WO2014054880A1 - Novel laxative composition with improved stability, containing polyethylene glycol and vitamin c - Google Patents

Abstract

The present invention relates to: a mixed-packaged laxative composition containing a polyethylene glycol and vitamin C prepared in the form of one or more types selected from a coated powder, a coated granule, a coated tablet, an uncoated tablet, and a capsule; and a pharmaceutical dosage form containing the same. As described above, vitamin C contained in a laxative composition is prepared in a coated form, thereby inhibiting a change in a characteristic of the laxative composition due to minimization of contact with other laxative compositions when a layer is separated from a mixture of other pharmaceutical ingredients, improving stability during storage or circulation, and maintaining bowel cleaning effects for diagnosis, examination, and surgery, or anti constipation effects.

Description

Intestinal Laxative Composition with Improved Stability Containing Novel Polyethyleneglycol and Vitamin Seeds

The present invention relates to a mixed packaged intestinal laxative composition containing polyethylene glycol and vitamin seeds and a pharmaceutical formulation comprising the same.

Vascular lavage has been used for endoscopy, diagnostic or surgical measures such as colonoscopy, barium enema X-rays and intravenous pyelography and first aid, and intestinal laxative compositions are used for such intestinal lavage. . In addition, the intestinal laxative composition as described above is characterized by constipation caused by strict constipation, rigid constipation, functional constipation such as rectal constipation, stenosis due to postoperative adhesion, and organic constipation caused by intestinal disease, drug-induced constipation, etc. It can also be used to treat and relieve symptoms.

In order to effectively provide for the diagnosis, treatment or surgical measures of intestinal diseases, pretreatment for intestinal lavage must be preceded. Therefore, such a pretreatment enteric cleanser (intestinal laxative composition) should be simple and safe, with good patient compliance and excellent cleansing effect.

As the enteric laxative composition for this purpose, a large amount of isotonic water mainly containing only electrolyte was used, and a method of inducing diarrhea by ingesting the isotonic water was used. As an example of the enteric laxative composition using the isotonic water as described above, there is an aqueous formulation composed of phosphate salt, the phosphate salt solution has an osmotic effect, the effect of promoting bowel movement by introducing a significant amount of water into the intestine. However, there is a disadvantage in that the preparation cannot be used in patients with nephropathy, heart disorder or high blood pressure because a large amount of water must be ingested.

Recently, enteric laxative compositions comprising polyethylene glycol / electrolyte consisting of sodium sulfate, potassium chloride, sodium chloride, sodium bicarbonate, and water-bonded polyethylene glycol are most used. However, the intestinal laxative composition comprising such polyethylene glycol / electrolyte should drink about 4 l of solution within a 2-3 hour cycle (Afridi et al., Gastrointest. Endosc., 1995, 41, 485-489), Of patients experience side effects such as discomfort, nausea, cramps and vomiting due to overdose (Dipalma et al., Am. J. Gastroenterol., 2003, 98, 2187-2191). It may also be offensive. Therefore, there have been attempts to reduce the amount of salt or add flavors to solve these side effects or discomfort.

On the other hand, US Patent No.7169381 provides a polyethylene glycol / electrolyte enteric laxative composition containing vitamin C in order to improve this problem, vitamin C increases the osmotic effect to reduce the weight of polyethylene glycol, the liquid phase immediately before administration It serves to reduce the volume of the composition in the state. In addition, it protects the intestinal cells, mitigates some of the toxicity that may be caused by excessive use of polyethylene glycol, and protects the intestines by inhibiting the death of intestinal useful bacteria. It can be said that the effect of compensating for the disadvantages of the composition is great.

However, the polyethylene glycol / electrolyte enteric laxative composition containing vitamin C is unstable in heat, light, moisture, etc., and is easily destroyed during storage or distribution, or an oxidation reaction and a browning reaction occur, and thus its utility is significantly lower than immediately after preparation. To this end, the United States Patent No. 7169381 has proposed to individually package the components of the intestinal laxative composition, such as vitamin C or to coat the vitamin C to protect from moisture. U.S. Patent No. 5274001 provides an enteric laxative composition in a single mixture in which vitamin C is coated with silicone or ethyl cellulose.

However, the patent of the prior document has the disadvantage that the management and manufacturing cost, etc. according to the separate packaging of vitamin C is increased, in the case of silicone or ethyl cellulose coated vitamin C, the solubility in aqueous solution is low, the powder form components It is difficult to use as a component of intestinal laxatives that need to be dissolved in water.

Therefore, the inventors of the present invention while studying a method for producing a high safety intestinal laxative composition during storage or distribution, when the vitamin C included in the intestinal laxative composition is coated with a water-soluble coating agent, the change in the appearance of the intestinal laxative composition is almost Without this, the present invention was completed by confirming that the coating agent of vitamin C was dissolved rapidly so that the use of the enteric laxative composition was easier than before.

It is an object of the present invention to provide a mixed packaged intestinal laxative composition containing polyethyleneglycol and vitamin C.

The present invention provides a mixed packaged intestinal laxative composition containing polyethylene glycol and vitamin C.

The present invention provides enteral laxative compositions that are capable of mixed packaging by minimizing direct contact by layering vitamin C with other components of the intestinal laxative compositions of the present invention to improve patient ease of use, manufacturing process and production costs.

Preferably, the present invention, polyethylene glycol, the first pharmaceutical component; Vitamin C, second pharmaceutical ingredient prepared in at least one form of coated powder, coated granules and coated tablet, capsule and uncoated tablet with a water-soluble coating agent; And a third pharmaceutical component consisting of a sweetener; and relates to a pharmaceutical entertaining laxative composition or a pharmaceutical formulation comprising the same, wherein the first to third pharmaceutical ingredients are mixed and packaged.

Vitamin C prepared in one form of the powder (powder), the coating granules and the coating tablet using the water-soluble coating agent is a natural or synthetic polymer series, the water-soluble coating base in the cellulose ether derivative series Phosphorus hypromellose (Hydroxypropyl methyl Cellulose), hydroxypropyl cellulose (Hydroxy propyl Cellulose), hydroxyethyl cellulose (Hydroxyethyl Cellulose), methyl cellulose (Methyl Cellulose), carboxymethyl cellulose (Carboxy methyl Cellulose), or methacrylate It may be coated with a water-soluble coating agent consisting of a coating agent selected from the group consisting of copolymer (Eudragit), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) alone or a mixture thereof.

Preferably, as the coating agent, it is preferable to use a coating base composed of a single or a mixture of polyvinyl alcohol and methacrylate copolymer which are water-soluble agents.

The coating layer may include, if necessary, pharmaceutically acceptable additives such as polyethylene glycol (PEG) in a plasticizer, talc in a coagulant inhibitor, sodium bicarbonate in a pH adjuster, a light shielding agent, a pigment, and the like. It may include, but not limited to.

The enteric laxative composition may further include an electrolyte supply salt, a flavoring agent, and other pharmaceutical excipients, more preferably, the enteric laxative composition may be 5 to 15 parts by weight of vitamin C, based on 100 parts by weight of polyethylene glycol, 5-15 parts by weight of the salt for the electrolyte supply, 0.01-3 parts by weight of the sweetener, 0.01-3 parts by weight of the flavoring agent and other pharmaceutical excipients may be mixed.

The 'Purgative' is a drug that acts to excrete the contents of the intestine, and when the colon (X-ray, endoscopy) is examined through a strong bowel (Stronger Catharsis) that completely or completely emptyes the large intestine (complete purgation). It can lead to mild catharsis that causes diarrhea (partial purgation) as well as pretreatment intestinal lavage, leading to weakening or releasing feces.

The enteric laxative composition of the present invention includes polyethylene glycol, vitamin C, and salts for supplying electrolyte as main components, and the polyethylene glycol is a high osmotic laxative and has a large molecular weight, which is not absorbed by the intestinal tract and remains in solution. Previously, due to the increase in osmotic pressure in the large intestine to interfere with the absorption of water into the body to soften the stool and to increase the volume serves to facilitate bowel movement in the form of a liquid.

The electrolyte supply salts are active ions or molecules that act as osmosis, are not absorbed in the intestinal tract, move water in the intestinal tract to facilitate bowel movement, and are rarely absorbed in the intestine. Used as a salt.

The vitamin C can be used in amorphous, crystalline or chloride form, and can be used alone or in combination of one or more. The function of vitamin C is to increase the osmotic effect of polyethylene glycol has the effect of reducing the amount of polyethylene glycol, protects the intestinal cells, and serves to protect the intestines by inhibiting the death of intestinal useful bacteria.

The polyethylene glycol is a relatively stable, non-toxic substance having different properties depending on the molecular weight, the average molecular weight of 200 ~ 35,000 is used, polyethylene glycol 400 (PEG 400) is a somewhat tacky transparent liquid, polyethylene glycol 1,500 (PEG 1,500) is a soft solid and polyethylene glycol 4,000-20,000 (PEG 4,000-20,000) is a white, light solid in the form of flakes or powders.

Polyethylene glycol that can be used as a laxative composition of the present invention has a powder (Powder) form to be uniformly mixed with other pharmaceutical ingredients, may have an average molecular weight of 2,000 ~ 8,000 range, preferably polyethylene glycol 3,350 (PEG 3,350 ), Polyethylene glycol 4,000 (PEG 4,000), polyethylene glycol 6,000 (PEG 6,000), polyethylene glycol 8,000 (PEG 8,000), and the like, among which polyethylene glycol 3,350 is most suitable.

In addition, the salt for electrolyte supply of the intestinal laxative composition of the present invention may include one or more electrolytes. Therefore, sodium ions, magnesium ions and calcium ions are suitable as salts for the electrolyte supply that can be used to alleviate this. These ions may be present in the form of suitable salts, for example their chlorides, bicarbonates, acetates, carbonates, citrates, fumarates, gluconates, malates, nitrates, phosphates, succinates or sulfates. Chlorides and sulfates are preferred, for example sodium chloride, potassium chloride and sodium sulfate. The electrolyte feed salts may be most preferably selected from sodium chloride, potassium chloride and sodium sulfate, more preferably the composition of the present invention comprises all of these electrolytes.

The sweetener of the enteric laxative composition of the present invention comprises at least one sweetener. As the sweetener, saccharin, which exhibits a sweetening effect and fast solubility even in a small amount in addition to glucose, sucrose, dextrose, fructose, maltose, which are common sugars, are used. ), Saccharin Sodium, Xylitol, Xylitol, Sorbitol, Mannitol, Maltitol, Lactitol, Isomalt, Stevioside, Erythritol ), Aspartame, Acesulfame Potassium and Sucralose may be used by mixing one or more sweeteners selected from the group consisting of 100 parts by weight of polyethylene glycol. 0.01 to 3 parts by weight may be included as a standard.

The intestinal laxative composition may be prepared by adding a flavoring agent in addition to the sweetening agent to improve the medication compliance of the patient, preferably the flavoring agent may be included 0.01 to 3 parts by weight based on 100 parts by weight of polyethylene glycol. In addition, the flavoring agent may include a liquid or powder (powder) or clathrate form.

Enteric laxative compositions of the present invention may be prepared in the form of powders, granules, or tablets. In this case, when prepared in powder or granular composition, the intestinal laxative composition of the present invention is separated from the layer, so that only vitamin C is coated with powder or coated granules or coated with a separate coating agent. It may be prepared in a tablet form, or may be prepared in an uncoated state or a capsule filled with vitamin C. However, the above examples are examples of layered enteric laxative compositions of the present invention and do not limit the spirit of the present invention.

In addition, the enteric laxative compositions of the present invention may include additional ingredients to enhance the characteristics of the solid dosage form, to maintain the particle state of the active substance during the formulation process, or to increase the safety of the composition. The additional component may be mixed with other components of the enteric laxative composition of the present invention, and may be one that does not adversely affect the osmotic pressure of the enteric laxative composition of the present invention. Additional ingredients that may be used in the formulations of the invention may include, for example, diluents, binders, glidants, glidants, colorants, disintegrants, flavoring agents, functional polymers or waxes.

Formulations of the enteric laxative compositions of the present invention may include glidants. Such lubricants include, but are not limited to, magnesium stearate, potassium stearate, talc, stearic acid, sodium lauryl sulfate and paraffin. Lubricants facilitate the preparation of solid dosage forms.

Carriers such as sodium citrate and di-calcium phosphate, stearates, silica, gypsum, starch, lactose, sucrose, glucose, mannitol, talc, and fillers or extenders such as silicic acid, hydroxypropylmethylcellulose, hydride Binders such as oxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone and acacia, humectants such as glycerol, agar, calcium carbonate, potato starch, tapioca starch, alginic acid, certain silicates, colloidal silicon dioxide, sodium starch glycolate , Disintegrants such as crospovidone and sodium carbonate, dissolution retardants such as paraffin, absorption accelerators such as quaternary ammonium compounds, wetting agents such as cetyl alcohol and glycerol monostearate, absorbents such as kaolin and bentonite clay, stables such as fumaric acid Topical, Colorant, Buffering Agent, Min Agents, preservatives, organic acids and salts may be included in the views of the present invention laxative composition, it is not limited thereto. The additional component serves to balance the electrolyte in the patient.

The enteric laxative composition of the present invention can be used as a solid dosage form dissolved in water immediately before administration. In addition, the appropriate dosage of the intestinal laxative compositions of the present invention can be varied depending on the individual to be treated and the purpose. For example, age, weight, medical history of the individual patient, and the like may affect the therapeutic effect of the treatment. Induction of mild catharsis may require low dose administration of the composition, whereas complete bowel movement for preoperative intestinal cleansing during colon (X-ray, endoscopic) examination may require higher doses. .

The enteric laxative composition of the present invention is provided in a mixed or separately packaged state as needed, preferably a mixed-packaged enteral laxative composition, 5-15 parts by weight of vitamin C, based on 100 parts by weight of polyethylene glycol, a compound for supplying an electrolyte 5 to 15 parts by weight and 0.01 to 3 parts by weight of sweetener, 0.01 to 3 parts by weight of flavoring agent and additional pharmaceutical ingredients, more specifically, 100 g of polyethylene glycol 3,350 (PEG 3,350), vitamin C (amorphous, crystalline) Or 10.6 g of chloride form alone or in a mixture of one or more), 11.206 g of salt for supplying electrolyte (mixed form of sodium sulfate, sodium chloride, potassium chloride), sweetening agent, flavoring agent, pharmaceutical additive, coating agent and polyvinyl alcohol / Methacrylate copolymer mixture.

The total daily dose for light bowel movements may be, for example, about 60 g (58-62 g) / 500 ml to about 120 g (116-124 g) / 1 L of enteric laxative composition of the present invention dissolved in water. .

In addition, higher dosages may be required for complete bowel bowel movements. The total dose used for complete bowel movement for pretreatment intestinal cleansing during colon (X-ray, endoscopy) examination is about 240 g (232-248) / 2 L of laxative composition of the present invention in a state dissolved in water. Can be taken, and can be taken in divided or divided doses.

Thus, the intestinal laxative composition according to the present invention provides a method for treating gastrointestinal disorders such as constipation when provided in low doses, and when provided in high doses, the colon is examined for colon (X-ray, endoscopy) examination or surgical operation. Provides a method of completing a toilet to pretreat.

Intestinal laxative compositions of the present invention may be prepared in pharmaceutical formulations conventional in the art such as powders, granules, capsules, pills, tablets, multi-layered tablets, suspensions and the like until the desired effect is achieved and up to a daily maximum Undivided or divided doses may be taken within dose limits.

If you explain how to take in more detail,

Water is added to the mixed packaged laxative composition of the present invention in a container and shaken well to prepare a homogeneous solution. If necessary, the solution can be refrigerated before drinking. Prepared solutions should be stored refrigerated and used within 24 hours.

Split dosing method: In the evening before colonoscopy, take 1 l of the preparation solution for 1 hour (1 cup of 250 ml every 15 minutes) and drink 0.5 l of water. The next morning 1 liter of the preparation solution is taken for 1 hour and 0.5 liters of water is consumed. This process must be completed at least one hour before the start of the colon (X-ray, endoscopy) examination.

Non-divided administration (evening administration) Method: At 6 pm on the evening before colonoscopy, 1 liter of the preparation solution is taken for 1 hour (250 ml 1 cup every 15 minutes), and 1 liter of the preparation solution is taken for 1 hour after 1.5 hours. Also take an additional 1 liter of water during the evening.

In addition, for the relief of constipation may be administered every 1-2 hours every 24 hours.

Intestinal laxative compositions of the invention can be administered via a variety of routes. For example, the laxative composition may be administered orally or may be administered via a tube such as a feeding tube or a feeding tube on the nose.

The present invention is polyethylene glycol and coated powder, coated granule, coated tablet, capsule and uncoated tablet. A mixed packaged intestinal laxative composition containing vitamin C prepared in one or more forms of the invention and a pharmaceutical formulation comprising the same. When the vitamin C included in the intestinal laxative composition as described above is separated from the mixture with other pharmaceutical ingredients, the contact with the other intestinal laxative composition is minimized, so that the phenomenon of change in the intestinal laxative composition is suppressed, and the storage or distribution process Increasing stability in the intestinal tract and the elimination of bowel or constipation for diagnostic tests and surgery is maintained.

1 is a photograph confirming the accelerated stability test results (acceleration day 10) of the first or third pharmaceutical components of the laxative composition of the present invention alone or mixed test examples 01 to 28 as a result of the formulation compatibility test.

Figure 2 is a photograph confirming the stability test results of Comparative Examples 29-34 and Comparative Example test results (acceleration day 10) for the cross-test of the salt for the electrolyte supply to the mixture of the first to third pharmaceutical ingredients as a result of the formulation compatibility test to be.

Figure 3 is a photograph confirming the solubility in vitamin C coated with a water-soluble coating or a water-insoluble coating.

Figure 4 is a photograph showing the coating vitamin C contained in the intestinal laxative compositions of Examples 25, 26, 27 and 29.

Figure 5 is a photograph showing the change in appearance of the six months accelerated stability test results of the enteric laxative composition of Example 32.

Figure 6 is a photograph showing the change in appearance of the accelerated stability test results of the intestinal laxative compositions of Example 36 and Comparative Example 02 with time (initial ~ 6 months).

Figure 7 is a photograph showing the change in appearance of the six months accelerated stability test results of the enteric laxative composition of Example 38.

Figure 8 is a photograph showing the change in appearance of the six months accelerated stability test results of the intestinal laxative compositions of Examples 43 and 44.

9 is a graph showing the measured values of vitamin C, which is one of the main ingredients, as a result of 6 months accelerated stability test of the enteric laxative compositions of Examples 26, 38 and 44 and the enteric laxative composition of Comparative Example 02.

FIG. 10 is a diagram showing a coating diagram in the form of powder (A), granules (B) and tablets (C) of vitamin C in the enteric laxative composition of the present invention.

Hereinafter, preferred test examples and examples of the present invention will be described in detail. The present invention is not limited to the embodiments described herein but may be embodied in other forms, but is provided to provide a thorough and complete description of the teachings herein and to fully convey the spirit of the invention to those skilled in the art.

<Standard Table> Appraisal Standards

<Test Examples 01-28> Formulation suitability test

Intestinal laxative compositions containing polyethylene glycol and vitamin C are known to be unstable in heat, light, and moisture, so that vitamin C is easily destroyed or oxidized and browned during storage or distribution. It is marketed in a packaged form.

The present inventors conducted an experiment to determine the suitability of the mixed packaging by vitamin C and other main ingredients and pharmaceutical excipients as a main component in order to make a vitamin C mixed package form. In order to observe the effects of the combination of the first and third pharmaceutical ingredients and other pharmaceutical excipients on the properties of the vitamin C, the second pharmaceutical ingredient, various combinations of experimental groups were prepared and mixed under the conditions of <Table 1>. And accelerated stability test was carried out, the results are as shown in FIG.

* Storage condition-proceed in constant temperature / humidity conditions

Long-term 25 ° C / 60% RH (relative humidity)

Acceleration 40 ℃ / 75% RH (relative humidity)

Packing: Falcon Tube (PE, PP) and Aluminum Pouch

Table 1

number	Vitamin c	Anhydrous sodium sulfate	Sodium chloride	Potassium chloride	PEG 3,350	Acesulfame Potassium	Aspartame
Test Example 01	O
Test Example 02	O	O
Test Example 03	O		O
Test Example 04	O			O
Test Example 05	O	O	O
Test Example 06	O	O		O
Test Example 07	O		O	O
Test Example 08	O	O	O	O
Test Example 09	O	O	O	O		O
Test Example 10	O	O	O	O			O
Test Example 11	O				O
Test Example 12	O	O			O
Test Example 13	O		O		O
Test Example 14	O			O	O
Test Example 15	O	O	O		O
Test Example 16	O	O		O	O
Test Example 17	O		O	O	O
Test Example 18	O	O	O	O	O
Test Example 19	O				O	O
Test Example 20	O	O	O		O	O
Test Example 21	O	O		O	O	O
Test Example 22	O		O	O	O	O
Test Example 23	O	O	O	O	O	O
Test Example 24	O				O		O
Test Example 25	O	O	O		O		O
Test Example 26	O	O		O	O		O
Test Example 27	O		O	O	O		O
Test Example 28	O	O	O	O	O		O

The test example of Table 1 will be described in detail as follows.

<Test Example 01>

In order to observe the change of appearance when vitamin C alone was stored under long-term and accelerated conditions, 15 g of vitamin C was packaged and stored for 10 days to visually check the appearance.

<Test Examples 02-08>

In order to observe the effects of the vitamin C and the salt for the electrolyte supply in the intestinal laxative composition, 20 g, 7.2 g, and 2.7 g of anhydrous sodium sulfate, sodium chloride, and potassium chloride were added to 15 g of vitamin C according to the above conditions. After mixing for 10 days under long-term and accelerated conditions, the appearance change was visually confirmed. In order to observe the change in appearance quickly and in detail, the amount of salt in the enteric laxative composition was mixed twice with the maximum weight of the main laxative laxative.

<Test Examples 09-10>

In order to observe the effect on the appearance by adding a sweetener to Test Example 08, 20g, 7.2g, 2.7g of anhydrous sodium sulfate, sodium chloride and potassium chloride were mixed with 15g of vitamin C and 2.2g of acesulfame potassium, respectively. Alternatively, aspartame 3.8g was added, and after 10 days of storage under long-term and accelerated conditions, the change of appearance was visually confirmed. In order to observe the change in appearance quickly and in detail, the amount of salt and sweetener in the enteric laxative composition was mixed twice with the maximum weight of the main laxative laxative.

<Test Examples 11-18>

Interaction observation when vitamin C and polyethylene glycol were mixed, and the test for observing the effect on the appearance by adding salts for electrolyte supply to Test Example 11, test example in which 266.7 g of polyethylene glycol was mixed with 15 g of vitamin C. In addition to 11 or 20g, 7.2g, 2.7g alone or at least one anhydrous sodium sulfate, sodium chloride, potassium chloride were added according to the above conditions, the change in appearance after 10 days storage under long-term and accelerated conditions was visually confirmed. In order to observe the change in appearance quickly and in detail, the amount of polyethylene glycol and salts in the enteric laxative composition was mixed twice with the maximum weight of the main laxative laxative.

<Test Examples 19-23>

Interactions when vitamin C, polyethylene glycol, and acesulfame potassium were mixed, and the effects of the addition of salts for the electrolyte supply to Test Example 19 to observe the effects on the appearance. After mixing 2.2 g of acesulfame potassium, respectively, additionally 20 g, 7.2 g, and 2.7 g of anhydrous sodium sulfate, sodium chloride, and potassium chloride were added according to the above conditions. Was visually confirmed. In order to observe the change in appearance quickly and in detail, the blending amount of polyethylene glycol, salts and sweeteners in the enteric laxative composition was mixed twice with the maximum weight of the main laxative laxative.

<Test Examples 24-28>

In order to observe the interaction when vitamin C, polyethylene glycol and aspartame are mixed, and to examine the effects of the addition of salts for the electrolyte supply to Test Example 24 on the appearance, vitamin C 15g, polyethylene glycol 266.7 g aspartame 3.8 20 g, 7.2 g, and 2.7 g of anhydrous sodium sulfate, sodium chloride, and potassium chloride were added according to the above conditions, respectively, and the appearance changes were visually confirmed after storage for 10 days under long-term and accelerated conditions. In order to observe the change in appearance quickly and in detail, the blending amount of polyethylene glycol, salts and sweeteners in the enteric laxative composition was mixed twice the maximum weight part that can be included in the enteric laxative composition.

<Result>

As a result of <Test Examples 01 to 18>, as shown in the results of FIG. 1, it was confirmed that the appearance change was not induced even under the acceleration condition. However, in the case of <Test Examples 19 ~ 23>, the appearance changed to pale reddish yellow after 10 days storage under accelerated conditions, and in the case of <Test Examples 24 ~ 28>, the appearance change occurred in red after 10 days storage under the same conditions. I could confirm that. Based on the above results, it could be inferred that the change in appearance caused by the mixed packaging of the intestinal laxative composition is not due to a single physicochemical change of a specific substance, which is a specific component of the composition, specifically It can be predicted that vitamin C and polyethylene glycol and sweetener aspartame or acesulfame potassium are due to their interaction.

<Test Examples 29-34>

In order to observe the effect of the type of salts for the electrolyte supply on the change of the properties generated during the mixed packaging of the intestinal laxative composition, the intestinal laxative composition is mixed under the conditions of <Table 2>, and after storage for 10 days under long-term and accelerated conditions It was visually confirmed whether there was a change. In order to observe the change in appearance quickly and in detail, the blending amount of polyethylene glycol, salts and sweeteners in the enteric laxative composition was mixed twice the maximum weight part that can be included in the enteric laxative composition. The control for this was that all components were mixed. Properties of the test results 29 to 34 is the same as FIG.

TABLE 2

ingredient	Test Example 29	Test Example 30	Test Example 31	Test Example 32	Test Example 33	Test Example 34
Vitamin c	O	O	O	O	O	O
PEG 3,350	O	O	O	O	O	O
Aspartame	O	O	O	O	O	O
Acesulfame Potassium	O	O	O	O	O	O
Anhydrous sodium sulfate	O			O	O	O
Sodium chloride		O		O	O	O
Potassium chloride			O			O
Sodium phosphate					O	O
Change of appearance	Severe	Severe	Severe	Severe	Severe	Severe

* Storage conditions are the same as Test Example 01

<Result>

As a result of the properties of <Test Examples 29 to 34>, as shown in the results of Figure 2, it was confirmed that the change in the red color similar to the <Comparative Example 02> in all the groups of <Test Examples 29 to 34>. Through this, it can be inferred that the change in properties generated during the mixed packaging of the intestinal laxative composition occurs irrespective of the type of the salt for supplying the electrolyte in the composition.

<Comparative Example 01>

In order to compare the changes in the properties of some of the <Test Examples 01 ~ 34> 100g polyethylene glycol 3,350 (PEG 3,350), 7.5g anhydrous sodium sulfate, 2.691g sodium chloride, 1.015g potassium chloride, 1.280g flavoring agent, <Comparative Example 01> is packaged separately with A and vitamin C 10.6g B, which contains 0.317g of sweetener (aspartame / acesulfame potassium), and whether there is a change in appearance after storage for 10 days under long-term and accelerated conditions. It was visually confirmed.

<Comparative Example 02>

<Comparative Example 02> was packaged and mixed with the same composition as the <Comparative Example 01> in order to compare the changes in the properties of some of the <Test Examples 01 ~ 34>, and after storage for 10 days under long-term and accelerated conditions It was visually confirmed whether there was a change.

* Storage conditions are the same as Test Example 01

The appearance confirmation result of <Comparative Examples 01-02> is the same as FIG.

However, the test example and the comparative example of the present invention are merely illustrative to help understanding, the content of the present invention is not limited thereto.

Examples of the present invention are as follows.

<Examples 01-06>

-Comparison of Mixing and Property Changes between Polyethylene Glycol and Each Component in Enteric Laxative Compositions

In the enteric laxative composition of the present invention, polyethylene glycol and the components of the remaining enteric laxative composition were separately mixed, and then visually checked for changes in properties. In the comparison group, all components were mixed. After storage for 10 days under long-term and accelerated conditions, the appearance change was visually confirmed.

To this end, add 100 g of polyethylene glycol 3350 (PEG 3350), vitamin C 10.6 g, anhydrous sodium sulfate 7.5 g, sodium chloride 2.691 g, potassium chloride 1.015 g, flavoring agent 1.280 g, sweetener (aspartame 0.2 g / acesulfame potassium 0.117 g) 0.317 A mixture of g may be used.

TABLE 3

ingredient	Weight (g)
	Example 01	Example 02	Example 03	Example 04	Example 05	Example 06	Comparative Example 02
PEG 3,350	100	100	100	100	100	100	100
Vitamin C (mixture)	10.6	-	-	-	-	-	10.6
Anhydrous sodium sulfate	-	7.5	-	-	-	-	7.5
Sodium chloride	-	-	2.691	-	-	-	2.691
Potassium chloride	-	-	-	1.015	-	-	1.015
Flavor	-	-	-	-	1.28	-	1.28
Sweetener	-	-	-	-	-	0.317	0.317
Appearance change (long term)	none	none	none	none	none	none	has exist
Appearance change (acceleration)	none	none	none	none	none	none	Severe

* Storage conditions are the same as Test Example 01

<Result>

Referring to the results of <Table 3>, it was found that there is a change in appearance only in Comparative Example 02, the intestinal laxative composition at this time was confirmed to have a red or yellow. On the other hand, when the respective components of polyethylene glycol and intestinal laxative composition were mixed separately, it was observed that there was no change in properties, and it was confirmed that the mixture of each component remained white or pale yellow.

<Examples 07-12>

-Comparison of mixing and appearance between vitamin C and each component in intestinal laxative composition

In the enteric laxative composition of the present invention, vitamin C and the components of the remaining enteric laxative composition were separately mixed under the conditions of <Table 4>, and then visually confirmed whether there was a change in appearance after storage for 10 days under accelerated conditions.

Table 4

ingredient	Weight (g)
	Example 07	Example 08	Example 09	Example 10	Example 11	Example 12	Comparative Example 02
PEG 3,350	-	-	-	-	-	-	100
Vitamin c	4.7	4.7	4.7	4.7	4.7	4.7	4.7
Vitamin C Sodium	5.9	5.9	5.9	5.9	5.9	5.9	5.9
Anhydrous sodium sulfate	-	7.5	-	-	-	-	7.5
Sodium chloride	-	-	2.691	-	-	-	2.691
Potassium chloride	-	-	-	1.015	-	-	1.015
Flavor	-	-	-	-	1.28	-	1.28
Sweetener	-	-	-	-	-	0.317	0.317
Appearance change (acceleration)	none	none	none	none	none	none	Severe

* Storage conditions are the same as Test Example 01, aluminum pouch packaging

<Result>

Referring to the results of <Table 4>, it was found that there is a change in the appearance only in Comparative Example 02, the intestinal laxative composition at this time was confirmed to have a red or yellow. On the other hand, when each component of the vitamin C and intestinal laxative composition was mixed separately, it was found that there was no change in appearance, and the mixture of each component was found to be white or light yellow.

<Examples 13-17>

-Comparison of Mixing and Property Changes between Polyethylene Glycol and Vitamin C in Each Intestinal Laxative Composition

In the enteric laxative composition of the present invention, polyethylene glycol, vitamin C and the components of the remaining enteric laxative composition were separately mixed under the conditions of <Table 5>, and then the change in appearance after 10 days storage under long-term and accelerated conditions was visually confirmed. In the comparison group, all components were mixed.

Table 5

ingredient	Weight (g)
	Example 13	Example 14	Example 15	Example 16	Example 17	Comparative Example 02
PEG 3,350	100	100	100	100	100	100
Vitamin C (mixture)	10.6	10.6	10.6	10.6	10.6	10.6
Anhydrous sodium sulfate	7.5	-	-	-	-	7.5
Sodium chloride	-	2.691	-	-	-	2.691
Potassium chloride	-	-	1.015	-	-	1.015
Flavor	-	-	-	1.28	-	1.28
Sweetener	-	-	-	-	0.317	0.317
Appearance change (long term)	none	none	none	none	has exist	has exist
Appearance change (acceleration)	none	none	none	none	Severe	Severe

* Storage conditions are the same as Test Example 01, aluminum pouch packaging

<Result>

Referring to the results of <Table 5>, it was found that the change of appearance in the acceleration conditions of Example 17 and Comparative Example 02 is severe, the intestinal laxative composition at this time was confirmed to have a red or yellow. On the other hand, when the polyethylene glycol and vitamin C each of the components separately mixed with each other as in Examples 13 to 16 it was found that there is no change in appearance compared to the initial properties.

<Examples 18-24>

-Comparison and Mixture Change of Polyethylene Glycol, Vitamin C, Anhydrous Sodium Sulfate, Sodium Chloride, Potassium Chloride, Flavoring Agent and Sweetener in Enteric Laxative Composition

After mixing the enteric laxative composition except for one of each component in the enteric laxative composition of the present invention under the conditions of <Table 6>, it was visually confirmed whether there was a change in appearance after storage for 10 days under accelerated conditions. The control for this was that all components were mixed.

Table 6

ingredient	Weight (g)
	Example 18	Example 19	Example 20	Example 21	Example 22	Example 23	Example 24	Comparative Example 02
PEG 3,350	-	100	100	100	100	100	100	100
Vitamin c	10.6	-	10.6	10.6	10.6	10.6	10.6	10.6
Anhydrous sodium sulfate	7.5	7.5	-	7.5	7.5	7.5	7.5	7.5
Sodium chloride	2.691	2.691	2.691	-	2.691	2.691	2.691	2.691
Potassium chloride	1.015	1.015	1.015	1.015	-	1.015	1.015	1.015
Flavor	1.28	1.28	1.28	1.28	1.28	-	1.28	1.28
Sweetener	0.317	0.317	0.317	0.317	0.317	0.317	-	0.317
Appearance change (acceleration)	none	none	Severe	Severe	Severe	Severe	none	Severe

* Storage conditions are the same as Test Example 01, aluminum pouch packaging

<Result>

Referring to the results of <Table 6>, it was found that there is a change in appearance in Comparative Example 02 and Examples 20 to 23, it was confirmed that the intestinal laxative composition is red or yellow. On the other hand, each drug mixture under the rest of the conditions was found to be white or pale yellow with no change in appearance. Analyzing the results of the above test examples and examples, it was confirmed that the enteric laxative composition of the present invention occurs only when polyethylene glycol, vitamin C, and sweetener components are mixed.

<Examples 25-26, Comparative Examples 03-05>

-Solubility Evaluation of Vitamin C Coatings

100 g polyethylene glycol 3,350 (PEG 3,350), vitamin C 10.6g, 7.5 g anhydrous sodium sulfate, sodium chloride 2.691 g, potassium chloride 1.015 g as a salt for the supply of electrolytes, 0.317 g of aspartame / acesulfame potassium as a sweetener was prepared to prepare an intestinal laxative composition However, vitamin C was powder-coated under the conditions of the following <Table 7>, and the result of dissolving the intestinal laxative composition in water is shown in [FIG. 3].

Vitamin C Coating Conditions of Example 25: HPMC

1,060 g of vitamin C mixture (470 g of vitamin C and 590 g of sodium vitamin C) were placed in a fluidized bed coater and coated with a hypromellose (HPMC) composition as a coating agent. The hypromellose (HPMC) composition was purified by 212 ml of purified water in 106 g of HPMC. 848 ml of ethanol was added thereto and then dissolved in a semi-aqueous coating solution.The coating process was performed at the inlet temperature of 32 ± 3 ° C. using the Glatt GPCG2 equipment (Bottom Spray method). It is preferable to proceed in the appropriate temperature range that is maintained).

Vitamin C Coating Conditions of Example 26: Triple Coating of HPMC / PVA / CMC

1,060 g of vitamin C mixture (470 g of vitamin C, 590 g of vitamin C sodium) were placed in a fluidized bed coater and subjected to a three layer coating with hypromellose / polyvinyl alcohol / CMC composition as a coating agent. The hypromellose / polyvinyl alcohol / CMC composition was prepared by dissolving 106 ml of purified water in 53 g of HPMC and then adding 424 ml of ethanol to prepare a dispersed one layer coating film with a semi-aqueous coating solution. Thereafter, 53 g of PVA was dissolved in 265 ml of purified water, and then 265 ml of ethanol was further added thereto, followed by spraying on a one layer coating layer to prepare a two layer coating layer. Next, 11.66 g of CMC was dissolved in 108.34 ml of purified water, and then sprayed on the two-layer coating layer continuously to prepare a three-layer coating layer.

Ehtyl cellulose-coated vitamin C of Comparative Example 03: Zepiascorbic acid (Purchase: Foil Chemical, DSM [UK])

Starch Coated Vitamin C of Comparative Example 04: Zepiascorbic Acid (Purchase: Foil Pharmaceutical, Manufacturer: DSM [UK])

Silicon Coating Vitamin C of Comparative Example 05: Hwawon Zepiascorbic Acid (Purchase: Hwawon Pharm., NorthEast China)

TABLE 7

Condition	Vitamin C Coatings
Example 25	HPMC
Example 26	Triple coating of HPMC / PVA / CMC
Comparative Example 03	Ethyl Cellulose
Comparative Example 04	Starch
Comparative Example 05	Silicone

<Result>

Comparison of the solubility of the drugs were compared with the composition of vitamin C without coating of Comparative Example 02 (100 g of polyethylene glycol 3,350 (PEG 3,350), vitamin C 10.6 g, 7.5 g of anhydrous sodium sulfate as salt for the electrolyte supply, 2.691 g of sodium chloride, potassium chloride) 1.015 g and 0.317 g of aspartame / acesulfame potassium as a sweetener).

Referring to the results of FIG. 3, Example 25 coated with vitamin C with HPMC, which is a water-soluble coating agent, and Example 26, triple coated with HPMC / PVA / CMC, were used in the same manner as Comparative Example 02 without coating with vitamin C. It was found to be well soluble in water and suitable for use as enteric laxative composition, and the dissolution time was also dissolved within 10 minutes in cold water (10 ° C or less) and within 5 minutes in hot water (60-70 ° C). It was found to dissolve in water in time.

On the other hand, Comparative Example 03 coated with ethyl cellulose, Comparative Example 04 coated with starch, and Comparative Example 05 coated with silicone are not suitable for use as enteric laxative composition because vitamin C is not dissolved well. there was.

<Examples 27-34>

-Vitamin C powder is coated using a fluidized bed coater

Vitamin C of the enteric laxative composition of the present invention was coated in the form of a coating powder under the conditions of Table 8 using a fluidized bed coater, and then each component (100 g of polyethylene glycol 3,350 (PEG 3,350), vitamin C 10.6 g, electrolyte 7.5 g of anhydrous sodium sulfate, 2.691 g of sodium chloride, 1.015 g of potassium chloride, and 0.317 g of aspartame / acesulfame potassium as sweeteners were mixed as a supply salt, and after six months of storage under accelerated conditions, the change in appearance was visually confirmed. It is shown in <Table 8>. The comparative group for this was set as Comparative Example 02 in which all components were mixed. In addition, a photograph of the coated vitamin C included in the intestinal laxative composition can be seen in [FIG. 4], and the change in the appearance was compared to include the enteric laxative compositions of Examples 25 and 26.

Table 8

Condition	Vitamin C Coatings	Change of appearance
Example 25	HPMC, 1 Layer Coating	none
Example 26	HPMC / PVA / CMC, 3 Layer Coating	none
Example 27	PVA, 1 Layer Coating	none
Example 28	PVA-Eudragit, 1 Layer Coating	none
Example 29	PVA-Eudragit / CMC, two layer coating	none
Example 30	HPMC / PVA, Two Layer Coating	none
Example 31	HPMC / PVA-Eudragit, Two Layer Coating	none
Example 32	HPMC / PVA-Eudragit / CMC, 3-Layer Coating	none

Vitamin C coating conditions of Example 27: PVA, one layer coating

1,060g of vitamin C mixture (470g of vitamin C, 590g of vitamin C sodium) was placed in a fluidized bed coater and coated with a single layer of polyvinyl alcohol (PVA) composition as a coating agent. The polyvinyl alcohol (PVA) composition was prepared by dissolving 530 ml of purified water in 106 g of polyvinyl alcohol and adding 530 ml of ethanol to disperse the semi-aqueous coating solution.

Vitamin C coating conditions of Example 28: PVA-Eudragit, 1 layer coating

1,060 g of vitamin C mixture (470 g of vitamin C and 590 g of sodium vitamin C) were placed in a fluidized bed coater and coated with a single layer of polyvinyl alcohol-Eudragit composition as a coating agent. The polyvinyl alcohol-Eudragit composition was prepared by dissolving 530 ml of purified water in 106 g of polyvinyl alcohol-Eudragit and spraying with a semi-aqueous coating solution by adding 530 ml of ethanol.

Vitamin C coating conditions of Example 29: PVA-Eudragit / CMC, two-layer coating

1,060 g of vitamin C mixture (470 g of vitamin C and 590 g of sodium vitamin C) were placed in a fluidized bed coater and subjected to a two layer coating with a polyvinyl alcohol-Eudragit / CMC composition as a coating agent. In the polyvinyl alcohol-Eudragit / CMC composition, 530 ml of purified water was dissolved in 106 g of polyvinyl alcohol-Eudragit, followed by addition of 530 ml of ethanol to spray a semi-aqueous coating solution to prepare a one-layer coating film, and CMC 11.66 g was purified water 108.34 It was dissolved in ㎖ continuously sprayed on the coating layer 1 to prepare a two-layer coating film.

Vitamin C coating conditions of Example 30: HPMC / PVA, two-layer coating

1,060 g of vitamin C mixture (470 g of vitamin C, 590 g of vitamin C sodium) was placed in a fluidized bed coater and subjected to two layer coating with a hypromellose-polyvinyl alcohol composition as a coating agent. In the hypromellose-polyvinyl alcohol composition, 106 ml of purified water was dissolved in 53 g of HPMC, and 424 ml of ethanol was further added thereto to prepare a dispersed one layer coating film with a semi-aqueous coating solution. Thereafter, 53 g of PVA was dissolved in 265 ml of purified water, and then 265 ml of ethanol was further added thereto, followed by spraying on a one layer coating layer to prepare a two layer coating layer.

Vitamin C coating conditions of Example 31: HPMC / PVA-Eudragit, two-layer coating

1,060 g of vitamin C mixture (470 g of vitamin C, 590 g of vitamin C sodium) were placed in a fluidized bed coater and subjected to a two layer coating with hypromellose / polyvinyl alcohol-Eudragit composition as a coating agent. The hypromellose / polyvinyl alcohol-Eudragit composition was prepared by dissolving 106 ml of purified water in 53 g of HPMC and then adding 424 ml of ethanol to prepare a dispersed one-layer coating film with a semi-aqueous coating solution. Thereafter, 53 g of polyvinyl alcohol-Eudragit was dissolved in 265 ml of purified water, and then 265 ml of ethanol was further added thereto, followed by spraying on one layer of coating to prepare a two-layer coating.

Vitamin C coating conditions of Example 32: HPMC / PVA-Eudragit / CMC, three layer coating

1,060 g of vitamin C mixture (470 g of vitamin C, 590 g of vitamin C sodium) were placed in a fluidized bed coater and coated with a hypromellose / polyvinyl alcohol-Eudragit / CMC composition as a coating. The hypromellose / polyvinyl alcohol-Eudragit / CMC composition was prepared by dissolving 106 ml of purified water in 53 g of HPMC and then adding 424 ml of ethanol to prepare a dispersed one layer coating film with a semi-aqueous coating solution. Thereafter, 53 g of polyvinyl alcohol-Eudragit was dissolved in 265 ml of purified water, and then 265 ml of ethanol was further added thereto, followed by spraying on one layer of coating to prepare a two-layer coating. 11.66 g of CMC was dissolved in 108.34 ml of purified water and sprayed on the two-layer coating film continuously to prepare a three-layer coating film.

<Result>

When the enteric laxative composition mixed with the coating vitamin C of Examples 25 to 32 was confirmed to have a change in appearance, it was confirmed that there was no change in all compositions (Table 8 and the intestine of Example 32 in FIG. 5). See laxative composition).

<Examples 33-34>

-In order to confirm the coating effect of vitamin C prepared in the tablet state of the intestinal laxative composition of the present invention, vitamin C was prepared uncoated.

<Example 33>

After mixing 470 mg of vitamin C and 590 mg of sodium vitamin C, a disintegrant (calcium hydrogen phosphate anhydrous 2 mg) and a lubricant (smg 2 mg) were added thereto and tableted by a direct stroke method.

<Example 34>

After mixing vitamin C 470 mg and vitamin C sodium 590 mg, primary lubricant (smg 2 mg), disintegrant (calcium hydrogen phosphate anhydrous 2 mg) was added, followed by dry granulation, secondary lubricant (talc 1 mg) and boron. Release (2 mg calcium hydrogen phosphate anhydrous) was added and tableted.

<Examples 35-38>

Zitata uncoated vitamin C of Example 33 was coated using the coating agent of <Table 9>, 100g polyethylene glycol 3,350 (PEG 3,350) in addition to vitamin C, 7.5g anhydrous sodium sulfate, sodium chloride 2.691g, potassium chloride as a salt for the electrolyte supply A bowel laxative composition was prepared by mixing 1.015 g and 0.317 g of aspartame / acesulfame potassium as a sweetener. The results of the appearance change at 6 months accelerated condition of the compositions are also shown in Table 9.

<Example 39>

The intestinal laxative composition was prepared in the same manner as in Examples 35 to 38, with the same orthogonal vitamin C of Example 33 as it was (not coated).

Table 9

Condition	Vitamin c	Coating	Change of appearance
Example 35	Straight uncoated tablet of Example 33	PVA	none
Example 36	Straight uncoated tablet of Example 33	PVA-Eudragit	none
Example 37	Straight uncoated tablet of Example 33	HPMC / PVA	none
Example 38	Straight uncoated tablet of Example 33	HPMC / PVA / CMC	none
Example 39	Straight uncoated tablet of Example 33	-	has exist
Comparative Example 02	-	-	Severe

<Result>

When checking the <Table 9>, when the enteric laxative composition mixed with the coating vitamin C of Examples 35 to 38 was confirmed to change in appearance after 6 months, it was confirmed that there is no change in all compositions, Comparative Example 02 Intestinal laxative compositions have been found to show severe changes in appearance over time. Among them, the change in appearance at 6 months accelerated conditions of the intestinal laxative compositions of Example 36 and Comparative Example 02 with time (initial ~ 6 months) is shown in Figure 6, 6 months of the intestinal laxative composition of Example 38 The change in appearance under the acceleration condition is shown in FIG. Intestinal laxative composition of Example 39 (including vitamin C uncoated tablet of Example 33) has no problem in commercialization because the content of vitamin C is preserved and the intestinal cleansing effect is maintained, but there is a change in the surface properties of the uncoated tablet to coat vitamin C uncoated tablet One coated tablet was found to be more desirable.

<Examples 40-43>

Dry granulated uncoated vitamin C of Example 34 was coated using the coating agent of Table 10, in addition to vitamin C, 100 g of polyethylene glycol 3,350 (PEG 3,350), 7.5 g of anhydrous sodium sulfate, sodium chloride 2.691 g, as a salt for the electrolyte supply, A bowel laxative composition was prepared by mixing 1.015 g of potassium chloride and 0.317 g of aspartame / acesulfame potassium as a sweetener. The results for the change of appearance after 6 months of the composition are shown in Table 10 below.

<Example 44>

-The dry granulated uncoated vitamin C of Example 34 was used as it is (no coating), and the remaining conditions were the same as in Examples 40 to 43, to prepare an enteric laxative composition.

Table 10

Condition	Vitamin c	Coating	Change of appearance
Example 40	Dry granulated uncoated tablet of Example 34	PVA	none
Example 41	Dry granulated uncoated tablet of Example 34	PVA-Eudragit	none
Example 42	Dry granulated uncoated tablet of Example 34	HPMC / PVA	none
Example 43	Dry granulated uncoated tablet of Example 34	HPMC / PVA / CMC	none
Example 44	Dry granulated uncoated tablet of Example 34	-	has exist

<Result>

Referring to <Table 10>, the enteric laxative composition in which the coated vitamin C tablets of Examples 40 to 43 were mixed, it was confirmed that there is no change in all compositions when the change in appearance after 6 months. Intestinal laxative composition of Example 44 (including vitamin C uncoated tablet of Example 34) has no problem in commercialization because the content of vitamin C is preserved and the intestinal cleansing effect is maintained, but there is a change in the surface properties of the uncoated tablet to coat vitamin C uncoated tablet It was considered more desirable to use one coated tablet.

<Examples 45-46>

After preparing the granules of vitamin C, the fluidized bed was coated under the conditions of the following <Table 11>. In addition to vitamin C, polyethylene glycol 3,350 (PEG 3,350) 100g, anhydrous sodium sulfate 7.5g, sodium chloride 2.691g, potassium chloride 1.015g, sweetener Aspartame / acesulfame potassium 0.317 g was mixed to prepare an intestinal laxative composition. The results for the change of appearance after 6 months of the composition are shown in the following <Table 11> and [FIG. 8].

<Comparative Example 06>

An intestinal laxative composition was prepared in the same manner as in Examples 45 and 46, but vitamin C was not coated after preparation of the granules.

Table 11

Condition	Vitamin C Dry Granules Manufacturing	Coating	Change of appearance
Example 45	After mixing vitamin C and vitamin C sodium, only the first glidant is added. After dry granulation, the second glidant is added and extruded.	Hypromellose / polyvinyl alcohol / CMC 3-layer coating	none
Example 46	After mixing vitamin C and vitamin C sodium, add only the first lubricant and dry granules, then add the second lubricant and disintegrant and extrude	Hypromellose / polyvinyl alcohol / CMC 3-layer coating	none
Comparative Example 06	After mixing vitamin C and vitamin C sodium, add only the first lubricant and dry granules, then add the second lubricant and disintegrant and extrude	-	Severe

Vitamin C Coating Method of Example 45—Hypromellose / Polyvinyl Alcohol-Eudragit / CMC, Three Layer Coating

After sieving the vitamin C granules prepared by dry granulation method (470 g of vitamin C and 590 g of vitamin C sodium, only primary glidant (smag 2 g) was added, and after dry granulation, secondary glidant (1 g of talc) was added and extruded). Particles were also selected by operation and then coated using a fluidized bed coater. To this end, the vitamin C granules were put in a fluidized bed coater and then coated with a hypromellose / polyvinyl alcohol-Eudragit / CMC composition as a coating. The hypromellose / polyvinyl alcohol-Eudragit / CMC composition was prepared by dissolving 106 ml of purified water in 53 g of HPMC and then adding 424 ml of ethanol to prepare a dispersed one layer coating film with a semi-aqueous coating solution. Thereafter, 53 g of polyvinyl alcohol-Eudragit was dissolved in 265 ml of purified water, and then 265 ml of ethanol was further added thereto, followed by spraying on one layer of coating to prepare a two-layer coating. Next, 11.66 g of CMC was dissolved in 108.34 ml of purified water, and then sprayed on the two-layer coating layer continuously to prepare a three-layer coating layer.

Vitamin C Coating Method of Example 46-Hypromellose / Polyvinyl Alcohol-Eudragit / CMC, Three Layer Coating

After dry granulation method (470g of vitamin C and 590g of vitamin C sodium), only the first glidant (smag 2g) is added, and after dry granulation, the second glidant (talc 1g) and disintegrant (calcium hydrogen phosphate anhydrous 2g) are added and extruded. Vitamin C granules) were prepared by sieving and coated with a fluidized bed coater. To this end, the vitamin C granules were put in a fluidized bed coater and then coated with a hypromellose / polyvinyl alcohol-Eudragit / CMC composition as a coating. The hypromellose / polyvinyl alcohol-Eudragit / CMC composition was prepared by dissolving 106 ml of purified water in 53 g of HPMC and then adding 424 ml of ethanol to prepare a dispersed one layer coating film with a semi-aqueous coating solution. Thereafter, 53 g of polyvinyl alcohol-Eudragit was dissolved in 265 ml of purified water, and then 265 ml of ethanol was further added thereto, followed by spraying on one layer of coating to prepare a two-layer coating. Next, 11.66 g of CMC was dissolved in 108.34 ml of purified water, and then sprayed on the two-layer coating layer continuously to prepare a three-layer coating layer.

<Result>

When checking the Table 11 and Figure 8, the enteric laxative composition of the coating vitamin C of Examples 45 and 46 was confirmed that there is no change in all compositions when the change in appearance after 6 months It became. On the other hand, the appearance change of Comparative Example 06 using the uncoated vitamin C granules was found to increase with time.

<Examples 47-49>

After preparing vitamin C powder (Powder) or granules into hard capsules, 100g of polyethylene glycol 3,350 (PEG 3,350) in addition to vitamin C, 7.5g anhydrous sodium sulfate, sodium chloride 2.691g, potassium chloride 1.015g as salt for electrolyte supply , Aspartame / acesulfame potassium 0.317 g as a sweetener was mixed to prepare an enteric laxative composition. The results for the change of appearance after 6 months of the composition are shown in the following Table 12.

Table 12

Condition	Vitamin c		Change of appearance
Example 47	powder	-	none
Example 48	Granules	After mixing vitamin C and vitamin C sodium, only the first glidant is added. After dry granulation, the second glidant is added and extruded.	none
Example 49		After mixing vitamin C and vitamin C sodium, add only the first lubricant and dry granules, then add the second lubricant and disintegrant and extrude	none

<Result>

When confirming the Table 12, the enteric laxative composition of the capsule-filled vitamin C of Examples 47-49 was confirmed that there is no change in all compositions when the change in appearance after 6 months. On the other hand, the appearance change of the vitamin C powder (Comparative Example 2) and granules (Comparative Example 6) not filled in the capsule was found to increase with time.

<Vitamin C Stability Test>

The change in the content of vitamin C, which is one of the main components of the intestinal laxative composition of the present invention, in addition to the change in sex under long-term and accelerated conditions for 6 months was measured (intestinal laxative compositions of Examples 26, 38, and 46 and the enteric laxative composition of Comparative Example 02 Check the content of vitamin C).

* Vitamin C (ascorbic acid) content analysis

1) Standard: 90.0% ~ 110.0% of display amount

2) Confirmation Method and Basis: HPLC analysis-According to the quantitative test method of vitamin test method among general test methods of Korean medicine

<Result>

The results of the test on vitamin C stability are as shown in FIG. 9, and it can be seen that the intestinal laxative compositions of Examples 26, 38, and 46 exhibited higher stability and preservation than those of Comparative Example 02. there was. Therefore, it is confirmed that the intestinal laxative composition of the present invention can be used as an intestinal laxative composition in which the intestinal laxative or constipation removal effect is kept constant during the intestinal shelf life by preserving vitamin C content without changing the appearance. Could.

Claims (15)

1. Polyethylene glycol, first pharmaceutical component;

   Coated powder, Coated granule, Coated tablet, Uncoated tablet and Capsule with water-soluble coating Vitamin C, second pharmaceutical ingredient prepared in one or more forms of And

   A third pharmaceutical ingredient consisting of a sweetener;

   To the pharmaceutical intestinal laxative composition comprising a package of the first to third pharmaceutical ingredients.
2. The method of claim 1,

   Coating powder, coating granules and coating tablet using the water-soluble coating agent Vitamin C prepared in at least one of the forms, Hydroxypropyl methyl Cellulose, Hydroxypropyl cellulose (Hydroxy propyl Cellulose), Hydroxyethyl cellulose (Hydroxyethyl Cellulose), Methyl cellulose (Methyl Cellulose), Carboxymethyl cellulose (Carboxy methyl Cellulose), methacrylate copolymer (Eudragit) series, polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA) is coated with a water-soluble coating consisting of a single or a mixture of coatings selected from the group consisting of Enteric laxative composition, characterized in that.
3. The method of claim 1,

   The enteric laxative composition is enteric laxative composition, characterized in that the mixture of 5 to 15 parts by weight of vitamin C and 0.01 to 3 parts by weight of sweetener based on 100 parts by weight of polyethylene glycol.
4. The method of claim 1,

   Enteric laxative composition, characterized in that prepared by adding one or more of the salt for the electrolyte supply to the intestinal laxative composition.
5. The method of claim 4, wherein

   The enteric laxative composition is an intestinal laxative composition, characterized in that 5 to 15 parts by weight based on 100 parts by weight of polyethylene glycol electrolyte.
6. The method according to claim 1 or 4,

   Enteral laxative composition, characterized in that prepared by adding 0.01 to 3 parts by weight of flavoring agent to the intestinal laxative composition.
7. The method of claim 1,

   The polyethylene glycol is an intestinal laxative composition, characterized in that the average molecular weight of 2,000 ~ 8,000.
8. The method of claim 1,

   The polyethylene glycol is selected from the group consisting of polyethylene glycol 2,000 (PEG 2,000), polyethylene glycol 3,350 (PEG 3,350), polyethylene glycol 4,000 (PEG 4,000), polyethylene glycol 6,000 (PEG 6,000) and polyethylene glycol 8,000 (PEG 8,000). Or intestinal laxative composition, characterized in that two or more compounds.
9. The method according to any one of claims 1 to 3,

   The vitamin C is an intestinal laxative composition, characterized in that it is used alone or in combination of two or more in amorphous, crystalline or chloride form.
10. The method of claim 4, wherein

    The enteric laxative composition, wherein the electrolyte supply salt is used alone or in combination of two or more selected from the group consisting of sodium ions, magnesium ions and calcium ions.
11. The method of claim 10,

    The electrolyte supply salt is a salt or a salt selected from the group consisting of chloride, bicarbonate, acetate, carbonate, citrate, fumarate, gluconate, malate, nitrate, phosphate, succinate, or sulfate form Enteric laxative composition, characterized in that a mixture of species or more is used.
12. The method of claim 11,

    The electrolyte supply salt is enteric laxative composition, characterized in that used alone or in combination of two or more selected from the group consisting of sodium chloride, potassium chloride and sodium sulfate.
13. The method according to any one of claims 1 to 3,

    In addition to glucose (Glucose), sucrose (Sucrose), dextrose (Dextrose), fructose (Fructose), maltose (Maltose) in addition to the saccharin (Saccharin), saccharin (sodium saccharin) showing sweetness effect and fast solubility (Saccharin Sodium), Xylitol, Xoritol, Sorbitol, Mannitol, Maltitol, Lactitol, Isomalt, Stevioside, Erythritol, Aspartame Aspartame), acesulfame potassium (Acesulfame Potassium), sucralose (Sucralose) intestinal laxative composition characterized in that it comprises a single or two or more sweeteners selected from the group consisting of.
14. The method of claim 2,

    Enteral laxative composition, characterized in that the pharmaceutically acceptable additive is added to the coating of the vitamin C is prepared.
15. A pharmaceutical formulation comprising the enteric laxative composition of any one of claims 1-6.

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