KR20230140488A - A composition for bowel cleansing - Google Patents

Abstract

The present invention provides anhydrous magnesium sulfate, potassium sulfate, anhydrous sodium sulfate; and a composition for colon cleansing containing prucalopride or sodium picosulfate.

Description

Composition for bowel cleansing {A COMPOSITION FOR BOWEL CLEANSING}

The present invention provides anhydrous magnesium sulfate, potassium sulfate, anhydrous sodium sulfate; and a composition for colon cleansing containing prucalopride or sodium picosulfate.

For an accurate colonoscopy, a bowel cleansing process that cleanses the intestines in advance is essential. Even if you fast for several days, stool will always remain in the colon, so the colon must be cleansed through an artificial method before the test. Intestinal cleansing agent is an essential medicine that allows for accurate colonoscopy by thoroughly washing away intestinal residues such as feces before colonoscopy.

The main ingredients of colon cleansers are divided into osmotic laxatives and stimulant laxatives depending on their mechanism of action. Osmotic laxatives are divided into isotonic products based on polyethylene glycol (PEG) and hypertonic products based on phosphate and sulfate. A representative stimulant laxative ingredient is sodium picosulfate, which is used in combination with osmotic laxative ingredients such as citric acid and magnesium.

The combination product of stimulant and osmotic laxative contains 10 mg of sodium picosulfate, 12.0 g of citric acid, and 3.5 g of magnesium oxide in one dose. The product is licensed in Korea as Chemlite acid, but compliance is still low in that the drug is dissolved in water and consumed, and the water dosage is not low at 250 mL per hour.

Not only are many people avoiding colonoscopy due to the difficulty of taking it, but they also stop taking the colon cleanser in a state where the colon cleansing agent is not sufficiently cleaned or expel the ingested colon cleanser due to vomiting. Accordingly, as medication convenience increases, research and development of compositions for colon cleansing to maintain the colon cleansing effect are continuously required.

Korean Patent Publication No. 10-2019-0142620

The object of the present invention is anhydrous magnesium sulfate, potassium sulfate, anhydrous sodium sulfate; and prucalopride or sodium picosulfate to provide a composition for colon cleansing that improves medication compliance.

One aspect of the present invention for achieving the above object is anhydrous magnesium sulfate, potassium sulfate, anhydrous sodium sulfate; and a composition for colon cleansing containing prucalopride or sodium picosulfate.

In the present invention, 'colon cleansing' is a medical technique for cleansing the intestines in preparation for colonoscopy or colon surgery, and can be achieved through oral ingestion of drugs or enema.

Intestinal cleansing agents used for colon cleansing are often painful because large amounts must be taken at once or they cause nausea. These intestinal cleansing agents are divided into isosmolar agents, hyperosmolar agents, and combination agents. Iso-osmotic agents are mainly composed of polyethylene glycol (PEG), and can maintain osmotic pressure in the intestinal tract by purifying the intestines without absorbing the drug into the body or irritating secretions in the colon lumen, and minimizing the movement of body fluids and electrolytes to prevent important physiological problems. It has the advantage of not causing changes, but has the disadvantage of requiring a large dose of 2 to 4 liters or more and having an unpleasant taste, making it burdensome to take.

Sulfate preparations containing sodium sulfate, magnesium sulfate, and potassium sulfate as main ingredients are high osmotic pressure preparations and are easier to take than liquid preparations containing polyethylene glycol (PEG) as the main ingredient. It has the disadvantage of causing fluid and electrolyte imbalance. In addition, the conventional preparation based on sulfate as the main ingredient also contains 15.75 g of anhydrous sodium sulfate, 2.8 g of potassium sulfate, and 1.4 g of anhydrous magnesium sulfate in one dose, so although the tablet size is large, the first dose of 14 tablets and the second dose of 14 tablets are administered each time. It still requires a large amount of tablets to be taken with 1 liter of water, making it less convenient to take.

In addition, the combination preparation consisting of a combination of sodium picosulfate, a stimulant laxative, and magnesium citrate, an osmotic laxative, has the side effects of mild digestive symptoms such as abdominal cramps, pain, nausea, and vomiting, as well as hyperosmolar and It has the disadvantage of causing hypermagnesemia due to its magnesium content.

The composition for colon cleansing of the present invention reduces the burden of a single dose by reducing the use of sulfate preparations, and when applied in tablet form, reduces the size of the tablet due to the reduction of the main ingredient and reduces the amount of tablets to be consumed. . Furthermore, it reduces the body fluid and electrolyte imbalance caused by sulfate and reduces the disadvantages of the combination preparation, thereby improving these disadvantages while maintaining or improving the original bowel cleansing effect.

Specifically, a single dose of anhydrous magnesium sulfate may be 1000.0 to 1300.0 mg. More specifically, it may be 1000.0 to 1225.0 mg.

Also specifically, a single dose of potassium sulfate may be 2000.0 to 2500.0 mg. More specifically, it may be 2100.0 to 2400.0 mg.

Also specifically, a single dose of the anhydrous sodium sulfate may be 11500.0 to 13500.0 mg. More specifically, it may be 11500.0 to 13400.0 mg.

Also specifically, the prucalopride may be included in an amount of 0.01 to 0.02% by weight of the total weight of anhydrous magnesium sulfate, potassium sulfate, and anhydrous sodium sulfate. More specifically, it may be included in 0.01 to 0.015% by weight.

Also specifically, the sodium picosulfate may be included in an amount of 0.05 to 0.15% by weight of the total weight of anhydrous magnesium sulfate, potassium sulfate, and anhydrous sodium sulfate. More specifically, it may be included in 0.05 to 0.1% by weight.

Also specifically, the composition may further include simethicone. Simethicone is an anti-foam agent that suppresses the generation of bubbles, and can be included to secure the view of the endoscope.

Additionally, specifically, the composition may be characterized as a solid preparation for oral administration, but is not limited thereto. More specifically, the solid preparation may be characterized as a tablet. The tablets include anhydrous magnesium sulfate, potassium sulfate, anhydrous sodium sulfate; It can be prepared by mixing prucalopride or sodium picosulfate and then compressing it into tablets, and the surface can be coated as needed.

Additionally, specifically, the composition of the present invention may not contain polyethylene glycol (PEG). When polyethylene glycol is applied as an isosmotic agent in liquid form, it cleanses the intestines without irritating the colon lumen and maintains osmotic pressure in the intestine, so it has been used as a purifying agent that does not cause significant physiological changes. However, it must be taken in large quantities, has a foul taste, and is not convenient. This has an extremely low disadvantage. Even in tablet-type bowel cleansing agents developed later, if polyethylene glycol is used as an excipient or additive such as a binder, an unpleasant taste may still be felt. Since the composition of the present invention can be manufactured in tablet form even if it does not contain polyethylene glycol, polyethylene glycol, which has an unpleasant taste, can be excluded or minimized.

The composition of the present invention can reduce the occurrence of body fluid and electrolyte imbalance, which is a side effect that may be caused by these ingredients, by reducing the content of sodium sulfate, magnesium sulfate, and potassium sulfate, and by reducing the content, the tablets that are actually administered can be reduced. Convenience can be improved by reducing the amount. Furthermore, while reducing the occurrence of side effects and improving the convenience of taking, the colon cleansing effect can be maintained or improved similar to that of existing drugs.

The effects of the present invention are not limited to the effects described above, and should be understood to include all effects that can be inferred from the configuration of the invention described in the detailed description or claims of the present invention.

Figure 1 shows the colon cleansing score of a composition for colon cleansing according to an example and comparative example of the present invention.
Figure 2 shows the results of confirming the cleansing effect in the large intestine extracted after treatment with the composition for colon cleansing according to an example and comparative example of the present invention.

Hereinafter, the present invention will be described in detail by examples. However, the following examples are merely illustrative of the present invention, and the present invention is not limited by the following examples.

Manufacturing example. Preparation of composition for colon cleansing

Sulfate components (anhydrous sodium sulfate, potassium sulfate, anhydrous magnesium sulfate) and sodium picosulfate were combined according to Table 1 below, weighed for one human dose, and dissolved in 425 mL of purified water. The amount of purified water referred to the dosage of Orapang tablets, and it was stirred at room temperature at 400 rpm for 30 minutes to confirm that it was completely dissolved and used as a test solution.

Specifically, Comparative Example 1 is purified water itself as a vehicle, and Comparative Example 2 is a single dose of a combination of sodium picosulfate, magnesium oxide, and citric acid, which are commercially approved products. Comparative Example 3 was set to a single dose of Orapang Tablet (insurance code 659901460), a commercially approved product.

Example 1 is a combination of 85% of the sulfate component of the Orapang tablet (Comparative Example 2) and a single dose of prucalopride, and Example 2 is a combination of 85% of the sulfate component of the Orapang tablet (Comparative Example 2). and a single dose of sodium picosulfate, and Example 3 is a combination of 75% of the sulfate component of the Orapang tablet (Comparative Example 2) and a single dose of sodium picosulfate.

Experimental Example 1. Osmotic pressure measurement

Korean Pharmacopoeia Dissolution Test Solution 1 (dissolve 2.0 g of sodium chloride with 7.0 mL of hydrochloric acid and water to make 1000 mL, pH is approximately 1.2) and Solution 2 (pH 6.8 phosphate buffer and water in a 1:1 ratio) The mixed liquid) was used as artificial gastric fluid (SGF) and artificial intestinal fluid (SIF), respectively. 50 mL of artificial gastric fluid was added to 425 mL of each test solution while stirring, and an appropriate amount of sample was taken. In turn, 100 mL of artificial intestinal fluid was added and an appropriate amount of sample was taken. In turn, 250 mL of purified water was added and an appropriate amount of sample was taken. After adding 250 mL of purified water, the sampling process was repeated four more times. 50 uL of each sample was dispensed and the osmotic pressure was measured using an osmometer (Gonotec osmomat 3000d). The water dosage varies depending on the product, but since the osmotic pressure unit is affected by the volume, the experiment was conducted after fixing the dosage at 425 mL, which is the dosage of the existing product, for comparison.

As a result, as shown in Table 2 below, the osmotic pressure range of the test solutions of Examples 1, 2, and 3 was compared with Comparative Example 2 when comparing the dilution results of artificial gastric fluid, artificial intestinal fluid, and additional water dose, assuming intake of the test solution. It was confirmed that it was diluted within the osmotic pressure range of Example 3. Bowel cleansers, which mainly contain sodium sulfate, magnesium sulfate, and potassium sulfate, are hyperosmolar agents and can cause fluid and electrolyte imbalance, so they are not recommended for patients with congestive heart disease, ascites, or severe renal failure. It is known that its use should be avoided. From the above results, it was confirmed that even if the contents of sodium sulfate, magnesium sulfate, and potassium sulfate were reduced, significant osmotic pressure could be achieved to wash out feces in the intestines.

Experimental Example 2. Confirmation of colon cleansing effect in animal model

14-week-old male SD rats were purchased from Samtaco Co., Ltd., and were allowed to freely consume food and water under conditions of a temperature of 22±3°C, a relative humidity of 50±10%, and a 12-hour light/dark cycle, and were kept in a laboratory environment. After an adaptation period of 7 days, it was used in the experiment.

The test substances of each example and comparative example were orally administered to SD rats. Considering the split therapy, it was administered orally in two doses, and considering the difference in bowel preparation time between humans and rats, the administration interval was set at 70% of the split dosing time for general colon preparation. In this experiment, the dose to the animal model was 1.5% of the human dose as shown in Table 3 below. After administration of each test substance, additional water was administered twice at 20-minute intervals. 7 hours after the first test substance was administered, the second test substance was administered, and additional water was administered twice at 20-minute intervals. 10 hours after the start of test substance administration, the animal was sacrificed and the large intestine was removed by laparotomy. The cleanliness and colon liquid status of the whole colon and dissected colon were observed and photographed. Photographs taken blind of the test substance were scored using a 3-point scale (“good”, 3 points: empty colon or clear liquid colon; “moderate”, 2 points: brown liquid or loose stool; “bad”, 1 point: presence of semi-solid or hard stool). The average value of the whole colon score multiplied by a weight of 1 and the dissection colon score by a weight of 2 was compared between groups. Data are expressed as mean ± standard deviation. The results of this experiment were analyzed using parametric multiple comparison procedures, assuming normality of the data. If the results of parametric one-way ANOVA were significant, Dunnett's multiple comparison test was used. A post hoc test was conducted using . Statistical analysis was performed using Prism 5 (GraphPad Software Inc., San Diego, CA, USA), and if the p value was less than 0.05, it was judged to be statistically significant (*p<0.05, ***p) <0.001 vs Comparative Example 1; ###p<0.001 vs Comparative Example 3).

As a result, as shown in Figure 1, the degree of bowel cleansing in Examples 1, 2, and 3 showed a significantly higher bowel cleansing effect compared to Comparative Example 1, and there was no statistically significant difference from Comparative Example 3, which was a positive control. didn't From these results, it was confirmed that the composition of the present invention was designed to maintain the colon cleansing effect.

In addition, as a result of removing the large intestine and checking the degree of intestinal cleansing, as shown in Figure 2, it was confirmed that in Comparative Example 2, almost no residual feces were removed in the large intestine, and that some residual feces existed in Comparative Example 3 as well. In Examples 1 to 3, it was confirmed that stool in the large intestine was well removed compared to Comparative Example 3, and it was confirmed that the colon cleansing effect can be maintained or improved even if medication convenience is improved.

That is, the composition of the present invention reduces the content of sodium sulfate, magnesium sulfate, and potassium sulfate by reducing the content of sodium sulfate, magnesium sulfate, and potassium sulfate, thereby reducing the occurrence of body fluid and electrolyte imbalance, which are side effects that may be caused by these ingredients. Convenience can be improved by reducing the amount of tablets actually administered by reducing the content. Furthermore, it has been confirmed that the colon cleansing effect is maintained or improved similarly to that of existing drugs while reducing the occurrence of side effects and improving the convenience of taking. The composition of the present invention can reduce the burden on the user.

The description of the present invention described above is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. will be. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive. For example, each component described as unitary may be implemented in a distributed manner, and similarly, components described as distributed may also be implemented in a combined form.

The scope of the present invention is indicated by the claims described below, and all changes or modified forms derived from the meaning and scope of the claims and their equivalent concepts should be construed as being included in the scope of the present invention.

Claims (9)

Anhydrous magnesium sulfate, potassium sulfate, anhydrous sodium sulfate; and
A composition for colon cleansing comprising prucalopride or sodium picosulfate. According to claim 1,
A composition for colon cleansing, wherein a single dose of the anhydrous magnesium sulfate is 1000.0 to 1300.0 mg. According to paragraph 1,
A composition for colon cleansing, wherein the single dose of potassium sulfate is 2000.0 to 2500.0 mg. According to paragraph 1,
A composition for colon cleansing, wherein a single dose of the anhydrous sodium sulfate is 11500.0 to 13500.0 mg. According to paragraph 1,
The prucalopride is included in an amount of 0.01 to 0.02% by weight of the total weight of anhydrous magnesium sulfate, potassium sulfate, and anhydrous sodium sulfate. According to paragraph 1,
The composition for colon cleansing, wherein the sodium picosulfate is contained in an amount of 0.05 to 0.1% by weight of the total weight of anhydrous magnesium sulfate, potassium sulfate, and anhydrous sodium sulfate. According to paragraph 1,
The composition is a composition for colon cleansing that additionally includes simethicone. According to paragraph 1,
A composition for colon cleansing, characterized in that the composition is a solid preparation for oral administration. According to clause 8,
A composition for colon cleansing, wherein the solid preparation is a tablet.