposed a solid laxative containing anhydrous magnesium sulfate, potassium sulfate, anhydrous sodium sulfate, and simethicone as its main components, through Korean Patent Publication No. 10-2019-0041233. This laxative is marketed under the name Orafang Tablets. Orafang Tablets have various advantages, including improved medication compliance and excellent bowel cleansing effects. However, after Orafang Tablets were marketed, some patients reported gastric mucosal damage and discomfort due to the large size of the tablets. Therefore, there is a need to develop a laxative that can solve these problems while maintaining excellent bowel cleansing effects. [Overview of the project] [Problems that the invention aims to solve]

[0009] The present invention aims to provide a colonic laxative tablet that prevents damage to the gastric mucosa due to physical collision between the tablet and the gastric mucosa, while allowing the permeable substance contained in the uncoated tablet to disintegrate quickly, thereby providing an excellent bowel cleansing effect even with a small dose. This is achieved by introducing a gel-forming coating layer mainly composed of alginate into an uncoated tablet containing a permeable substance.

[0010] The present invention also aims to provide a laxative that can be easily taken through a packaging bag. [Means for solving the problem]

[0011] The present invention relates to a laxative tablet comprising: a penetrating substance, simethicone, and a water-soluble binder; and a gel-forming coating layer formed on the naked tablet, the gel-forming coating layer comprising alginate as the main component, wherein the penetrating substance comprises one or more selected from the group consisting of anhydrous sodium sulfate, potassium sulfate, anhydrous magnesium sulfate, sodium sulfate hydrate, magnesium sulfate hydrate, sodium picosulfate hydrate, light magnesium oxide, citric acid, polyethylene glycol, sodium chloride, potassium chloride, ascorbic acid, sodium ascorbate, sodium bicarbonate, anhydrous sodium hydrogen phosphate, sodium dihydrogen phosphate monohydrate, magnesium oxide, and potassium sulfate, and the alginate is present in an amount of 50% by weight or more based on the total weight of the gel-forming coating layer.

[0012] In one example, the permeable substance may include anhydrous sodium sulfate, potassium sulfate, and anhydrous magnesium sulfate.

[0013] In one example, the colonic laxative tablet may contain 60 to 90 parts by weight of anhydrous sodium sulfate, 5 to 25 parts by weight of potassium sulfate, and 1 to 15 parts by weight of anhydrous magnesium sulfate per 100 parts by weight of the permeable substance.

[0014] In one example, the colonic laxative tablet may contain 0.1 to 2 parts by weight of simethicone and 0.5 to 20 parts by weight of a water-soluble binder per 100 parts by weight of the permeable substance.

[0015] In one example, the water-soluble binder may be one or more selected from the group consisting of copovidone, polyethylene glycol, and povidone.

[0016] In one example, the alginate may be one or more selected from the group consisting of sodium alginate, potassium alginate, and magnesium alginate.

[0017] In one embodiment, the gel-forming coating layer may further contain an adhesion improving agent.

[0018] In one example, the adhesion improving agent may be one or more selected from the group consisting of polyvinyl alcohol-polyethylene glycol graft copolymer, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, por, gelatin, carboxymethyl cellulose, and povidones.

[0019] In one embodiment, the gel-forming coating layer may further contain a mucosal protective agent.

[0020] In one example, the mucosal protective agent may be one or more selected from the group consisting of ecabet sodium hydrate, ilsogladine maleate, and polaprezinc.

[0021] In one embodiment, the colonic laxative tablet may further include an adhesion-improving coating layer on the gel-forming coating layer, the adhesion-improving coating layer having an adhesion-improving agent as its main component.

[0022] In one example, the laxative tablet may contain 50% by weight or more of the adhesion improving agent based on the total weight of the adhesion improving coating layer.

[0023] In one implementation example, when evaluating the dissolution pattern of the permeable substance of a tablet in a solution with a pH of 2 or lower using the second method of the dissolution test, the permeable substance can be dissolved within 5 minutes at a concentration of 30% by weight or less.

[0024] In one implementation example, when evaluating the dissolution pattern of the permeable substance of a tablet in a solution with a pH of 3.5 to 5.5 using the second method of the dissolution test, the permeable substance can be dissolved at a rate of 30% or more by weight within 5 minutes.

[0025] In one implementation example, when evaluating the dissolution pattern of the permeable substance of a tablet using the second method of the dissolution test with a pH of 6 to 8.5, 40% or more by weight of the permeable substance can be dissolved within 5 minutes.

[0026] The present invention can also provide a laxative comprising two or more packaging bags each containing two or more laxative tablets, and taking the laxative tablets contained in one of the packaging bags per administration.

[0027] The present invention can also relate to a pharmaceutical composition for a laxative, in which, on the day before a colonoscopy, after taking 160 laxative tablets and 425 ml of water as described above, 850 ml of water is additionally taken twice in portions of 425 ml each, and on the day of the examination, the laxative tablets and water are repeatedly taken in the same manner as above, and the total dose of the laxative is 38 to 55 g.

[0028] The present invention can also relate to a pharmaceutical composition for a laxative, in which, on the day of a colonoscopy, after taking 160 laxative tablets and 425 ml of water as described above, taking 850 ml of water in portions of 425 ml each and repeating the additional intake twice, and the total dose of the laxative is 38 to 55 g. [Effect of the Invention]

[0029] By introducing a gel-forming coating layer mainly composed of alginate into a naked tablet containing a permeable substance, the present invention can provide a laxative tablet that prevents gastric mucosal damage caused by physical collision between the tablet and the gastric mucosa, while the permeable substance contained in the naked tablet is quickly disintegrated, and has an excellent intestinal cleansing effect. The laxative tablet according to the present invention can exhibit an excellent intestinal cleansing effect even with a small dosage, and can further improve medication compliance by selectively miniaturizing the tablet or introducing an adhesion-improving coating layer.

[0030] The present invention can also provide a laxative that can be easily taken through a packaging bag for the above-mentioned laxative tablet.

[0031] The effects of the present invention are not limited to the above effects, and it should be understood to include all effects inferable from the configuration of the invention described in the description or claims of the present invention. [Brief explanation of the drawing]

[0032] [Figure 1] The image shows the tablets from Example 1 gelled in a solution with a pH of approximately 1.2. [Figure 2] This image shows the results of evaluating the gelation process of the tablets from Example 1 based on pH. [Figure 3] These images show the results of evaluating the dissolution behavior over time for the tablets of the examples and comparative examples. [Figure 4] This graph shows the results of evaluating the dissolution pattern of anhydrous sodium sulfate in the tablets of the examples and comparative examples. [Figure 5] This is a schematic diagram showing the current status of participation and management of clinical trial participants. [Modes for carrying out the invention]

[0033] The intent, operation, and effects of the present invention will be described in detail below through embodiments of the present invention and specific examples relating thereto. However, the following examples are presented as illustrations to aid in understanding the present invention and do not define or limit the scope of the invention.

[0034] The terms and words used in this specification and in the claims should not be construed to be limited to their ordinary or dictionary meanings, but rather to be construed in a sense and concept consistent with the technical idea of ​​the present invention, based on the principle that an inventor can appropriately define the concept of a term in order to best describe their invention.

[0035] Therefore, it should be understood that the configurations of the embodiments described herein represent only one of the most preferred embodiments of the present invention and do not represent the entire technical concept of the present invention, and that at the time of filing, there may be a variety of equivalents and modifications that can substitute for them.

[0036] In this specification, singular expressions include plural expressions unless the context clearly indicates otherwise.

[0037] In this specification, when a part is said to "contain" a component, this means, unless otherwise stated, that it may contain other components rather than excluding them. Thus, for example, a composition containing compound A may contain other compounds other than A. However, the term "contains" also encompasses, in its particular embodiment, the more restrictive meanings of "essentially / essentially from" and "consisting of," so for example, a "composition containing compound A" may also (essentially / essentially) consist of compound A.

[0038] In connection therewith, terms such as “equipped with” or “possessing” as used herein are intended to specify the presence of implemented features, figures, stages, components, or combinations thereof, and should be understood not to preemptively exclude the possibility of the presence or addition of one or more different features, figures, stages, components, or combinations thereof.

[0039] In this specification, when any member is said to be located "on" any other member, this includes not only cases where such member is in contact with another member, but also cases where there are other members or materials between the two members.

[0040] Wherever a quantity, concentration, or other value or parameter is given herein as a range, preferred range, or enumeration of preferred upper and lower limits, it should be understood that this specifically discloses all ranges that can be formed by any pair of any upper range limits or preferred values ​​and any lower range limits or preferred values, regardless of whether the range is otherwise disclosed. Wherever a range of numerical values ​​is referred herein, unless otherwise specified, such as with limiting terms like greater than or less than, the range is intended to include its endpoint and all integers and fractions within that range. The scope of the present invention is intended not to be limited to any specific values ​​referred to when defining a range.

[0041] The present invention may relate to a laxative tablet comprising: a penetrating substance, simethicone, and a water-soluble binder; and / or a gel-forming coating layer formed on the naked tablet, the gel-forming coating layer comprising alginate as the main component, wherein the penetrating substance may include one or more selected from the group consisting of anhydrous sodium sulfate, potassium sulfate, anhydrous magnesium sulfate, sodium sulfate hydrate, magnesium sulfate hydrate, sodium picosulfate hydrate, light magnesium oxide, citric acid, polyethylene glycol, sodium chloride, potassium chloride, ascorbic acid, sodium ascorbate, sodium bicarbonate, anhydrous sodium hydrogen phosphate, sodium dihydrogen phosphate monohydrate, magnesium oxide, and potassium sulfate, and the alginate may be present in an amount of 50% by weight or more based on the total weight of the gel-forming coating layer.

[0042] In one example, the gel-forming coating layer containing alginate as the main component may contain alginate in an amount of 60% or more by weight, 70% or more by weight, 80% or more by weight, 90% or more by weight, 95% or more by weight, 96% or more by weight, 97% or more by weight, 98% or more by weight, or 99% or more by weight, based on the total weight of the gel-forming coating layer.

[0043] In one embodiment, the alginate can be included in an amount of 0.1 to 20 parts by weight per 100 parts by weight of the permeable substance. In another embodiment, the alginate can be included in an amount of 0.2 parts by weight or more, 0.3 parts by weight or more, 0.4 parts by weight or more, 0.5 parts by weight or more, 0.6 parts by weight or more, 0.7 parts by weight or more, 0.8 parts by weight or more, 0.9 parts by weight or more, 1.0 parts by weight or more, 1.1 parts by weight or more, 1.2 parts by weight or more, 1.3 parts by weight or more, 1.4 parts by weight or more, 1.5 parts by weight or more, 2 parts by weight or more, 2.5 parts by weight or more, 3 parts by weight or more, 3.5 parts by weight or more, 4 parts by weight or more, or 4.5 parts by weight or more per 100 parts by weight of the permeable substance, or 18 parts by weight or less, 16 parts by weight or less, 14 parts by weight or less, 12 parts by weight or less, 10 parts by weight or less, 8 parts by weight or less, or 6 parts by weight or less. The laxative tablets of the present invention, by containing alginate as described above, enable the formation of a gel-forming coating layer uniformly on the uncoated tablet with an appropriate thickness.

[0044] In one implementation example, the thickness of the gel-forming coating layer may be in the range of 0.001 mm to 1 mm. In another implementation example, the thickness of the gel-forming coating layer may be 0.005 mm or more, 0.01 mm or more, 0.02 mm or more, 0.03 mm or more, 0.04 mm or more, 0.05 mm or more, 0.06 mm or more, 0.07 mm or more, 0.08 mm or more, or 0.09 mm or more, or 0.9 mm or less, 0.8 mm or less, 0.7 mm or less, 0.6 mm or less, 0.5 mm or less, 0.4 mm or less, 0.3 mm or less, or 0.2 mm or less.

[0045] The colonic laxative tablets of the present invention, by introducing a gel-forming coating layer onto the uncoated tablet as described above, have an excellent bowel cleansing effect while preventing damage to the gastric mucosa due to physical collision between the tablet and the gastric mucosa.

[0046] In one example, the permeable substance may include anhydrous sodium sulfate, potassium sulfate, and anhydrous magnesium sulfate.

[0047] In one embodiment, the permeable substance may contain 60 to 90 parts by weight of anhydrous sodium sulfate, 5 to 25 parts by weight of potassium sulfate, and / or 1 to 15 parts by weight of anhydrous magnesium sulfate per 100 parts by weight of the permeable substance. In another embodiment, the permeable substance may contain 65 parts by weight or more, 70 parts by weight or more, or 75 parts by weight or more, or 85 parts by weight or less, or 80 parts by weight or less, per 100 parts by weight of the permeable substance. In yet another embodiment, the permeable substance may contain 7 parts by weight or more, 9 parts by weight or more, 11 parts by weight or more, or 13 parts by weight or more, or 23 parts by weight or less, 21 parts by weight or less, 19 parts by weight or less, 17 parts by weight or less, or 15 parts by weight or less, per 100 parts by weight of the permeable substance. In further implementations, the permeable substance may contain 2 parts by weight or more, 3 parts by weight or more, 4 parts by weight or more, 5 parts by weight or more, or 6 parts by weight or more of anhydrous magnesium sulfate per 100 parts by weight, or 14 parts by weight or less, 13 parts by weight or less, 12 parts by weight or less, 11 parts by weight or less, 10 parts by weight or less, 9 parts by weight or less, or 8 parts by weight or less.

[0048] The colonic laxative tablets of the present invention can have an excellent colon cleansing effect even with a small dose by controlling the type and / or weight ratio of the permeable substance as described above, thereby improving medication compliance. This effect can be further maximized by introducing simethicone and / or a water-soluble binder as described below.

[0049] In one embodiment, the colonic laxative tablet of the present invention may contain 0.1 to 2 parts by weight of simethicone and / or 0.5 to 20 parts by weight of a water-soluble binder per 100 parts by weight of the permeable substance. In another embodiment, the colonic laxative tablet of the present invention may contain 0.2 parts by weight or more, 0.3 parts by weight or more, 0.4 parts by weight or more, 0.5 parts by weight or more, 0.6 parts by weight or more, or 0.7 parts by weight or more of simethicone per 100 parts by weight of the permeable substance, or 1.9 parts by weight or less, 1.8 parts by weight or less, 1.7 parts by weight or less, 1.6 parts by weight or less, 1.5 parts by weight or less, 1.4 parts by weight or less, 1.3 parts by weight or less, 1.2 parts by weight or less, 1.1 parts by weight or less, 1.0 part by weight or less, or 0.9 parts by weight or less. In further examples, the laxative tablets of the present invention may contain 1 part by weight or more, 1.5 parts by weight or more, or 2 parts by weight or more, or 18 parts by weight or less, 16 parts by weight or less, 14 parts by weight or less, or 12 parts by weight or less of a water-soluble binder, per 100 parts by weight of the permeable substance.

[0050] In one example, the water-soluble binder may be one or more selected from the group consisting of copovidone, polyethylene glycol, and povidone, and from the viewpoint of improving the disintegration rate, it may be preferable to use copovidone or polyethylene glycol, and more preferably polyethylene glycol.

[0051] In one implementation example, the weight-average molecular weight of the polyethylene glycol may be in the range of 3,000 to 10,000 g / mol. In another implementation example, the weight-average molecular weight of the polyethylene glycol may be 4,000 g / mol or more, or 5,000 g / mol or more, or 9,000 g / mol or less, 8,000 g / mol or less, or 7,000 g / mol or less. By introducing polyethylene glycol with a weight-average molecular weight within the above range, the disintegration rate can be further improved.

[0052] In one example, the alginate may be one or more selected from the group consisting of sodium alginate, potassium alginate, and magnesium alginate, and sodium alginate may be preferred from the viewpoint of preventing damage to the gastric mucosa by gelling in the gastric environment without inhibiting the permeability of the tablet and increasing the effect of improving the disintegration rate. In this specification, "gastric environment" may mean the gastric environment in a natural state and / or the gastric environment when a large amount of water has been introduced.

[0053] In one embodiment, the gel-forming coating layer may further contain an adhesion improving agent.

[0054] In one example, the adhesion improving agent may be one or more selected from the group consisting of polyvinyl alcohol-polyethylene glycol graft copolymer, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, por, gelatin, carboxymethyl cellulose, and povidones.

[0055] In one embodiment, the gel-forming coating layer may further contain a mucosal protective agent.

[0056] In one example, the mucosal protective agent may be one or more selected from the group consisting of ecabet sodium hydrate, ilsogladine maleate, and polaprezinc.

[0057] The colonic laxative tablet of the present invention can further improve the gastric mucosal protective effect by selectively including a mucosal protective agent in the gel-forming coating layer.

[0058] In one embodiment, the laxative tablet of the present invention may further include an adhesion-improving coating layer on the gel-forming coating layer, the adhesion-improving agent being the main component of the coating.

[0059] In one embodiment, the adhesion improving agent may be present in an amount of 50% by weight or more based on the total weight of the adhesion-improving coating layer. In another embodiment, the adhesion improving agent may be present in an amount of 60% by weight or more, 70% by weight or more, 80% by weight or more, or 90% by weight or more based on the total weight of the adhesion-improving coating layer.

[0060] In one embodiment, the adhesion improving agent may be present in amounts of 0.1 to 20 parts by weight per 100 parts by weight of the penetrating substance. In another embodiment, the adhesion improving agent may be present in amounts of 0.2 parts by weight or more, 0.3 parts by weight or more, 0.4 parts by weight or more, 0.5 parts by weight or more, 0.6 parts by weight or more, 0.7 parts by weight or more, 0.8 parts by weight or more, 0.9 parts by weight or more, 1.0 part by weight or more, 1.1 parts by weight or more, 1.2 parts by weight or more, 1.3 parts by weight or more, 1.4 parts by weight or more, 1.5 parts by weight or more, 1.6 parts by weight or more, or 1.7 parts by weight or more per 100 parts by weight of the penetrating substance, or 18 parts by weight or less, 16 parts by weight or less, 14 parts by weight or less, 12 parts by weight or less, 10 parts by weight or less, 8 parts by weight or less, 6 parts by weight or less, or 4 parts by weight or less. The laxative tablets of the present invention, by further including the adhesion-improving coating layer described above, can further enhance the convenience of taking medication by masking the unpleasant taste and smell when taking the tablets and improving their ability to stick to the mouth. This effect can be further maximized if the gel-forming coating layer does not contain an adhesion-improving agent.

[0061] In one implementation, when evaluating the dissolution pattern of the permeable substance of a tablet in a solution with a pH of 2 or lower using the second method of the dissolution test, the permeable substance can be dissolved within 5 minutes at a rate of 30% by weight or less. In this specification, the dissolution of a% by weight of the permeable substance can mean that a% by weight of the total weight of the permeable substance contained in the tablet is dissolved. In another implementation, when evaluating the dissolution pattern of the permeable substance of a tablet in a solution with a pH of 2 or lower using the second method of the dissolution test, the permeable substance can be dissolved within 5 minutes at a rate of 29% by weight or less, 28% by weight or less, 27% by weight or less, 26% by weight or less, 25% by weight or less, 24% by weight or less, 23% by weight or less, 22% by weight or less, 21% by weight or less, 20% by weight or less, 19.5% by weight or less, 19% by weight or less, or 18.5% by weight or less, or at a rate of 1% by weight or more, 2% by weight or more, 3% by weight or more, 4% by weight or more, or 5% by weight or more. In this specification, the permeable substance used in the evaluation of the elution pattern of the permeable substance by the second method of the elution test may be, for example, anhydrous sodium sulfate.

[0062] In one implementation example, when evaluating the dissolution pattern of the permeable substance of a tablet in a solution with a pH of 3.5 to 5.5 using the second method of the dissolution test, the permeable substance can be dissolved at a rate of 30% by weight or more within 5 minutes. In another implementation example, when evaluating the dissolution pattern of the permeable substance of a tablet in a solution with a pH of 2.5 to 5.5 using the second method of the dissolution test, the permeable substance can be dissolved at a rate of 35% by weight or more, 40% by weight or more, 45% by weight or more, 50% by weight or more, 55% by weight or more, 60% by weight or more, 65% by weight or more, 70% by weight or more, 75% by weight or more, or 80% by weight or more within 5 minutes, or at a rate of 95% by weight or less, 90% by weight or less, 85% by weight or less, 80% by weight or less, 75% by weight or less, 70% by weight or less, 65% by weight or less, 60% by weight or less, or 55% by weight or less.

[0063] In one implementation example, when evaluating the dissolution pattern of the permeable substance of a tablet in a pH 6 to 8.5 solution using the second method of the dissolution test, the permeable substance can be dissolved at a rate of 40% by weight or more within 5 minutes. In another implementation example, when evaluating the dissolution pattern of the permeable substance of a tablet in a pH 6 to 8.5 solution using the second method of the dissolution test, 45% by weight or more, 50% by weight or more, 55% by weight or more, 60% by weight or more, 65% by weight or more, 70% by weight or more, 75% by weight or more, 80% by weight or more, 85% by weight or more, or 90% by weight or more can be dissolved within 5 minutes, or 99% by weight or less, 98% by weight or less, 95% by weight or less, 90% by weight or less, 85% by weight or less, or 80% by weight or less can be dissolved.

[0064] In one embodiment, the colonic laxative tablet of the present invention may be round or rectangular, and from the viewpoint of ease of administration, it may be round with a diameter of 10 mm or less, more preferably with a diameter of 7 mm or less.

[0065] The present invention may also include two or more packaging bags, each containing two or more of the laxative tablets, and may relate to a laxative in which one laxative tablet contained in one packaging bag is taken at a time.

[0066] In one implementation, the total dose of laxatives may be 38 to 55 g. In this specification, the total dose of laxatives may mean the total amount of laxatives taken the day before and / or on the day of a colonoscopy. In another implementation, the total dose of laxatives may be 39 g or more, 40 g or more, 41 g or more, or 42 g or more, or 54 g or less, 53 g or less, 52 g or less, 51 g or less, 50 g or less, 49 g or less, or 48 g or less.

[0067] In one example, each packaging bag may contain 5 or more, 10 or more, 15 or more, 20 or more, 25 or more, 30 or more, or 35 or more tablets of laxatives, or 80 or fewer, 70 or fewer, 60 or fewer, 50 or fewer, 40 or fewer, 30 or fewer, 20 or fewer, or 10 or fewer tablets, but is not limited to these, and can be appropriately adjusted according to the size of the tablets.

[0068] The laxative of the present invention can be taken through a packaging bag as described above, thereby further improving the convenience of taking the medication.

[0069] The present invention may also relate to a pharmaceutical composition for colonoscopy in which, on the day before a colonoscopy, 160 laxative tablets and 425 ml of water are taken, followed by two additional doses of 850 ml of water divided into 425 ml portions, and on the day of the examination, laxative tablets and water are taken repeatedly in the same manner as described above, with a total dose of laxative of 38 to 55 g. The timing of administration on the day before and the day of the examination can be selected according to known methods depending on when the colonoscopy is performed.

[0070] The present invention may also relate to a pharmaceutical composition for a colonic laxative in which, on the day of a colonoscopy, 160 laxative tablets and 425 ml of water are taken, followed by two additional doses of 850 ml of water divided into two 425 ml portions, repeated twice, resulting in a total laxative dose of 38 to 55 g. The timing of each of the two doses on the day of the examination can be selected according to known methods depending on the time of the colonoscopy.

[0071] In the following, the present invention will be described in detail with reference to examples in order to specifically illustrate the disclosures of the present invention as described above and the intended functions and effects of the present invention. However, the examples may be modified into several different forms, and the scope of this specification should not be construed as being limited to these examples alone. It should be emphasized that the examples are provided to illustrate the present invention in more detail to those skilled in the art.

[0072] <Example 1> Manufacturing of unwrapped tablets Anhydrous sodium sulfate, potassium sulfate, anhydrous magnesium sulfate, and simethicone were mixed in a high-speed mixer, and then polyethylene glycol (PEG 6000) was added and mixed further. The mixed composition was then compressed into tablets using a rotary tablet press to produce uncoated tablets. The weight of each component in each uncoated tablet was as shown in Table 1 below. Formation of coating layer I Coating solution I was prepared by completely dissolving sodium alginate in purified water. Subsequently, the uncoated tablets and coating solution I were placed in a film coating machine and coated under the conditions of an exhaust temperature of 40-60°C, a coating pan speed of 2-10 rpm, and a film coating solution pump speed of 20-80 rpm. The weight of sodium alginate contained in each tablet formed by this process is shown in Table 1 below. Formation of coating layer II A coating solution II was prepared by completely dissolving a polyvinyl alcohol-polyethylene glycol graft copolymer in purified water. Subsequently, the sodium alginate coated tablets and coating solution II were placed in a film coating machine and coated under the conditions of an exhaust temperature of 40-60°C, a coating pan of 2-10 rpm, and a film coating solution pump of 20-80 rpm to produce tablets. The weight of the polyvinyl alcohol-polyethylene glycol graft copolymer contained in each tablet formed was as shown in Table 1 below. How to take It can be taken in one of the following ways: divided doses or whole doses. i) Split doses On the evening before the examination, take 40 tablets / packet (4 packs) of this medication with 425 mL of water, then take an additional 850 mL of water (425 mL twice). On the morning of the examination, repeat the same procedure as the day before. ii) Undivided doses Take 40 tablets / packet (4 packs) of this medication with 425 mL of water, then take an additional 850 mL of water (425 mL twice). Repeat this on the day of the examination.

[0073] <Example 2> Except for the composition and weight of the tablets being as shown in Table 1 below, the tablets were manufactured using the same method as in Example 1. On the other hand, the medication was taken in the same manner as in Example 1, except that 14 tablets were taken instead of 4 packets of 40 tablets / packet.

[0074] <Comparative Example 1> The tablets were manufactured using the same method as in Example 1, except that the coating layer I was not formed. The method of administration was also the same as in Example 1.

[0075] <Comparative Example 2> Except for introducing sodium alginate into the uncoated tablets, the tablets were manufactured using the same method as in Example 1. The method of administration was also the same as in Example 1.

[0076] <Comparative Example 3> The tablets were manufactured using the same method as in Example 1, except that polaprezinc was introduced instead of sodium alginate as coating layer I. The method of administration was also the same as in Example 1.

[0077] <Comparative Example 4> Except for the absence of coating layer I, the tablets were manufactured using the same method as in Example 2. The method of administration was also the same as in Example 2.

[0078] [Table 1] TIFF2026516149000003.tif137149

[0079] The tablets from Example 1 were grouped into 1, 11, and 40 tablets, and each group was left in a 0.1N HCl solution (pH approximately 1.2) at 25-30°C for 30 minutes. The presence or absence of gelation was then checked. As a result, as shown in Figure 1, it was confirmed that the coating layer containing sodium alginate had gelled. On the other hand, the tablets from Example 1 were left in HCl solutions at pH 1.0, pH 2.0, and pH 3.0 at 25-30°C for 30 minutes, and the gelation behavior at different pH levels was observed. As a result, as shown in Figure 2, it was confirmed that gelation was maintained under all conditions of pH 1.0, 2.0, and 3.0. This suggests that the coating layer containing sodium alginate reacts with stomach acid to form a gel, which is a physical protective factor, and that even if the pH in the stomach rises slightly when ingested with a large amount of water, the gelation is maintained, indicating an excellent gastric mucosal protective effect.

[0080] <Evaluation Example 2. Dissolution Pattern> The tablets of the examples and comparative examples were placed in 410 mL of purified water in a beaker at approximately 25-30°C, and the beaker was shaken for approximately one hour. Examples 1 and 2, by introducing a coating layer containing sodium alginate, showed a faster initial dissolution rate relative to the tablet size compared to Comparative Examples 1, 2, and 4, which contained sodium alginate in the uncoated tablets or did not contain any, and the initial dissolution rate was similar to that of Comparative Example 3, which was coated with polaprezinc. From this, it can be expected that in the examples, not only does sodium alginate gel in the stomach, but it also dissolves rapidly relative to the tablet size, resulting in a superior gastric mucosal protective effect (Figure 3).

[0081] <Evaluation Example 3: Osmotic Pressure> The tablets of the examples and comparative examples were manufactured using the osmotic pressure measurement method, one of the general test methods of the Korean Pharmacopoeia. The osmotic pressure was then measured using the Osmamat 3000 analytical instrument (manufactured by gonolec). As shown in Table 2 below, it was confirmed that there was no significant difference in osmotic pressure between the examples and comparative examples. This suggests that even with the introduction of a gel-forming coating layer, the bowel cleansing effect due to osmotic pressure or electrolyte imbalance is low.

[0082] [Table 2]

[0083] <Evaluation Example 4. Elution characteristics of anhydrous sodium sulfate> The dissolution pattern of anhydrous sodium sulfate from the tablets of Example 1 and Comparative Example 1 was evaluated using the second dissolution test method. Specifically, 900 ml each of test solutions at pH 1.2 (0.1N HCl), pH 4.0, and pH 6.8 were prepared. After placing the test solutions together with the tablets in a dissolution test apparatus (paddle method), the dissolution pattern of anhydrous sodium sulfate over time was observed while stirring at a speed of approximately 50 rpm (at a temperature of 37±2℃). As a result, in the case of Example 1, less than 20% was dissolved within 5 minutes at pH 1.2, more than 40% was dissolved within 5 minutes at pH 4.0, and more than 60% was dissolved within 5 minutes at pH 6.8. On the other hand, in the case of Comparative Example 4, more than 20% by weight was dissolved within 5 minutes at pH 1.2, less than 10% by weight was dissolved within 5 minutes at pH 4.0, and 15% by weight or less was dissolved within 5 minutes at pH 6.8. Therefore, it can be predicted that the tablets of Example 1 have an excellent bowel cleansing effect because the rate of dissolution of permeable substances in the body is fast (Figures 4(a) to (c)).

[0084] <Evaluation Example 5. Results of Clinical Trials> (1) Indications Bowel cleansing as a pre-examination procedure for colonoscopy. (2) Methodology This clinical trial was designed as a prospective, randomized, single-blind study with three treatment arms, parallel treatment groups, active-controlled, and multi-center study. Clinical trial participants who met the selection criteria through a screening visit (V1) were assigned to a clinical trial drug (Test Group 1 (divided dose of Example 1), Test Group 2 (undivided dose of Example 1), and Control Group (divided dose of Comparative Example 4)) through a randomization visit (V2). After taking the drug according to the individual dosage instructions (undivided dose - 1 day / divided dose - 2 days), a visit for colonoscopy (V3) was performed. (3) Dosage and Administration <Test reagent (Example 1)> -Dosage [Based on one colonoscopy examination]: 8 cans (40 tablets per can). - Dosage: Administer orally twice (the day before and the day of the examination) or once (on the day of the colonoscopy). • Test Group 1 (Example 1_Divided Dosage): After taking four packets of this drug and 425 mL of water, an additional 850 mL of water (425 mL twice) was taken. The above procedure was repeated the day before and the day of the test. • Test Group 2 (Example 1_Undivided Dosage): After taking four packets of this medication and 425 mL of water, an additional 850 mL of water (425 mL twice) was taken. The above procedure was repeated starting 4-5 hours before the test. <Control drug (Comparative Example 4)> -Dosage [Based on one colonoscopy examination]: 28 tablets - Dosage: Administer orally twice (the day before and the day of the examination). - After taking 14 tablets of this medication and 425 mL of water, an additional 850 mL of water (425 mL twice) was taken. The above procedure was repeated the day before and the day of the examination. (4) Assignment to treatment group Participants were randomly assigned to receive the clinical trial drug according to their assigned treatment group. The number of participants in each treatment group is shown in Figure 5. (5) Statistical analysis group (Statistical Methods) 1) Safety analysis group (Safety Set) This refers to the group of subjects who were randomly assigned to this clinical trial, received at least one dose of the clinical trial drug, and underwent safety-related follow-up. 2) FA analysis group (Full Analysis set; FAS) This refers to the group of subjects who were randomly assigned to this clinical trial, received at least one dose of the clinical trial drug, and had at least one efficacy assessment measured after administration. If, despite taking the clinical trial drug (colon cleansing agent), the rectal stool was not clean or an abnormal reaction occurred due to taking the clinical trial drug, and a colonoscopy could not be performed, the segment was categorized as "unsuccessful cleansing" on the Harefield cleansing scale when evaluating the efficacy variable related to the degree of colon cleansing. Furthermore, in segments where a colonoscopy could not be completed due to insufficient colon cleansing despite taking the clinical trial drug (colon cleansing agent), the segment was scored at 0 points and categorized as "unsuccessful cleansing" on the Harefield cleansing scale when evaluating the efficacy variable. 3) PP1 analysis group (Principal Efficacy analysis set) This refers to a group of subjects who were randomly assigned, administered the clinical trial drug, underwent at least one efficacy evaluation, and did not experience any significant protocol violations (such as violations of selection / exclusion criteria or drug compliance). Drug compliance was defined as 80%. Among the selection / exclusion criteria, violations of BMI and pregnancy test-related matters that were deemed not to interfere with efficacy evaluation were not excluded from the evaluation. 3) PP2 analysis group This refers to the group of participants in the PP1 group who completed the clinical trial without any serious violations. statistical analysis The efficacy evaluation will target the FAS, PP1, and PP2 groups, while the safety evaluation will target the Safety group. The principal efficacy analysis set will be group PP1. Missing values ​​will not be substituted with other values. For technical statistics, the basic principles are the mean, standard deviation, median, minimum and maximum values ​​for continuous data, and frequency and proportion for categorical data, with more detailed data provided as needed. All statistical analyses, excluding non-inferiority assessments, will, in principle, be performed using two-tailed tests at a significance level of 0.05. To control the significance level to 5% or less in the primary efficacy evaluation, a gatekeeping method will be applied. If it is confirmed that test group 1 is not inferior to the control group under Hypothesis 1, Hypothesis 2 will be tested without further adjustment for the significance level. (6) Discussion and overall conclusions 1) Foam removal ability Along with the degree of cleansing, the foam scores evaluated using colonoscopy showed no statistically significant differences between test groups 1 and 2 and the control group, not only in the total score but also in the scores for each individual compartment, regardless of whether the evaluator was the effectiveness evaluation committee or the colonoscopy operator. Since it has already been confirmed that simethicone, which is included in the control drug, removes bubbles in the intestinal tract, it was determined that test groups 1 and 2 would also remove bubbles in the intestinal tract, which would be helpful in securing a clear view during colonoscopy. 2) Subjective satisfaction with taking the medication Subjective satisfaction with medication, as assessed by the patients, did not show a statistically significant difference between the treatment groups. Therefore, it was determined that treatment groups 1 and 2 did not impair subjective satisfaction with medication compared to the control group, which received tablets. 3) Evaluation of the quality of colonoscopy Since the quality of colonoscopy performed in all treatment groups met the conventionally recommended target level, we concluded that the quality of colonoscopies performed in this clinical trial was very good. 4) Incidence of acute gastric mucosal injury caused by drugs While the treatment group showed lower results compared to the control group, the incidence of drug-induced acute gastric mucosal injury was not statistically significant between the treatment groups. However, among subjects with a very high correlation to drug use (acute injury score of 8 or higher), treatment group 1 showed lower results compared to the control group, and this was statistically significant. Previous studies evaluating the presence or absence of acute gastric mucosal injury involved scoring based on evaluation criteria, followed by a final determination of causality with the drug by an independent team of evaluators. In contrast, this study evaluated solely based on scores from the evaluation criteria. Furthermore, since gastroscopy was not performed before administration of the investigational drug in this study, the baseline degree of gastric injury could not be confirmed. Considering the bias of the evaluators' subjective assessments, the percentage of subjects with an acute injury score of 8 or higher, indicating a very high correlation with the drug, is considered a more clinically significant variable for comparing differences between treatment groups. As a result, it is concluded that sodium alginate (Alginic Acid), a component of the investigational drug, reduced acute gastric mucosal injury. 5) Safety (i) Abnormal cases No deaths were reported, and only one serious adverse event was reported that was not causally related to the clinical trial drug. Only one adverse event resulting in withdrawal from the clinical trial was reported as a drug reaction. Considering the current status of occurrence of abnormal cases, drug adverse reactions, and abnormal cases ((1) abdominal distension, (2) nausea, (3) vomiting, (4) abdominal pain) that were planned to be collected in advance for drug tolerance evaluation, including the current status of occurrence of serious abnormal cases and abnormal cases that resulted in withdrawal from the study, the safety profiles of study groups 1 and 2 were similar to those of the control group, and the safety profiles were judged to be good. (ii) Laboratory test values It is well known that the administration of colon cleansing agents can induce transient fluctuations in hematological and blood chemistry tests. Particular attention should be paid to the fact that electrolyte fluctuations can trigger or worsen arrhythmias and seizures. For both hematological and blood chemistry tests, a comparison was made between groups to determine whether there were any changes in normal / abnormal hematological values ​​after administration (V3) compared to before administration (V2). The results showed no significant differences between groups for any of the test items, and no clinically significant abnormalities in laboratory test values ​​were reported. While some hematological and blood chemistry test items showed statistically significant changes over time, these were largely considered to reflect physiological changes corresponding to the temporary fluid loss and hemoconcentration caused by diarrhea, which is the pharmacological effect of the colon cleansing agent. Furthermore, considering that the significant changes in the average values ​​over time were mostly reversible changes that normalized, and that the amount of change was negligible, the clinical significance of the changes in the average values ​​of hematological and blood chemistry test items was judged to be small. (iii) Signs of vitality, physical examination, and electrocardiogram findings The mean changes over time in vitality signs compared to before administration of the clinical trial drug did not show significant differences between treatment groups for any vitality sign evaluation item. The intragroup changes in vitality signs on the day of colonoscopy after administration of the clinical trial drug (decreased systolic and diastolic blood pressure, increased pulse rate, weight loss, and a tendency toward a decrease in body mass index) were presumed to be consistent with fluid loss. No subjects were reported to have clinically significant abnormal findings based on physical examination and electrocardiogram results. 6) Conclusion When the above-described matters were comprehensively evaluated, it was found that test groups 1 and 2 were not inferior to the control group in terms of cleansing performance as measured by the Harefield scale. In addition, it was confirmed that they removed foam from the intestinal tract to a similar level as the comparison group, which helped to secure a clear view during colonoscopy, and that they were similar to Orafang tablets in terms of ease of administration and satisfaction, which are subjective evaluation items felt by users of the colon cleansing agent. Furthermore, analysis and evaluation of the results of laboratory tests such as evaluation of abnormal cases that occurred, systematic collection using questionnaires, assessment of vitality signs and physical examination findings, hematological and blood chemistry tests, and urinalysis confirmed that both test groups 1 and 2 showed no difference from the control group in terms of safety, and were confirmed to be colon cleansing agents with a good safety profile. When considering all the results mentioned above together, test groups 1 and 2 were judged to be good pharmaceuticals not only in terms of the effectiveness of colon cleansing for colonoscopy compared to the control group, but also in terms of safety. The specific results are shown in Tables 3 through 8 below.

[0085] [Table 3] Table 3 shows the percentage of each participant who was evaluated on the Harefield cleanliness scale, which was categorized into four levels: A, B, C, and D, as assessed by the evaluation committee.

[0086] In this specification, N means the number of subjects, A means that all of the above segments have a score of 3 or 4, B means that there is one or more segments with a score of 2, C means that there is one or more segments with a score of 1, and D means that there is one or more segments with a score of 0. In this specification, segment means rectum, sic colon, descending colon, transverse colon, and ascending colon. Here, the score on the 5-point HAREFIELD colon cleansing scale for each segment was scored according to the following criteria. -0 points: Large amounts of hard, unremovable stools. -1 point: Semi-solid stools that can be partially removed. -2 points: Removable brown liquid removable semi-solid stools. -3 points: Clear liquid -4 points: Empty and clean

[0087] [Table 4] Table 4 shows the percentage of subjects who were rated A, B, C, or D on the Harefield lavage scale as assessed by colonoscopists.

[0088] [Table 5] Table 5 shows the percentage of subjects who were categorized into four levels (A, B, C, and D) on the Harefield lavage scale as assessed by colonoscopists.

[0089] [Table 6] Table 6 shows the percentage of subjects who evaluated the taste of a drug used in clinical trials after oral administration, classifying it into four categories: "no taste or good taste," "bad but tolerable," "unbearable," and "cannot drink."

[0090] [Table 7] Table 7 shows information on subjects who tested negative for H. pylori (score: 3 points or overall evaluation NA) and who developed drug-induced acute gastric mucosal injury as assessed by the endoscopist during gastroscopy after oral administration of a drug for clinical trials.

[0091] [Table 8] Table 8 shows the results of a group comparison of the percentage of participants in the overall study who scored more than 8 points on the acute injury scale.

Claims

1. Uncoated tablets containing a penetrating substance, simethicone, and a water-soluble binder, The uncoated tablet comprises a gel-forming coating layer mainly composed of alginate, The aforementioned permeable substance includes one or more selected from the group consisting of anhydrous sodium sulfate, potassium sulfate, anhydrous magnesium sulfate, sodium sulfate hydrate, magnesium sulfate hydrate, sodium picosulfate hydrate, light magnesium oxide, citric acid, polyethylene glycol, sodium chloride, potassium chloride, ascorbic acid, sodium ascorbate, sodium bicarbonate, anhydrous sodium hydrogen phosphate, sodium dihydrogen phosphate monohydrate, magnesium oxide, and potassium sulfate. A laxative tablet containing 50% by weight or more of the aforementioned alginate, based on the total weight of the gel-forming coating layer.

2. The laxative tablet according to claim 1, wherein the permeable substance comprises anhydrous sodium sulfate, potassium sulfate, and anhydrous magnesium sulfate.

3. The colonic laxative tablet according to claim 2, comprising 60 to 90 parts by weight of anhydrous sodium sulfate, 5 to 25 parts by weight of potassium sulfate, and 1 to 15 parts by weight of anhydrous magnesium sulfate per 100 parts by weight of the permeable substance.

4. The colonic laxative tablet according to claim 1, comprising 0.1 to 2 parts by weight of simethicone and 0.5 to 20 parts by weight of a water-soluble binder per 100 parts by weight of the permeable substance.

5. The colonic laxative tablet according to claim 1, wherein the water-soluble binder is one or more selected from the group consisting of copovidone, polyethylene glycol, and povidone.

6. The colonic laxative tablet according to claim 1, wherein the alginate is one or more selected from the group consisting of sodium alginate, potassium alginate, and magnesium alginate.

7. The laxative tablet according to claim 1, wherein the gel-forming coating layer further comprises an adhesion improving agent.

8. The laxative tablet according to claim 7, wherein the adhesion improving agent is one or more selected from the group consisting of polyvinyl alcohol-polyethylene glycol graft copolymer, hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, pol, gelatin, carboxymethylcellulose, and povidone.

9. The laxative tablet according to claim 1, wherein the gel-forming coating layer further comprises a mucosal protective agent.

10. The colonic laxative tablet according to claim 9, wherein the mucosal protective agent is one or more selected from the group consisting of ecabet sodium hydrate, ilsogladine maleate, and polaprezinc.

11. The colonic laxative tablet according to claim 1, further comprising an adhesion-improving coating layer containing an adhesion-improving agent as the main component on the gel-forming coating layer.

12. The colonic laxative tablet according to claim 11, comprising 50% by weight or more of the adhesion improving agent based on the total weight of the adhesion improving coating layer.

13. The colonic laxative tablet according to claim 1, wherein, according to the second method of dissolution testing, when evaluating the dissolution pattern of the permeable substance of the tablet in a solution with a pH of 2 or less, the permeable substance dissolves within 5 minutes at a rate of 30% by weight or less.

14. The colonic laxative tablet according to claim 1, wherein, according to the second method of dissolution testing, when evaluating the dissolution pattern of the permeable substance of the tablet in a solution of pH 3.5 to 5.5, 30% or more by weight of the permeable substance is dissolved within 5 minutes.

15. The colonic laxative tablet according to claim 1, wherein, according to the second method of dissolution testing, when evaluating the dissolution pattern of the permeable substance of the tablet in a solution of pH 6 to 8.5, 40% or more by weight of the permeable substance is dissolved within 5 minutes.

16. A laxative comprising two or more packaging bags, each containing two or more laxative tablets as described in claim 1, wherein the patient takes one laxative tablet from one of the packaging bags at a time.

17. A pharmaceutical composition for colonoscopy, wherein the patient takes 160 laxative tablets and 425 ml of water the day before a colonoscopy, then takes 850 ml of water in two 425 ml portions, and on the day of the examination, takes laxative tablets and water repeatedly in the same manner as described above, with a total dose of laxative being 38 to 55 g.

18. A pharmaceutical composition for a colonic laxative, wherein on the day of a colonoscopy, 160 colonic laxative tablets according to claim 1 and 425 ml of water are taken, and then 850 ml of water is taken in two additional doses of 425 ml each, and this is repeated twice, resulting in a total dose of 38 to 55 g of colonic laxative.

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