KR101659746B1 - Colonic purgative compositions comprising sulfate salts and a method for preparing the same - Google Patents

Abstract

The present invention relates to a composition for the preparation of a topical preparation containing magnesium sulfate, potassium sulfate, and sodium sulfate as active ingredients, and a method for producing the same, comprising the steps of administering an excess amount of a polyethylene glycol- It solves the problem of safety such as acute phosphoric acid nephropathy and solves the problem of using preservative to reduce the possibility of microorganism alteration in existing liquid formulations and excessive use of sweeteners for improving taste and speedy drug efficacy by shortening disintegration time It is possible to completely clean the large intestine, thereby reducing the possibility of false positives caused by foreign matter remaining in the colonoscopy.

Description

[0001] The present invention relates to a long-acting composition containing a sulfate and a method for preparing the same,

The present invention relates to a long-line dressing composition containing a sulfate and a method of producing the same.

Before colonoscopic and surgical operations, complete removal of fecal residues is a prerequisite. Various types of enteric detergents have been developed to effectively perform this procedure.

Although the polyethylene glycol-electrolyte solution is safe and effective in powder form, it suffers from the disadvantage of consuming an excess of 4 liters of solution within a 2 to 3 hour period for intestinal cleansing (Afridi et al. (1995), Gastrointest. Endosc. 41 : 485-489). Most patients experience side effects such as discomfort, abdominal pain, and vomiting due to overdose (Dipalma et al. (2003) Am. J. Gastroenterol. 98: 2187-2191). In addition, excessive sweetening and flavoring agents are used to improve flavor because of the peculiar smell and salty taste of polyethylene glycol and electrolytes, but these formulations have disadvantages that cause patients to give up colorectal cancer screening (Harewood et < RTI ID = 0.0 > al. (2002) Am. J. Gastroenterol. 97: 3186-3194).

Fleet ^® PhosphoSoda (CB Fleet Company), a small water-based formulation made of phosphate, is an agent that promotes ovulation by introducing water and electrolytes from the plasma into the intestines by causing an osmotic effect. Although sodium phosphate is advantageous in small doses, Adverse side effects, such as vomiting, abdominal swelling, pain, and dizziness, are similar to those of polyethylene glycol-electrolytes (Kolts et al. (1993) Am. J. Gastroenterol. 88: 1218-1223). In addition, Visicol (Salix Pharmaceuticals, Inc.) tablets containing sodium phosphate as a main ingredient were developed, but microcrystalline cellulose was included in the main ingredient, which interfered with endoscopic observation. To improve this, tablets with the product name Osmoprep (Salix Pharmaceuticals, Inc.) were developed to improve ease of use with a 2-liter dose of water.

Osmoprep contains 398.0 mg of sodium hydrogen phosphate anhydrous per 1 tablet (1,676 mg), 1,102 mg of sodium dihydrogenphosphate monohydrate, PEG 8000, and magnesium stearate, and does not need to consume excessive water, Helped.

However, in some patients, these sodium phosphate preparations have been reported to have serious safety problems such as acute pancreatic nephropathy. Therefore, there is a need to develop a formulation containing relatively safe sulphate salts because sodium phosphate is not contained and is not absorbed by the human body .

Sulfate formulations provide sulphate anions that are a mechanism of action that causes the water to persist throughout the gastrointestinal tract by causing the osmotic effects of these sulphate anions that are not well absorbed in the body and are not absorbed.

In this connection, Korean Patent Laid-Open Publication No. 2013-0048790 related to OSMOPREP products enumerated sodium hypophosphite sulfate and magnesium sulfate components, but mention is made only of the composition of the embodiment and the capacity setting range. In addition, these two types of osmotic agents alone have diarrhea and adverse effects that lead to changes in electrolytes and metabolic phases including hypermagnesemia, hypochloremia, hypokalemia and low serum osmotic pressure. Therefore, in order to minimize these electrolyte imbalances, (2011) 7 (1): 89-101), a product composed of three sulphates such as magnesium, potassium sulfate and sodium sulfate has been reported to be safer and more effective (see SUPERP BOWEL PREP KIT (Braintree Laboratories, Inc., US) "was developed.

The SUPREP product contains 1.6 grams of magnesium sulfate per tablet (6 units), 3.13 grams of potassium sulfate, 17.5 grams of sodium sulfate, and other sweetening and preservative agents, containing sodium phosphate, which may cause adverse side effects and electrolyte imbalance And it is evaluated as relatively safe because there is no safety problem such as acute phosphoric acid nephropathy. In a clinical trial comparing Nulytely (Braintree), a polyethylene glycol-electrolytic product, which is actually safe and excellent in colon cleansing, and a SUPREP product consisting of these three sulfates, the SUPREP product showed superiority in terms of cleanliness and side effects (Rex et al. (2010) 72 (2): 328-336).

However, in the case of a sulfate preparation, there is a problem that compliance with taking is poor due to a salty taste of a sulfate such as sodium sulfate and a strong odor of a sulfate. Therefore, Nulytely and TriLyte products of polyethylene glycol- electrolyte solution long- (1990), 98 (1): 11-16). In the case of SUPREP products, excessive sweeteners and flavoring agents were added to eliminate the odor of eggs It has been developed as a product in the form of a highly concentrated liquid formulation that is diluted with excess water using preservatives and stabilizers for storage and distribution.

However, such a sulfate-containing product has problems such as the use of a preservative to reduce the possibility of microbial alteration by a microorganism and the use of an excessive amount of sweetener for improving the taste, and the increase in the packaging volume of the liquid formulation causes an increase in distribution costs and logistics costs There is a fear of damage during transportation and contamination of product due to this, so there has been a need to develop a solid preparation for improvement.

Korean Patent No. 10-1268559 (colloid-containing composition containing a soluble binder, 2013.05.22) Korean Patent No. 10-1323628 (colloid-containing composition containing a soluble binder, 2013.10.24) U.S. Patent No. 6,946,149 B2 (Salt solution for colon cleansing, September 20, 2005)

Fordtran JS, snata ance, Cleveland M. A low-sodium solution for gastrointestinal lavage. Gastroenterology, 1990, 98 (1), 11-16 Margaret Adamcewicz, Dilip Bearelly, Gail Porat, and Frank K. Freidenberg., Mechanism of action and toxicities of purgatives used for colonoscopy preparation. Expert Opin Drug Metab Toxicol, 2011, 7 (1), 89-101. Douglas K. Rex, Jack A.Di Palma, Reynaldo Rodriguez, John McGowan, and Mark Cleveland., A randomized clinical study with reduced-volume oral sulfate solution with standard 4-liter sulfate-free electrolyte as a preparation for colonoscopy. Gastrointestinal endoscopy, 2010, 72 (2), 328-336.

It is an object of the present invention to provide a long-lyase preparation containing a sulfate and a process for producing the same.

Another object of the present invention is to provide an oral preparation (powder, granule, tablet, capsule, caplet) excluding excipients such as preservatives, stabilizers, sweeteners and flavoring agents, , And to provide a sulfate-containing enteric coating composition which improves adherence to medicines by reducing nausea and vomiting due to the speciality of sulfate salts.

The present invention relates to a long-line dressing composition containing a sulfate and a method of producing the same.

A topical composition according to one aspect of the present invention comprises

As the active ingredient, magnesium sulfate, potassium sulfate, and sodium sulfate;

As excipients, polyethylene glycol; And

As the lubricant, it contains stearyl fumarate.

In addition, the topical composition according to another embodiment of the present invention contains 3 to 13 parts by weight of magnesium sulfate, 10 to 20 parts by weight of potassium sulfate, and 70 to 85 parts by weight of sodium sulfate based on 100 parts by weight of the total of the active ingredient. The topical composition according to the present invention contains 3 to 20 parts by weight of polyethylene glycol and 0.3 to 2.0 parts by weight of stearyl sodium fumarate based on 100 parts by weight of the total of the active ingredients.

The polyethylene glycol preferably has an average molecular weight of 3,000 to 9,000, and more preferably an average molecular weight of 7,000 to 9,000.

The formulations of the pharmaceutical compositions may be powders, granules, capsules, tablets, caplets, or a combination of one or more thereof.

The tablets may be a tablet mix with the active ingredient, an excipient and a lubricant mixed therein, or the compressed tablet may be a coated tablet coated with a single-layer or multi-layer film coating.

Wherein the film coating agent comprises at least one polymer substrate selected from the group consisting of polyvinyl alcohol, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and at least one polymer substrate selected from the group consisting of polyethylene glycol, glyceryl monostearate, sodium lauryl sulfate, It may be composed of at least one additive selected from the group consisting of maltodextrin, maltodextrin, maltodextrin, dextrose, sodium citrate, lecithin, sodium bicarbonate, triethyl citrate and stearic acid and may be coated in the form of a single film or a multilayer film.

Further, a method for producing a composition for a topical lotion according to another aspect of the present invention comprises:

(a) mixing magnesium sulfate, potassium sulfate, and sodium sulfate as active ingredients;

(b) mixing the mixture produced in the step (a) with polyethylene glycol as an excipient;

(c) mixing the mixture produced in the step (b) with sodium stearyl fumarate as a lubricant; And

(d) tableting with the oral tablet while applying pressure to the mixture produced in step (c).

In addition, the preparation method of the long-

(a) mixing 3 to 13 parts by weight of magnesium sulfate, 10 to 20 parts by weight of potassium sulfate, and 70 to 85 parts by weight of sodium sulfate based on 100 parts by weight of the total of the active ingredients;

(b) mixing 3 to 20 parts by weight of polyethylene glycol, which is an excipient, based on 100 parts by weight of the total amount of the active ingredient, into the mixture produced in the step (a);

(c) mixing 0.3 to 2.0 parts by weight of stearyl sodium fumarate as a lubricant with respect to 100 parts by weight of the total amount of the active ingredient;

(d) tableting with the oral tablet while applying pressure to the mixture produced in step (c).

Hereinafter, the present invention will be described in more detail.

The topical composition of the present invention may contain magnesium sulfate, potassium sulfate, and sodium sulfate as active ingredients; Polyethylene glycol as an excipient; And sodium stearyl fumarate as a lubricant.

The intestinal laxative composition of the present invention is an osmotic laxative agent which is difficult to be absorbed in the intestinal tract and maintains osmotic equilibrium, and induces diarrhea and empties the intestines by inducing moisture in the body. The active ingredient of the osmotic laxative, sulfuric acid Magnesium, potassium sulfate and sodium sulfate each have a structure represented by the following formulas (1) to (3).

In the composition for intestinal care of the present invention, it preferably contains 3 to 13 parts by weight of magnesium sulfate, 10 to 20 parts by weight of potassium sulfate, and 70 to 85 parts by weight of sodium sulfate based on 100 parts by weight of the total of the active ingredient, To 10 parts by weight, 12 to 17 parts by weight of potassium sulfate, and 75 to 80 parts by weight of sodium sulfate.

Preferably, the topical composition of the present invention is mixed with 3.0 to 20 parts by weight of polyethylene glycol as an excipient based on 100 parts by weight of the total amount of the active ingredient. When the content of the polyethylene glycol is less than 3.0 parts by weight or more than 20 parts by weight The tablets are broken or the content uniformity of the active ingredient is lowered, and the tablets are large in size, which is not preferable for the convenience of oral solid preparations which are easy to take. The average molecular weight of the polyethylene glycol is preferably 3,000 to 9,000, more preferably 7,000 to 9,000.

In addition, the sodium stearyl fumarate is used zero lubricant, based on the total active components 100 parts by weight, 0.3 - it is preferable to use 2.0 parts by weight, less than 0.3 part by weight or when prepared in tablet form when the 2.0 parts by weight exceeds the punch And the disintegration time is prolonged, and the time for the efficacy is delayed.

The topical composition of the present invention may be prepared as a solid dosage form, not a liquid dosage form, as a powder, granule, capsule, tablet, caplet, or a combination of one or more thereof, so that excessive preservatives and sweeteners There is an effect of solving the problems such as increase in distribution and distribution cost due to an increase in packing volume, breakage in transportation, and product contamination due to such.

In addition, the intestinal lipid composition of the present invention can be prepared by mixing polyethylene glycol as an excipient and sodium stearyl fumarate as a lubricant to prepare tablets for oral use, thereby improving the properties of the sulfates used as active ingredients Lt; RTI ID = 0.0 > nausea and vomiting. ≪ / RTI > Furthermore, both the polyethylene glycol and the sodium stearyl fumarate used in the present invention are water-soluble preparations which are not left in the large intestine after the administration, but they disintegrate within a short time, so that the colon can be completely washed out with rapid drug efficacy, There is an advantage to reduce the possibility of wrongdoing by foreign body.

In a preferred embodiment of the present invention, the enteric coating composition may be prepared by compressing compressed tablets by applying a pressure in the form of a mixture of three active ingredients and an excipient, or a coated tablet coated with a film coating agent.

At this time, the film coating agent constituting the coating film may be at least one kind of polymer substrate such as polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose sodium, methacrylic acid copolymer or cellulose, and at least one of polyethylene glycol, Stabilizers and pigments such as glyceryl monostearate, sodium lauryl sulfate, maltodextrin, dextrose, sodium citrate, lecithin, talc, sodium bicarbonate, triethyl citrate, titanium oxide and stearic acid , In the form of a single membrane or a multilayer film, and it is possible to use a solvent in the form of a flowable, aqueous or semi-aqueous system depending on the polymer substrate.

(A) 3 to 13 parts by weight of magnesium sulfate based on 100 parts by weight of the total of the three active ingredients in the mixer, the potassium sulfate and the potassium sulfate in the mixture, and the magnesium sulfate, potassium sulfate and sodium sulfate, 10 to 20 parts by weight, and 70 to 85 parts by weight of sodium sulfate;

(b) adding 3.0 to 20.0 parts by weight of polyethylene glycol as a pharmaceutically acceptable excipient to 100 parts by weight of the total active ingredient, and mixing the mixture obtained in step (a);

(c) adding 0.3 to 2.0 parts by weight of stearyl fumarate as a pharmaceutically usable lubricant based on 100 parts by weight of the total of the active ingredients to the mixture obtained in the step (b); And

(d) titrating the mixture obtained in step (c) with an oral tablet while applying a pressure.

In addition, the method for manufacturing the enteric coating composition may further include (e) coating the compressed tablet compressed in the step (d) with a film coating agent.

The pharmaceutical composition of the present invention can be produced according to a conventional formulation method, for example, a wet granulation method using a general organic solvent, a dry granulation method or a direct compression method , Of which the direct method is used.

In the manufacturing method related to "OSMOPREP" tablets of Salix Pharmaceuticals, Inc. (US), which is specified in the existing patent, the main component and polyethylene glycol are mixed and milled in a storage mixer containing a temperature-controlled jacket, The granules are produced by lowering the temperature, followed by milling and post-mixing of the lubricant and a tabletting process.

The manufacturing process presented in this patent is a direct measurement method and it does not require the expensive storage mixing device used in "OSMOPREP" Tablets and the temperature control facility of heating and cooling, and it is a simple and economical manufacturing process of mixing and tabletting, .

In addition, the enteric coating compositions containing the three total active ingredients of the present invention may further comprise additional water soluble additives to enhance the characteristics of the solid dosage form, to maintain the particle state of the active material during the formulation process, ≪ / RTI >

The additional ingredients may be mixed with other ingredients that do not affect the topical composition composition containing the three total active ingredients of the present invention. As additional components that may be used in the formulations of topical compositions containing the three active ingredients of the present invention, for example, diluents, binders, lubricants, lubricants, colorants, disintegrants, flavorings, pH adjusting agents, functional polymers or waxes , But the topical composition of the present invention is not limited thereto.

In order to maximize the convenience of taking the dosage form and the effect of the colostrum preparation, the tablets preparation is divided into two divided doses, and each tablet is divided into 15 minutes at intervals of 1 minute to take up the divided tablets. For example, if you only take a day before colonoscopy, take 15 tablets (3 tablets per tablet), 4 tablets per tablet (total 20 tablets), 1 tablet (5 tablets per tablet, total of 25 tablets, 6 tablets per tablet, total of 30 tablets can be adjusted to the tablet size).

According to the present invention, a topical composition containing three active ingredients, magnesium sulfate, potassium sulfate and sodium sulfate, can be obtained. The topical composition of the present invention improves the possibility of deterioration by a microorganism, which is a problem of a liquid preparation, and the use of a preservative to reduce it, and an excessive use of a sweetener and a flavoring agent to improve taste, And storage stability was secured by weight reduction.

In addition, the topical composition of the present invention does not contain the sodium phosphate salt associated with safety problems such as severe acute pancreatic nephropathy which occasionally occurs in some patients, and is caused by the peculiar taste of the excess polyethylene glycol-electrolyte solution There is little nausea and vomiting, and there is an effect of improving safety and compliance with medication.

Fig. 1 is a photograph of the purified water and the turbidity of Example 1 and Comparative Example 6 (the total amount of each dissolved in 1 L of 37 ° C purified water).
FIG. 2 is a photograph comparing Osmoprep (Salix) tablets and tablets according to the design of this patent (Example 1) (each total dose is dissolved in 1 L of 37 ° C purified water).

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein, but may be embodied in other forms. Rather, the disclosure is thorough and complete, and is provided to enable those skilled in the art to fully understand the spirit of the invention.

1. Preparation and evaluation of tablets containing three active ingredients, magnesium sulfate, potassium sulfate and sodium sulfate

The following three active ingredients of Example 1 were mixed with magnesium sulfate, potassium sulfate, sodium sulfate, three active ingredients, an oral excipient and a lubricant under the conditions shown in Table 1 below. Respectively.

Example  1: Containing three total active ingredients Nap  Produce

(Manufactured at 1,000 times the amount shown in Table 1)

1) Weigh each main ingredient and excipient and apples (35mesh).

2) Add 106.67 g of magnesium sulfate as active ingredient, 208.67 g of potassium sulfate, and 1166.67 g of sodium sulfate into a universal mixer for wrapping and mix at 15 rpm for 10 minutes.

3) 86.67 g of polyethylene glycol 8000 was weighed into the mixture produced in the step 2), and the mixture was put into a universal mixer for rapping and mixed at 15 rpm for 10 minutes.

4) 6.32 g of stearyl sodium fumarate is added to the mixture produced in the step 3) into a universal mixer for wrapping and mixed for 5 minutes at 15 rpm.

5) The mixture produced in the step 4) is compressed and purified in a rotary tablet press to a pre-pressurization of 3 KN and a main pressure of 4 KN, followed by demineralization using demineralization.

6) Process inspection was carried out with the fixture obtained in the step 5) (Experimental Example 1)

COMPARATIVE EXAMPLES 1 TO 5: Manufacture of an emulsion containing three total active ingredients

In the same manner as in Example 1, except for using polyethylene glycol 8000 instead of hydroxypropylcellulose, co-povidone, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, Povidone K-30 were mixed to prepare tablets of Comparative Examples 1 to 5.

Condition
Three total active ingredients Polyethylene glycol
8000 Hydroxypropyl methylcellulose (2910-603)
(mg)
Co-povidone
(mg) Hydroxypropylmethylcellulose-L
(mg) Povidone K-30
(mg) Sodium stearyl fumarate
(mg)
total
(mg) Example 1 1482.01 86.67 0 0 0 0 6.32 1575.0 Comparative Example 1 1482.01 0 0 0 0 0 6.32 1488.33 Comparative Example 2 1482.01 0 86.67 0 0 0 6.32 1575.0 Comparative Example 3 1482.01 0 0 86.67 0 0 6.32 1575.0 Comparative Example 4 1482.01 0 0 0 86.67 0 6.32 1575.0 Comparative Example 5 1482.01 0 0 0 0 86.67 6.32 1575.0

Experimental Example 1: Evaluation of tablets containing three total active ingredients

≪ Properties of tablets, hardness, disintegration, weight,

The properties, hardness, disintegration and weight loss of the tablets according to polyethylene glycol 8000 and various excipients in the three active ingredient preparations of Example 1 and Comparative Examples 1 to 5 were examined and the results are shown in Table 2.

How to measure

10 tablets of each of the examples and comparative examples were taken and evaluated as average values after the evaluation, and the tablets were measured according to the following apparatuses and methods.

- Thickness, Diameter, Hardness: Automatic hardness tester (ERWEKA)

- Masondo: Masson pottery (Labfine), 25 rpm, 4 minutes

- Disintegration time: Disintegration tester, Korean Pharmacopoeia 10 revision

Condition Hardness (KP) Disintegration (minute) Weight (mg) Massono
(Within 0.5%) Example 1 8 ~ 9 10 minutes 1575.0 0.3% Comparative Example 1 No tablets formed Comparative Example 2 6 to 9 15 minutes 1575.0 1.5% Comparative Example 3 6 to 8 15 minutes 1575.0 1.6% Comparative Example 4 4 to 6 20 minutes 1575.0 1.2% Comparative Example 5 12 to 15 15 minutes 1575.0 0.65%

Referring to the results shown in Table 2, the tablet of Comparative Example 1 was not formed, and the results of Example 1 and Comparative Examples 2 to 5 were favorable in terms of titability, hardness, and disintegration. A composition using polyethylene glycol 8000 having a fast disintegration force showed the most preferable test results in all process tests.

2. Manufacture and evaluation according to the amount of polyethylene glycol 8000 in the manufacture of tablets containing three active ingredients, magnesium sulfate, potassium sulfate and sodium sulfate

The following three active ingredients were mixed with magnesium sulfate, potassium sulfate and sodium sulfate under the conditions shown in Table 3 below, polyethylene glycol 8000 as an excipient and stearyl sodium fumarate as a lubricant, The concrete method is as follows.

Examples 2 to 7: Preparation according to the amount of polyethylene glycol 8000 in the preparation of the tablets containing three total active ingredients

(Manufactured at 1,000 times the amount shown in Table 3)

1) Weigh each main ingredient and excipient and apples (35mesh).

2) Add 106.67 g of magnesium sulfate as active ingredient, 208.67 g of potassium sulfate, and 1166.67 g of sodium sulfate into a universal mixer for wrapping and mix at 15 rpm for 10 minutes.

3) The mixture obtained in the step 2) was mixed with 8000 parts of polyethylene glycol under the conditions shown in Table 3 in a universal mixer for wrapping and mixed at 15 rpm for 10 minutes.

4) 6.32 g of stearyl sodium fumarate is added to the mixture produced in the step 3) into a universal mixer for wrapping and mixed for 5 minutes at 15 rpm.

5) The mixture produced in the step 4) is compressed and purified in a rotary tablet press to a pre-pressurization of 3 KN and a main pressure of 4 KN, followed by demineralization using demineralization.

6) Process inspection was carried out with the fixture obtained in the step 5) (Experiment 2)

Condition Three total active ingredients
(mg) Polyethylene glycol 8000 (mg)
[Content (w / w)] ^* Sodium stearyl fumarate (mg)
 [Content (w / w)] ^* Total amount
( mg ) Example 1 1482.01 86.67 [5.9%] 6.32 [0.43%] 1,575 Example 2 1482.01 38.1 [2.6%] 6.32 [0.43%] 1,526.4 Example 3 1482.01 62.0 [4.2%] 6.32 [0.43%] 1,550.3 Example 4 1482.01 136.67 [9.2%] 6.32 [0.43%] 1,624.7 Example 5 1482.01 165.67 [11.2%] 6.32 [0.43%] 1,654 Example 6 1482.01 222.2 [15.0%] 6.32 [0.43%] 1,710.5 Example 7 1482.01 297.0 [20.0%] 6.32 [0.43%] 1,785.3 * Content% (w / w): Percentage by weight of each ingredient relative to weight of active ingredient

Experimental Example  2: Evaluation of tablets containing three total active ingredients

≪ Properties of tablets, hardness, disintegration, weight,

The properties, hardness, disintegration and weight loss of the tablets according to the amounts of polyethylene glycol 8000 contained in the total of three active ingredients in Examples 1 to 7 were examined and the results are shown in Table 4.

How to measure

Ten tablets of each of the examples were taken as average values after evaluation and measured according to the following apparatus and method.

- Thickness, Diameter, Hardness: Automatic hardness tester (ERWEKA)

- Masondo: Masson pottery (Labfine), 25 rpm, 4 minutes

- Disintegration time: Disintegration tester, Korean Pharmacopoeia 10 revision

Condition Hardness (KP) Disintegration (minute) Weight (mg) Massono
(Within 0.5%) Example 1 8 ~ 9 10 minutes 1,575 0.3% Example 2 7 to 8 9 minutes 1,526.4 incongruity
Refining failure Example 3 7 to 8 10 minutes 1,550.3 0.4% Example 4 9-10 11 minutes 1,624.7 0.3% Example 5 9-11 11 minutes 1,654 0.2% Example 6 10 to 11 12 minutes 1,710.5 0.17% Example 7 11-12 12 minutes 1,785.3 0.15%

The results of Examples 1 to 7 show that the stability, hardness, and disintegration of each of the compositions are preferable, but when polyethylene glycol 8000 is less than 3 parts by weight based on 100 parts by weight of the active ingredient as in Example 2 When the amount of polyethylene glycol 8000 is in the range of 3.0 to 20.0 parts by weight based on 100 parts by weight of the active ingredient, all process results are suitable. .

In addition, it was confirmed that the amount of polyethylene glycol 8000 which can reduce the size of the tablet easily while showing suitable process results, is 5.0-15.0 parts by weight based on 100 parts by weight of the active ingredient.

3. Manufacture and evaluation of nail formulations according to the weight of sodium stearyl fumarate and the weight of magnesium stearate in the manufacture of the tablets containing the three active ingredients of magnesium sulfate, potassium sulfate and sodium sulfate

The total active ingredients of three types of magnesium sulfate, potassium sulfate and sodium sulfate under the conditions shown in Table 5 were mixed with polyethylene glycol 8000 as an excipient and stearyl sodium fumarate as a lubricant to prepare a nail containing the three total active ingredients of Example 1 The concrete method is as follows.

Examples 8 to 12: Preparation according to the weight of sodium stearyl fumarate in the manufacture of an emulsion containing three total active ingredients

(Manufactured at 1,000 times the amount shown in Table 5)

1) Weigh each main ingredient and excipient and apples (35mesh).

2) Add 106.67 g of magnesium sulfate as active ingredient, 208.67 g of potassium sulfate, and 1166.67 g of sodium sulfate into a universal mixer for wrapping and mix at 15 rpm for 10 minutes.

3) 86.67 g of polyethylene glycol 8000 was weighed into the mixture produced in the step 2), and the mixture was put into a universal mixer for rapping and mixed at 15 rpm for 10 minutes.

4) Sodium stearyl fumarate as specified in Table 5 is added to the mixture produced in the step 3) in a universal mixer for wrapping and mixed for 5 minutes at 15 rpm.

5) The mixture produced in the step 4) is compressed and purified in a rotary tablet press to a pre-pressurization of 3 KN and a main pressure of 4 KN, followed by demineralization using demineralization.

6) Process inspection was carried out with the fixture obtained in the step 5) (Experimental Example 3)

COMPARATIVE EXAMPLES 6 to 8: Preparation according to the weight of magnesium stearate in the manufacture of the tablets containing three total active ingredients

The tablets of Comparative Examples 6 to 8 were prepared by mixing the magnesium stearate with each of the three active ingredients under the same conditions and conditions as those in Example 1 except that the tablets were prepared under the conditions shown in Table 5 below.

Condition
Three total active ingredients ( mg ) Polyethylene glycol
8000 ( mg ) Fumaric acid
Sodium stearyl (mg)
[Content (w / w)] * Stearic acid
Magnesium (mg)
[Content (w / w)] *
Total amount
(mg) Example 1 1482.01 86.67 6.32
[0.43%] 1,575 Example 8 1482.01 86.67 3.14
[0.21%] 1,571.82 Example 9 1482.01 86.67 9.47
[0.64%] 1,578.15 Example 10 1482.01 86.67 12.66
[0.85%] 1,581.34 Example 11 1482.01 86.67 22.3
[1.5%] 1,590.98 Example 12 1482.01 86.67 30.0
[2.0%] 1,598.68 Comparative Example 6 1482.01 86.67 6.32
[0.43%] 1,575 Comparative Example 7 1482.01 86.67 3.14
[0.21%] 1,571.82 Comparative Example 8 1482.01 86.67 22.3
[1.5%] 1,590.98 * % (W / w):% of each component weight relative to weight of active ingredient

Experimental Example  3: Evaluation of tablets containing three total active ingredients

≪ Properties of tablets, hardness, disintegration, weight,

The properties, hardness, disintegration and weight loss of the tablets according to the lubricant in the three active ingredients of Examples 1 and 8 to 12 and Comparative Examples 6 to 8 were examined and the results are shown in Table 6.

How to measure

10 tablets of each of the examples and comparative examples were taken and evaluated as average values after the evaluation, and the tablets were measured according to the following apparatuses and methods.

- Thickness, Diameter, Hardness: Automatic hardness tester (ERWEKA)

- Masondo: Masson pottery (Labfine), 25 rpm, 4 minutes

- Disintegration time: Disintegration tester, Korean Pharmacopoeia 10 revision

Condition
Hardness( KP )
Disintegration (minute)
weight( mg ) Massono
(Within 0.5%)
Turbidity
Remarks Example 1 8 ~ 9 10 minutes 1,575 0.3% Great
Example 8
9-10
8 minutes
1,571.82
0.3%
Great Cling to punch engraving when tableting Example 9 9-11 11 minutes 1,578.15 0.2% Great Example 10 10 to 11 13 minutes 1,581.34 0.15% Great Example 11 10 to 11 15 minutes 1,590.98 0.1% Great Example 12 11-12 23 minutes 1,598.68 0.1% usually Comparative Example 6 9-10 19 minutes 1,575 0.2% Poor Comparative Example 7 9-10 15 minutes 1,571.82 0.3% Poor Comparative Example 8 7 to 8 32 minutes 1,590.98 0.5% Poor

Turbidity criterion table (visual observation with black letter background) Very good The liquid is transparent and the background letters look sharp. Great The liquid is translucent but the background letters look sharp. usually The background letter is visible but not sure. Poor The liquid is opaque and background characters are not visible.

In the results of the above Table 6, in the test results of Comparative Examples 6 to 8 and Examples 1 and 8 to 12, when 0.21 part by weight of stearyl fumarate (Example 8) is compared with 100 parts by weight of the active ingredient, . The more the weight was increased, the more the grinding was improved, but the disintegration time was increased. Comparing Example 1 and Comparative Example 6 in which the same parts by weight of magnesium stearate and sodium stearyl fumarate were used, the disintegration time was increased and the degree of grindability was not good when magnesium stearate was used. It is possible to confirm the problem of increase.

Therefore, when the same weight part of the lubricant is added, stearyl sodium fumarate having a hydrophilic structure as shown in the formula (4) is more hydrophilic than magnesium stearate as in the case of the non-water-soluble lubricant, It has excellent merits such as rapid drug efficacy and high melting point.

From the results shown in Table 6, it was confirmed that when the amount of stearyl fumarate was in the range of 0.3 to 2.0 parts by weight based on 100 parts by weight of the active ingredient, favorable process results were obtained in the shortening of the disintegration time and in the turbidity drawing.

Preferably, 0.4 to 1.5 parts by weight of stearyl fumarate can be used to reduce tablet size and haze while showing suitable process results.

Table 8 and FIG. 2 show the results of the comparison with Example 1, in which Osmoprep tablet, a conventional sodium phosphate preparation using magnesium stearate as a lubricant, sodium stearyl fumarate as a lubricant, and active ingredient is a sulfate preparation, are shown. As a result, in Example 1, compared with Osmoprep tablets, total administered tablet weight and tablet size were reduced, thereby improving medication adherence, disintegration time and turbidity as well as improving colonoscopy.

Example 1 OSMOPREP tablet Total number of tablets administered (tablets) 30 32 Tablet weight (mg) 1575.0 1676.0

Lubricant Kinds Sodium stearyl fumarate Magnesium stearate Lubricant content
(% By weight relative to the active ingredient) 0.43 0.56 Weight of lubricant (mg / tablet) 6.32 8.38 Total amount of lubricant (mg) 189.6 268.16 Disintegration time (minutes) 10 15 Turbidity ^* Great Poor *: Refer to the turbidity table in [Table 7] for the turbidity reference.

Claims (9)

As the active ingredient, magnesium sulfate, potassium sulfate, and sodium sulfate;
As the excipient, polyethylene glycol having an average molecular weight of 7,000 to 9,000; And
As a lubricant, stearyl fumarate;
3 to 13 parts by weight of magnesium sulfate, 10 to 20 parts by weight of potassium sulfate, 70 to 85 parts by weight of sodium sulfate, 3 to 20 parts by weight of polyethylene glycol and 0.3 to 2.0 parts by weight of sodium stearyl fumarate based on 100 parts by weight of the total of the above- Or a pharmaceutically acceptable salt thereof. delete delete delete delete The method according to claim 1,
Wherein the tablet is a coated tablet obtained by mixing the active ingredient, the excipient and the lubricant with a compressed nail or the compressed nail is coated with a single membrane or a multilayer film coating agent. The method according to claim 6,
Wherein the film coating agent comprises at least one polymer substrate selected from the group consisting of polyvinyl alcohol, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, methacrylic acid copolymer and cellulose, and at least one polymeric substrate selected from the group consisting of polyethylene glycol, glyceryl mono Characterized in that it consists of at least one additive selected from the group consisting of stearate, sodium lauryl sulfate, maltodextrin, dextrose, sodium citrate, lecithin, talc, sodium bicarbonate, triethyl citrate, titanium oxide and stearic acid Refined tablets made to improve the compliance of medication. A method for producing a tablet preparation of tablets, which improves adherence compliance,
(a) mixing magnesium sulfate, potassium sulfate, and sodium sulfate as active ingredients, wherein 3 to 13 parts by weight of magnesium sulfate, 10 to 20 parts by weight of potassium sulfate, and 70 to 70 parts by weight of sodium sulfate 70 To 85 parts by weight;
(b) mixing 3 to 20 parts by weight of polyethylene glycol having an average molecular weight of 7,000 to 9,000 as an excipient, based on 100 parts by weight of the total amount of the active ingredient, in the mixture produced in the step (a);
(c) mixing 0.3 to 2.0 parts by weight of stearyl sodium fumarate as a lubricant with respect to 100 parts by weight of the total amount of the active ingredient; And
(d) titrating the mixture produced in step (c) with an oral tablet while applying pressure;
Wherein the pharmaceutical preparation has improved adherence compliance. delete

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