WO2013119002A1 - Laxative composition containing polyethylene glycol and vitamin c - Google Patents

Abstract

The present invention relates to a mixed packaged laxative composition containing polyethylene glycol and vitamin C, and to a pharmaceutical dosage form containing same. Of the components contained in the laxative composition, if polyethylene glycol, vitamin C, or a sweetening agent is subject to layer separation with mixtures of other pharmaceutical components, contact between the mixtures is minimized so that a phase change such as a physical-chemical reaction is inhibited in the laxative composition. Even in the case of mixed packaging, stability is high during storage or distribution, and colonic irrigation effects or anti-constipation effects are maintained for diagnosis, examination, and operation.

Description

Enteric Laxative Composition Containing Polyethyleneglycol and Vitamin Seeds

The present invention relates to enteric laxative compositions containing polyethylene glycol and vitamin C and pharmaceutical formulations comprising the same.

Intestinal lavage has been used in endoscopy, diagnostic or surgical measures such as colonoscopy, barium enema X-rays and intravenous renal angiography, and first aid, for which intestinal laxative compositions are used. do. 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 It can also be used to treat and relieve symptoms.

In the diagnosis and treatment of intestinal disease, sufficient pretreatment must be preceded in order to provide a safe and effective test in the endoscopy, diagnostic or surgical measures, and the ideal pretreatment enteric cleaner is safe, simple and patient compliance. It should be good and excellent in the cleansing effect.

As an enteric laxative composition for this purpose, a method of inducing diarrhea by ingesting a large amount of isotonic water containing only an electrolyte was used. An example of this is an aqueous formulation consisting of phosphate salts, in which the phosphate salt solution produces an osmotic effect, inducing a significant amount of water into the intestine to promote bowel movement. However, because a large amount of water must be consumed, the preparations cannot be used in patients with nephropathy, heart disorders or hypertension.

Recently, enteric laxative compositions comprising polyethyleneglycol / electrolyte consisting of sodium sulfate, potassium chloride, sodium chloride, sodium bicarbonate and the like, and water-bound polyethyleneglycol are most commonly used. However, most of these enteric laxative compositions containing polyethyleneglycol / electrolyte have to drink about 4 L of solution within 2-3 hours 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.

In order to remedy this problem, US Patent No.7169381 provides a polyethylene glycol / electrolyte enteric laxative composition containing vitamin C, which increases the osmotic effect to reduce the weight of polyethylene glycol, thereby reducing the weight of the liquid state immediately before administration. There is an effect that can reduce the volume of the composition. 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 also proposed to separate or separate the components of the intestinal laxative composition, such as vitamin C, from the mixture of other pharmaceutical ingredients, but the management and manufacturing costs according to the packaging There is a disadvantage of being increased. US Patent No. 5274001 provides a single mixture of enteric laxative compositions in which the least stable vitamin C of the components of the enteric laxative composition is coated with silicone or ethyl cellulose. . However, the intestinal laxative composition disclosed in the patent has a disadvantage in that the overall manufacturing cost according to the coating cost is increased because the total composition ratio of vitamin C is high. There is also a controversy that vitamin C can be easily destroyed by the heat generated during coating, resulting in lower stability.

However, the silicone or ethyl cellulose-coated vitamin C has low solubility in aqueous solution, and thus it is difficult to use as a component of intestinal laxatives in which powder components are dissolved in water and drinkable.

On the other hand, the inventors of the present invention while studying a method for producing a highly safe intestinal laxative composition during storage or distribution, when some of the components included in the intestinal laxative composition is separated from the mixture of the other pharmaceutical ingredients and the layer, It was found that there is little change in the composition of the composition, it was confirmed that the stability even when mixed packaging, it was possible to complete the present invention by confirming that the production cost for this can be significantly reduced.

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.

Preferably,

The present invention, polyethylene glycol, the first pharmaceutical component;

Vitamin C, second pharmaceutical ingredient;

A third pharmaceutical ingredient consisting of a sweetener;

It relates to a pharmaceutical enteric laxative composition or a pharmaceutical formulation comprising the same, characterized in that one of the first to third pharmaceutical ingredients is separated in order to minimize direct contact with the enteric laxative mixture of the present invention.

One of the first to third pharmaceutical ingredients, such as coating powder (powder), coating granules, coating tablets, capsules and uncoated tablets to minimize physical contact with the mixture of other pharmaceutical ingredients It may be a sweetener prepared in more than one state.

Preferably, the mixed-packed enteral laxative composition of the present invention is prepared by separating the third pharmaceutical component in consideration of each part by weight, manufacturing process, and production cost of the first to third pharmaceutical ingredients of the enteric laxative composition of the present invention. to provide.

As the coating base of each component prepared in one form of the coating powder (Powder), coated granules and coated tablets,

Natural or synthetic polymers

Water-soluble [Hydroxypropyl methyl Cellulose), Hydroxypropyl Cellulose, Hydroxyethyl Cellulose, Methyl Cellulose, Carboxymethyl Cellulose in Cellulose Ether Derivatives (Carboxy methyl Cellulose) and water insoluble [Ethyl Cellulose, Cellulose Acetate], or

A single or a mixture of coating bases selected from the group consisting of methacrylate copolymer (Eudragit) series, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) may be used. Preferably, as the coating agent, it is best to use a coating base consisting of a mixture of a polyvinyl alcohol and a methacrylate copolymer which are water-soluble agents.

The coating layer, if necessary, pharmaceutically acceptable additives,

For example, polyethylene glycol (PEG) in plasticizers,

Talc as a coagulant inhibitor,

Sodium Bicarbonate in pH Control

The light-shielding agent, but may include titanium dioxide (TiO ₂ ), etc. in the pigment, but is not significantly limited.

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 contains polyethylene glycol, vitamin C and salts for supplying electrolyte as main components,

The polyethylene glycol is a high osmotic laxative, and in the case of a polymer having a large molecular weight, it is not absorbed by the intestine but remains in solution and is transferred to the large intestine. It 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.

Polyethylene glycol of the present invention is a relatively stable, non-toxic substance having different properties according to the molecular weight, the average molecular weight of about 200 to 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, polyethylene glycol 4,000-20,000 (PEG 4,000-20,000) is a white, light solid in the form of flakes or powders. Powdered to allow for uniform mixing with chemical components, 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) and the like are suitable, of which polyethylene glycol 3,350 is most suitable.

In addition, the salt for electrolyte supply of the intestinal laxative composition of the present invention includes at least one electrolyte. Polyethyleneglycol may remain in solution rather than absorbed by the intestinal tract, altering the concentration of electrolytes in the patient's body, preventing the absorption of water into the body due to increased osmotic pressure in the colon.

Sodium ions, magnesium ions, and calcium ions are suitable 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 sulphates such as sodium chloride, potassium chloride and sodium sulfate are particularly preferred.

Preferably, the electrolyte feed salt is selected from sodium chloride, potassium chloride and sodium sulfate. Most preferably the composition of the present invention comprises both of these electrolytes.

The sweetener of the intestinal laxative composition of the present invention comprises at least one sweetener. In addition to the usual sugars Glucose, Sucrose, Dextrose, Fructose and Maltose, saccharin and saccharin exhibit sweetness and fast solubility even in small amounts. Sodium (Saccharin Sodium), Xylitol (Xylitol), Sorbitol (Sorbitol), Mannitol (Mannitol), Maltitol, Lactitol, Isomalt, Stevioside, Erythritol, Aspartame (Aspartame), acesulfame potassium (Acesulfame Potassium), sucralose (Sucralose) may be used in combination with one or more sweeteners selected from the group consisting of, preferably the sweetener based on 100 parts by weight of polyethylene glycol 0.01 3 parts by weight may be included.

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. At this time, when prepared in a powder (powder) or granular composition,

By separating the intestinal laxative composition and the layer of the present invention, only the sweetener can be prepared in powder or coated granules or coated tablets with a separate coating, even in uncoated or capsule-filled sweeteners. Can be prepared. However, the above example is an example of the layered enteric laxative composition of the present invention, which does not limit the spirit of the present invention, and the same by the layer separation of polyethylene glycol (PEG), one of the main components, or the layer separation of vitamin C. You can expect the effect.

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.

In addition, the formulation of the enteric laxative compositions of the present invention may comprise a glidant. 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.

In addition, 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, moisturizers 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 thereof, 11.206 g of an electrolyte supply salt (mixed form of sodium sulfate, sodium chloride, potassium chloride), sweetener (0.317 g of aspartame and one or more mixed forms), complex Flavor and pharmaceutical additives and coating base polyvinyl alcohol / methacrylate copolymer mixtures.

The total daily dose for light bowel movement is, for example, from about 60 g (58-62 g) / 500 mL to about 120 g (116-124 g) / 1 L of enteric laxative composition in which the layer of the present invention is dissolved in water You can be the best.

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) / intestinal laxative composition in which the layer of the present invention is dissolved in water. It can be 2L of laxative and is taken with or without splitting.

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: Take 1L of the preparation solution for 1 hour (1 cup 250mL every 15 minutes) the evening before colonoscopy and drink 0.5L of water. The next morning, take 1L of the preparation solution for 1 hour and drink 0.5L of water. This process must be completed at least one hour before the start of the colon (X-ray, endoscopy) examination.

Non-split administration (evening administration) Method: At 6 pm the day before colonoscopy, take 1L of the preparation solution for 1 hour (1 cup of 250mL every 15 minutes), and 1L of the preparation solution 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 relates to a mixed packaged intestinal laxative composition containing polyethylene glycol and vitamin C, wherein the phase change of the intestinal laxative composition is obtained by separating some of the components included in the intestinal laxative composition from a mixture of other pharmaceutical ingredients and the layer. In addition, it was found that the vitamin C content is maintained, thereby maintaining stability during storage or distribution and maintaining an intestinal cleaning or constipation removal effect for diagnostic tests and surgery during shelf life.

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 showing the change in the appearance of the properties of the intestinal laxative composition of the present invention comprising a sweetener powder or granules coated with a mixed coating base of polyvinyl alcohol and methacrylate copolymer and stability results for 6 months of acceleration.

Figure 4 is a photograph showing the change in the appearance of the properties of the intestinal laxative composition of the present invention comprising a sweetener tablet or uncoated tablet coated with a mixed coating base of polyvinyl alcohol and methacrylate copolymer and stability results for 6 months of acceleration.

Figure 5 shows the appearance of the change in appearance and stability of the intestinal laxative composition of the present invention comprising a capsule filled with a sweetener powder or granules coated with a mixed coating base of polyvinyl alcohol and methacrylate copolymer It is a photograph.

Figure 6 is a photograph showing the change in the appearance of the properties of the intestinal laxative composition of the present invention comprising a capsule filled with sweetener powder or granules and stability results for 6 months of acceleration.

FIG. 7 shows a composition of the present invention mixed packaged in one or more of a powder, coated granules, coated tablets, capsules and uncoated tablets to minimize physical contact with the mixture of pharmaceutical ingredients. It is a schematic diagram about.

8 is a measurement of the content of vitamin C, one of the main components, as a result of 6 months accelerated stability test of the laxative composition of the present invention, in which the layers are separated.

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 ensure that the teachings presented herein are thorough and complete, and that the spirit of the invention can be fully conveyed to those skilled in the art.

<Standard Table> Appraisal Standards

<Test Examples 01-28> Formulation suitability test

Enteric 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 during storage or distribution, and oxidation and browning reactions occur. It is distributed in the market in a separately packaged form.

The present inventors conducted an experiment to determine the suitability of the mixed packaging according to 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 vitamin C, the second pharmaceutical ingredient, various combinations of experimental groups were prepared and mixed as shown in <Table 1>. An accelerated stability test was conducted, and the results are shown in FIG. 1.

* 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

Referring to the test examples and examples of the <Table 1> in detail, as follows.

<Test Example 01>

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

<Test Examples 02-08>

In order to observe the effects on the appearance when mixed with vitamin C and salts 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 mixed with 15 g of vitamin C according to the above conditions. After storage for 10 days under long-term and accelerated conditions, the appearance change was visually confirmed. For rapid and detailed observation of the change in appearance, the amount of salt in the enteric laxative composition was mixed twice 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, 20 g, 7.2 g, and 2.7 g of anhydrous sodium sulfate, sodium chloride, and potassium chloride were mixed with 15 g of vitamin C, followed by 2.2 g of acesulfame potassium, respectively. Alternatively, aspartame 3.8g was added, and after 10 days of storage under long-term and accelerated conditions, the appearance change was visually confirmed. For rapid and detailed observation of the change in appearance, the amount of salt and sweetener in the enteric laxative composition was mixed twice the maximum weight of the main laxative laxative.

<Test Examples 11-18>

In order to observe the interaction between the mixing of vitamin C and polyethylene glycol and to observe the effect on the appearance by adding salts for the electrolyte supply to Test Example 11, Test Example 11 in which polyethylene glycol 266.7g is mixed with 15g of vitamin C In addition, 20 g, 7.2 g, and 2.7 g of anhydrous sodium sulfate, sodium chloride, and potassium chloride alone or in addition to each other were added according to the above conditions, and the appearance change was visually confirmed after storage for 10 days under long-term and accelerated conditions. For rapid and detailed observation of the change in appearance, the blending amount of polyethylene glycol and salts in the enteric laxative composition was mixed twice the maximum weight of the present enteric laxative.

<Test Examples 19-23>

In order to observe the interaction effect when mixed with vitamin C, polyethylene glycol and potassium acesulfame, and to observe the effect on the appearance by adding the salt for the electrolyte supply in Test Example 19, 15 g of vitamin C, 266.7 g of polyethylene glycol 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. For rapid and detailed observation of the change in appearance, the blending amount of polyethylene glycol, salts and sweeteners in the enteric laxative composition was mixed twice the maximum weight of this laxative laxative.

<Test Examples 24-28>

In order to observe the interaction effect when mixing with vitamin C, polyethylene glycol and aspartame, and to examine the effect of the addition of the salt for the electrolyte supply to Test Example 24, the effect on the appearance, vitamin C 15g, polyethylene glycol 266.7g 3.8g After mixing, respectively, 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, and after 10 days of storage under long-term and accelerated conditions, the appearance change was visually confirmed. For rapid and detailed observation of the change in appearance, the blending amount of polyethylene glycol, salts and sweeteners in the enteric laxative composition was mixed twice the maximum weight of this laxative laxative.

<Result>

As a result of <Test Example 01 ~ 18> as shown in the results of Figure 1 it was confirmed that the appearance change is not induced even under the acceleration conditions. However, in the case of <Test Examples 19 ~ 23>, the appearance changed to pale reddish yellow after 10 days of storage under accelerated conditions, and in the case of <Test Examples 24 ~ 28>, the appearance change occurred to red after 10 days of 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 was not due to the sole physicochemical change of the specific substance, 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 in properties generated during the mixed packaging of the intestinal laxative composition, the intestinal laxative composition is mixed according to 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. The control for this was that all components were mixed. Properties of the test results 29 to 34 is the same as FIG.

* Storage conditions are the same as Test Example 01

TABLE 2

<Test Result Summary>

As a result of the properties of <Test Examples 29 to 34>, as shown in the result 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 appearance occurring when the mixed packaging of the intestinal laxative composition occurs regardless of the kind 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> was packaged separately with A and vitamin C 10.6g B, which mixed 0.317g of sweetener (aspartame / acesulfame potassium), and stored for 10 days under long-term and accelerated conditions. 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, 100 g of polyethylene glycol 3350 (PEG 3350), 10.6 g of vitamin C, 7.5 g of anhydrous sodium sulfate, 2.691 g of sodium chloride, 1.015 g of potassium chloride are added, 1.280 g of flavoring agent, sweetener (aspartame 0.2 g / acesulfame potassium 0.117 g) 0.317 A mixture of g may be used.

TABLE 3

* 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 according to 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

* 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 according to 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

* 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 in appearance in the accelerated conditions in Example 17 and Comparative Example 02 is severe, the intestinal laxative composition at this time was confirmed to have a red or yellow. Therefore, when mixed with the other components of each of the components of polyethylene glycol and vitamin C, as in Examples 13 to 16, it can be seen 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 intestinal laxative composition except for one of the components in the intestinal 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

* 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 25-41>

-Comparison of Properties in Mixed Packaging According to Sweetener Types in Intestinal Laxative Compositions

* Super sweetener is a small amount, and general sweetener was set up by tasting evaluation of the amount of sweetness similar to the super sweetener.

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 7>, it was visually confirmed whether there was a change in appearance after storage for 10 days under accelerated conditions. In the comparison group, all components were mixed.

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

TABLE 7

<Result>

Referring to the results of <Table 7>, it can be seen that there is a change in appearance in Comparative Example 02 and Examples 25 to 41, the intestinal laxative composition at this time was confirmed to have a red or yellow. When the D agent (sweetener powder state) is added to the C agent (uncoated powder state), the change in properties is observed irrespective of the type. Change was confirmed to occur.

<Examples 42-49>

-Comparison of coating and property change of each component

One of each component of the intestinal laxative composition of the present invention was prepared in the form of a coating powder or granules using a fluidized bed coater, and then all the components were mixed under the conditions of <Table 8>, under accelerated conditions After storage for 10 days, the change of appearance was visually confirmed. In the comparison group, all components were mixed.

<Example 42>

1,000 g of polyethylene glycol 3,350 was placed in a fluidized bed coater and coated with a polyvinyl alcohol (PVA) composition as a coating base.

The polyvinyl alcohol (PVA) composition was prepared by dissolving or dispersing 500 g of purified water in 25 g of polyvinyl alcohol. The coating process was carried out under the conditions of inlet air 4.2 bar, spray air 1.8 bar, outlet air temperature 28 ℃, inlet air temperature 29 ℃, flow 8, outlet air flat 40%.

<Example 43>

1,120.6 g of salt (750 g of sodium sulfate anhydride, 269.1 g of sodium chloride and 101.5 g of potassium chloride) were placed in a fluidized bed coater and coated with a polyvinyl alcohol (PVA) composition as a coating base.

This polyvinyl alcohol (PVA) composition was prepared by dissolving or dispersing 560 g of purified water in 28 g of polyvinyl alcohol. The coating process was carried out under the conditions of inlet air 4.2 bar, spray air 1.8 bar, outlet air temperature 35 ℃, inlet air temperature 37 ℃, flow 8, outlet air flat 40%.

<Example 44>

1,000 g of the flavoring agent was placed in a fluidized bed coater and coated with a polyvinyl alcohol (PVA) composition as a coating base.

This polyvinyl alcohol (PVA) composition was prepared by dissolving or dispersing 500 g of purified water in 25 g of polyvinyl alcohol. The coating process was carried out under the conditions of inlet air 4.2 bar, spray air 1.8 bar, outlet air temperature 35 ℃, inlet air temperature 37 ℃, flow 8, outlet air flat 40%.

<Example 45>

951 g of a sweetener (600 g of aspartame, 351 g of acesulfame potassium) was placed in a fluidized bed coater and coated with a polyvinyl alcohol (PVA) composition as a coating base.

The polyvinyl alcohol (PVA) composition was prepared by dissolving or dispersing 475 g of purified water in 23.78 g of polyvinyl alcohol. The coating process was carried out under the conditions of inlet air 4.2 bar, spray air 1.8 bar, outlet air temperature 37 ℃, inlet air temperature 38 ℃, flow 8, outlet air flat 40%.

<Example 46>

951 g of sweetener (600 g of aspartame, 351 g of acesulfame potassium mixture) was placed in a fluidized bed coater and coated with a polyvinyl alcohol (PVA) / methacrylate copolymer (PMMA) composition as a coating base.

The polyvinyl alcohol (PVA) composition was prepared by dissolving or dispersing 4.756 g of methacrylate and 950 g of purified water in 42.80 g of polyvinyl alcohol. The coating process was carried out under the conditions of inlet air 4.2 bar, spray air 1.8 bar, outlet air temperature 37 ℃, inlet air temperature 38 ℃, flow 8, outlet air flat 40%.

<Example 47>

951 g of sweetener (600 g of aspartame, 351 g of acesulfame potassium) was placed in a fluidized bed coater and coated with a polyvinylpyrrolidone (PVP K-25) composition as a coating base.

The polyvinylpyrrolidone (PVP K-25) composition was prepared by dissolving or dispersing 570 g of purified water in 28.53 g of polyvinylpyrrolidone (PVP K-25). The coating process was carried out under the conditions of inlet air 4.2 bar, spray air 1.8 bar, outlet air temperature 37 ℃, inlet air temperature 38 ℃, flow 8, outlet air flat 40%.

<Example 48>

951 g of a sweetener (600 g of aspartame, 351 g of acesulfame potassium) was placed in a fluidized bed coater and coated with a hydroxypropylmethylcellulose (HPMC 2910, 50 cps) composition.

This hydroxypropyl methyl cellulose composition was prepared by dissolving or dispersing 760 g of purified water in 38.04 g of hydroxypropyl methyl cellulose (HPMC 2910, 50 cps). The coating process was carried out under the conditions of inlet air 4.2 bar, spray air 1.8 bar, outlet air temperature 37 ℃, inlet air temperature 38 ℃, flow 8, outlet air flat 40%.

<Example 49>

951 g of a sweetener (600 g of aspartame, 351 g of acesulfame potassium) was placed in a fluidized bed coater and coated with a methacrylate copolymer (PMMA) composition as a coating base.

This methacrylic acid copolymer (PMMA) composition was prepared by dissolving or dispersing 570 g of purified water in 28.53 g of methacrylate copolymer (PMMA). The coating process was carried out under the conditions of inlet air 4.2 bar, spray air 1.8 bar, outlet air temperature 37 ℃, inlet air temperature 38 ℃, flow 8, outlet air flat 40%.

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

Table 8

<Result>

Referring to the results of <Table 8>, it can be seen that in Example 42 and Examples 45 to 49 there is little or no change in the appearance, the polyethylene glycol of the uncoated powder (Powder) state or the coated state When the sweetener was added, it was observed that there was almost no change in appearance regardless of the type, and the intestinal laxative composition of the present invention was able to be mixed and packaged in a stable state even when one of the components of polyethylene glycol and sweetener was separated (coated). It was confirmed. However, in the case of Example 42, the proportion of the total weight part of the enteric laxative composition is high, and in the case of polyethylene glycol, since the melting point should be set at a low temperature during coating, there is a disadvantage in that the manufacturing time is long and the coating yield is low. In terms of manufacturing, it can be seen that the sweetener coating is more preferred.

<Examples 50-59>

-Preparation of uncoated sweetener and coated sweetener

In addition to the formulation (Examples 45-59) in which the sweetener, one of each component of the enteric laxative composition of the present invention, is packaged in the form of a coated powder or coated granules (Examples 45 to 59), it is carried out to ensure the variety and potential of the formulation. After preparing in the form of uncoated tablets or coated tablets of Examples 50-59, each component was mixed under the conditions of the following <Table 9>, and the change in appearance after 30 days storage under long-term and accelerated conditions was visually confirmed. The control for this was that all components were mixed.

<Example 50>

951 g of sweetener (351 g of acesulfame, 600 g of sodium saccharin) was wet granulated, dried, and then mixed with tablets to prepare uncoated tablets.

1. First, mix 351 g of sweetener acesulfame and 600 g of sodium saccharin.

2. Dissolve 30 g of the binder PVP-K25 to be used in wet granules completely in 533 mL of water.

3. Add the mixed sweetener and binder to the high speed mixer and proceed with the granulation process.

4. Granules are granulated and placed in a dryer to dry.

5. After sizing, add 348 g of disintegrant crospovidone and mix.

6. Add 21 g of magnesium stearate to the mixture of 5, and after final mixing, tableting.

(Tablet weight 450 mg, tableting at hardness 8 ~ 10 Kp)

<Example 51>

951 g of sweetener (351 g of acesulfame and 600 g of sucralose) was wet granulated, dried, and then mixed and compressed to prepare uncoated tablets.

1. First, mix 351g sweetener acesulfame and 600g sucralose.

2. Dissolve 30 g of the binder PVP-K25 to be used in wet granules completely in 533 mL of water.

3. Add the mixed sweetener and binder to the high speed mixer and proceed with the granulation process.

4. Granules are granulated and placed in a dryer to dry.

5. After sizing, add 348 g of disintegrant crospovidone and mix.

6. Add 21 g of magnesium stearate to the mixture of 5, and after final mixing, tableting.

(Tablet weight 450 mg, tableting at hardness 8 ~ 10 Kp)

<Example 52>

951 g of sweeteners (351 g of acesulfame and 600 g of aspartame) were wet granulated, dried, and then mixed and compressed to prepare uncoated tablets.

1. First, mix 351 g of sweetener acesulfame and 600 g of aspartame.

2. Dissolve 30 g of the binder PVP-K25 to be used in wet granules completely in 533 mL of water.

3. Add the mixed sweetener and binder to the high speed mixer and proceed with the granulation process.

4. Granules are granulated and placed in a dryer to dry.

5. After sizing, add 348 g of disintegrant crospovidone and mix.

6. Add 21 g of magnesium stearate to the mixture of 5, and after final mixing, tableting.

(Tablet weight 450 mg, tableting at hardness 8 ~ 10 Kp)

<Example 53>

The sweetener uncoated tablet of Example 50 was water-coated with PVA to prepare a film-coated tablet (2.5% coating of the sweetener uncoated weight).

<Example 54>

The sweetener uncoated tablet of Example 51 was water-coated with PVA to prepare a film-coated tablet (2.5% coating of the sweetener uncoated weight).

<Example 55>

The sweetener uncoated tablet of Example 52 was water-coated with PVA to prepare a film-coated tablet (2.5% coating of the sweetener uncoated weight).

<Example 56>

The sweetener uncoated tablet of Example 50 was water-coated with a PVA / PMMA copolymer mixture to prepare a film-coated tablet. (2.5% coating of sweetener uncoated weight)

<Example 57>

The sweetener uncoated tablet of Example 51 was water-coated with a PVA / PMMA copolymer mixture to prepare a film-coated tablet. (2.5% coating of sweetener uncoated weight)

<Example 58>

The sweetener uncoated tablet of Example 52 was water-coated with a PVA / PMMA copolymer mixture to prepare a film-coated tablet. (2.5% coating of sweetener uncoated weight)

<Example 59>

The sweetener uncoated tablet of Example 52 was water-coated with a PVA / PMMA Copolymer mixture to prepare a film-coated tablet form (5.0% coating of sweetener uncoated weight).

Table 9

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

<Result>

Referring to the results of <Table 9>, it was found that there is no change in appearance in the enteric laxative compositions Examples 53 to 59 prepared by tableting or granulating the sweetener and then coating it. Intestinal Laxative Compositions Containing Uncoated Sweeteners Examples 50-52 showed no change in appearance under long-term conditions, but little change in acceleration under conditions, resulting in incorporation of a coated sweetener after tableting or granulation. It can be seen that the effect of inhibiting the appearance change of the laxative compositions Examples 53 to 59 is more excellent.

<Example 60-68>-Preparation of sweetener capsule

<Examples 60-62>

One of the components of the intestinal laxative composition of the present invention was prepared in the form of a powder or granule in which a sweetener was not coated and filled in a hard capsule, and then each component was prepared under the conditions of the following <Table 10>. All were mixed, and after 30 days of storage under long-term and accelerated conditions, the appearance change was visually confirmed. The control for this was that all components were mixed.

<Examples 63-68>

One of the components of the intestinal laxative composition of the present invention, the sweetener is prepared in the form of a powder (coated powder) or coated granules filled in a hard capsule, and then each component is the conditions of the following <Table 10> All of them were mixed, and after 30 days of storage under long-term and accelerated conditions, the appearance change was visually confirmed. The control for this was that all components were mixed.

Table 10

<Result>

Referring to the results of <Table 10>, in Example 60-68 enteric laxative composition prepared in the form of a sweetener capsule was observed that almost no change in appearance under accelerated conditions, the layer of the present invention through a mixed packaging in a separate formulation When the contact area was reduced and the reactivity was suppressed, it was observed that the possibility of change of properties was low.

<Vitamin C Stability Test>

In addition to the change in sex, the change in the content of vitamin C in the long-term and accelerated conditions of vitamin C, one of the main components of the intestinal laxative composition of the present invention was measured.

* 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 'Drugs Standard of Korean Medicines'

<Result>

The results are as shown in FIG. 8, and it can be seen that the mixed-packed enteric laxative composition in the form of the separated layers showed higher stability than Comparative Example 02. It was confirmed that the mixed packaging of the layer separated form of the present invention is effective even in the suppression of the change of phase and the stability of vitamin C. Therefore, the mixed packaged intestinal laxative composition of the present invention has no change in appearance, and maintains the effect of intestinal washing or constipation for diagnostic tests and surgery during securing stability and shelf life in a constant content.

Claims (17)

1. Polyethylene glycol, first pharmaceutical component;

   Vitamin C, second pharmaceutical ingredient; And

   A third pharmaceutical ingredient consisting of a sweetener;

   Wherein said one of said first or third pharmaceutical ingredients is separated to minimize direct contact with said mixture of other pharmaceutical ingredients.
2. 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.
3. The method of claim 1,

   The third pharmaceutical component, the sweetener, is a coating powder, coated granules, coated tablets, capsules and to minimize physical contact with the mixture of other first to second pharmaceutical ingredients of the intestinal laxative composition A pharmaceutical enteric laxative composition, characterized in that it is a sweetener prepared in one or more forms of uncoated tablets.
4. The method of claim 1,

   The first pharmaceutical component polyethylene glycol is a coating powder, coated granules, coated tablets, capsules and to minimize physical contact with the mixture of the other second to third pharmaceutical components of the intestinal laxative composition Pharmaceutical enteric laxative composition, characterized in that it is prepared in one or more forms of uncoated tablets.
5. 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.
6. The method of claim 5,

   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.
7. The method of claim 6,

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

   The polyethylene glycol is enteric laxative composition, characterized in that the polyethylene glycol corresponding to an average molecular weight of 2,000 ~ 8,000.
9. The method according to any one of claims 1 to 7,

   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 5,

    The salt for electrolyte supply is enteric laxative composition, characterized in that 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 7,

    In addition to glucose (Glucose), sucrose (Sucrose), dextrose (Dextrose), fructose (Fructose), maltose (Maltose) in addition to the sweetness and saccharin (Saccharin), saccharin sodium that shows a fast solubility (Saccharin Sodium), Xylitol, Xoritol, Sorbitol, Mannitol, Maltitol, Lactitol, Isomalt, Stevioside, Erythritol, Aspartame Enteral laxative composition comprising aspartame, Acecesulfame Potassium, Sucralose, or a sweetener selected from the group consisting of two or more
14. The method according to any one of claims 1 to 7,

    The sweetener or polyethylene glycol prepared in one form of the coating powder, the coating granules and the tablet tablet, hydroxypropyl methyl cellulose, hydroxypropyl cellulose (Hydroxy propyl cellulose), hydroxyethyl cellulose (Hydroxyethyl Cellulose, Methyl Cellulose, Carboxy methyl Cellulose, Ethyl Cellulose, Cellulose Acetate, Methacrylate Copolymer (Eudragit), Polyvinylpyrrolidone (PVP) ) And polyvinyl alcohol (PVA) enteric laxative composition, characterized in that the coating is made of a coating agent consisting of a single or a mixture of coating bases selected from the group consisting of.
15. The method of claim 14,

    Enteral laxative composition, characterized in that the pharmaceutically acceptable additives are added to the coating to the intestinal laxative composition.
16. A pharmaceutical formulation comprising the intestinal laxative composition of claim 1.
17. The method of claim 8,

    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) Intestinal laxative composition, characterized in that it is at least two compounds.

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