KR100632431B1 - Transparent solution and soft capsule formulation of laxative formulation - Google Patents

Abstract

 The present invention relates to a soft capsule of a laxative clear liquid, a composition and a manufacturing method thereof, and more particularly, to a transparent liquid and soft capsule preparation for all components excluding dietary fiber and vegetable laxative in a composition laxative (laxative) composition. The present invention relates to a technique for preparing a transparent liquid or soft capsule contents by using a hydrophilic solvent and a nonionic / cationic surfactant as a basic solubilizer and adjusting the pH to an appropriate pH using a stabilizer and a pH adjuster.

The present invention relates to a transparent liquid formulation and soft capsule formulation containing not only basic laxative functional raw materials, but also suits and vitamins that can be used to minimize side effects caused by laxative use.

Laxatives, docuate sodium, bisacodeyl, solvents, surfactants, pH adjusters, clear liquids, clear soft capsules, solubilization

Description

Soft capsule of laxative transparent liquid formulation, its composition and manufacturing method {Transparent solution and soft capsule formulation of laxative formulation}

1 is a first graph showing the results of experiments on the disintegration of the capsule coating and the content change of bisacyl and dosytate sodium, leaching of the contents according to the present invention.

Figure 2 is a second graph showing the results of experiments on the content of the disintegration and bisaccordyl, sodium doxosate and urosodexisocholic acid, leaching the contents of the capsule coating.

Figure 3 is a third graph showing the results of experiments on the disintegration of the capsule coating and the content of bisacodeyl, sodium dositate, hydrochloric acid amine, leaching of the contents.

Figure 4 is a fourth graph showing the results of the disintegration and dissociation of the capsule film, the content of sodium docetate, urethane dexoxycholic acid, pyridonic acid hydrochloride, leaching of the contents.

5 is a fifth graph showing the results of the disintegration and the content of the dissociation of the capsule film, the content of sodium dodecate, sodium uroxexocholic acid, calcium pantothenate, leaching of the contents.

Figure 6 is a sixth graph showing the experimental results for the disintegration and the content of the disintegration of the capsule film, bisacodeyl, sodium doxosate, urethanexoxic acid, chiamine hydrochloride, pyridoxine, calcium pantothenate, leaching the contents.

  The present invention relates to a soft capsule of a laxative clear liquid, a composition and a manufacturing method thereof, and more particularly, to a transparent liquid and soft capsule preparation for all components excluding dietary fiber and vegetable laxative in a composition laxative (laxative) composition. The present invention relates to a technique for preparing a transparent liquid or soft capsule contents by using a hydrophilic solvent and a nonionic / cationic surfactant as a basic solubilizer and adjusting the pH to an appropriate pH using a stabilizer and a pH adjuster. The present invention relates to a transparent liquid formulation and a soft capsule formulation including not only basic laxative functional ingredients but also formal medicines and vitamins that can be used to minimize side effects caused by laxative use.

Laxatives can be classified into chlorinated laxatives, swellable laxatives, infiltrating laxatives, and irritant laxatives. Among these, chlorine laxatives include magnesium oxide, magnesium magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium carbonate, and magnesium sulfate. The raw material of the swellable laxative is carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, and cellulose type which is the electron carrier blood. Infiltrating laxatives include choras, supak, polosacol, and docuate sodium. Irritant laxatives include raw materials representative of diphenylmethane derivatives, bisacodeyl and phenolphthalein, anthraquinone derivatives, phenolphthalein and dantron, sagrada, and extracts thereof. (E.g. Casantranol), Presbytery, Rhubarb, Senna Fruit, Senna Leaf, Aloe Youngsil, Flangulapi, and Black Shaft.

As a formal agent for preventing intestinal fatigue and health of the intestines due to laxatives, compounds represented by dihydrocholine acid, dimethicone, urodexisocholic acid, and sodium bicarbonate, dry yeast, intestinal probiotics, licorice, deficiency, gill herb , Donkey, jujube, bark skin, horseback riding, wood bile x, ungdam, uiin, peony, jihwang, tobokyeong, celestial organ, gentiana, cinnamon, medicinal herbs, skin, die menthol, elmenthol, mokyang, mint, peppermint, white ginseng There are, extract, ginger, leaflet, gentian, fruit, dermis, creation, condurango, golden, rhubarb, yellow white, homica extract, fennel, pepper.

In addition, nicotinic acid amide, vitamin B1 and its derivatives, vitamin B6 and its derivatives, and calcium pantothenate may be used to balance intestinal vitamins and nutrition.

However, saline laxatives, swellable laxatives and plant-stimulating laxatives containing dietary fiber and cellulose strains can be formulated only in the form of granules and powders at least once in order to show efficacy, and the patient's compliance with the dose. Is not so high.

 In the case of laxatives using the raw materials included in the present invention, tablets or capsules have already been developed, but the present invention is the first in the formulation technology for a transparent liquid or soft capsule. Of course, the Republic of Korea Patent 1999-0031276 describes a method for producing a transparent soft capsule using casanthranol and docuate, but the degree of solubility can not be measured with a dark brown suspension of the contents of the very low transparency. This is the limit of Casantranol as a cascara sagrada plant extract.

The preparation of the formulation transparently has the advantage that the bioavailability time of the formulation can be purposefully designed because the product is produced in a completely dissolved form.

For example, in case of laxatives, taking three times a day can cause discomfort throughout the day. At this time, usually taken before going to bed, laxatives through the stomach and intestines, the time to reach the large intestine is the morning, when the maximum effect should be expressed, too early or too late will cause inconvenience.

However, dissolution of invasive laxatives, including docuate sodium, takes more than a few hours as a general technique, and irritant laxatives, including bisacryl, are insoluble in water and thus cannot be prepared in a conventional manner. However, a transparent liquid formulation can be prepared by the method according to the present invention, and the preparation of the transparent liquid contents in the form of a mixture of the two drugs is also only according to the present invention.

In addition, in the case of the soft capsule described in the present invention, the liquid was divided into small amounts in consideration of the constitution of each person, so that one to three capsules can be selected at a time according to the symptoms and constitution, thereby completing the present invention.

In order to achieve the above object, the configuration of the present invention will be described.

Invasive laxatives, such as docuate sodium, basically act as a surfactant, reducing the oil-water surface tension of hard stools in the large intestine, allowing water and oil to mix well, softening the stools to promote bowel movement. . This raw material is a white, sticky waxy semi-solid material. It has a solubility of 1.5% or higher at high temperature in water, and melts at higher temperatures in other solvents.

Stimulant laxatives are polymers that are not digested / absorbed in the small intestine and descend to the large intestine, where they are broken down by bacteria present in the large intestine and transferred to active substances. The active substance stimulates the inner wall of the colon to promote bowel movements to induce bowel movements.

However, irritant laxatives are strongly pushed out of the stool, so if there is no softening and lubricating action of the invasive laxative, the patient will suffer. For this reason, most laxatives are prescribed in combination with irritation and invasiveness.

The present invention is that water is insoluble in irritation and does not stop digestion / absorption in the small intestine, therefore, it is necessary to induce the drug to be expressed at a certain time by being immediately transferred to the large intestine by colon bacillus. It has been concluded that formulations in fully solubilized form are essential for this purpose, and that it is necessary to prepare transparent liquid contents by this method, and for this purpose hydrophilic solvents, surfactants, stabilizers and pH adjusting agents are used. To prepare a clear solution.

Looking at the configuration according to the invention in more detail,

Per 1 part by weight of irritant,

Mixing 1 to 80 parts by weight of the hydrophilic solvent and 0.05 to 100 parts by weight of the surfactant;

Heating the mixture to 50-70 ° C., adding 0.5-8 parts by weight of the infiltrating agent and stirring for 20-30 minutes;

When the transparent liquid is made in the above step, stirring by adding 1 part by weight of irritant and 0.001 to 1 part by weight of pH adjusting agent;

The soft capsule of the laxative clear liquid is prepared through the configuration.

 As a basic raw material of the laxatives included in the present invention, doucate sodium, choras, supak, polosacol and stimulating laxative bisacodil, phenolphthalein and dantron, which have a small amount of effective content and are easy to form, are the main raw materials of laxatives. Dehydrocholine acid, dimethicone and urodexisocholic acid may be mixed in the form of a form functional ingredient, and vitamin B1 and a derivative vitamin thereof that can be used as a liquid among the formulatable vitamins. Even if B6 and its derivative calcium pantothenate are mixed, it can be manufactured as a transparent liquid or soft capsule.

In a liquid mixture of a hydrophilic solvent and a surfactant, an infiltrating laxative such as sodium docusate is added and stirred well to obtain a completely transparent solution. At this time, when heated to 60 ° C. or lower, the infiltrating laxative, particularly docuate sodium, can be dissolved in a transparent solubilization time within 30 minutes. In this case, by adding irritant laxatives, including bisacryl, and adding an acidifying agent as a pH adjuster to adjust to a constant pH, completely transparent liquid contents can be obtained.

The hydrophilic solvent that can be used at this time is a solubilizing solvent representative of polyethylene glycol (the significant difference from PEG 200 to PEG 6000 is the difference in viscosity of the contents) .Caster oil and corn oil , Cottonseed oil, ethyl oleate, glycerin monostearate, glycofurol, isopropyl palmitate, lecithin, mineral oil, polyoxyethylene alkyl ether (Polyoxyethylene Alkyl Ether), Sesame Oil, Soy Bean Oil, Sunflower Oil, and Triacetin may be used.

Nonionic and cationic are suitable as surfactants, and these include polyoxyethylene sorbitan fatty acid esters (the significant difference of Tween 20 to 80 is the difference in the viscosity of the solution). Glycerin Monooleate and Polyoxyethylene Caster Oil Glycosides (Cremopher), Ploxamer, Labrafil, and Span may be used.

Stabilizing and dissolving aids may be used glycerin, sodium edetate, crospovidone, ranulin alcohol, hydroxypropylcellulose, alginic acid and sodium alginate, vegetable oil (Vegetable Oil).

The acidifying agent as the pH adjusting agent may be citric acid, and acetic acid, hydrochloric acid, ascorbic acid, edetic acid, fumaric acid, lactic acid, malic acid, phosphoric acid, propionic acid, sodium ascorbate, and taric acid may be used.

As an alkalizing agent as a pH adjuster, diethanolamine, potassium citrate, potassium hydroxide, sodium bicarbonate (heavy bath), sodium citrate dihydrate, triethanolamine, and sodium hydroxide can be used.

Formal dehydrocholine and ursodexisocholine acids are basically insoluble in ether or water, but they are solubilized transparently by stirring in a solution prepared above and stirring.

Dimethicone is generally a clear liquid, which can also be formulated as a clear liquid through pH adjustment.

On the other hand, vitamins can be prepared with transparent contents using water as an intermediate medium. Water can soften the soft capsule film, but the small amount of water used as the intermediate role of the two solutions had no effect on soft capsule film softening.

Chiamine hydrochloride, pyridoxine hydrochloride and calcium pantothenate were dissolved in 1 to 10 parts by weight of water, and the solution was mixed with the base material of the laxative, and the pH was adjusted with an acidifying agent or an alkalizing agent to obtain a transparent liquid content.

The preferred ratio at this time is 0.5 to 8 parts by weight of the invasive laxative with respect to 1 part by weight of the irritant, 1 to 80 parts by weight of the solvent, 0.05 to 100 parts by weight of the surfactant, 0.5 to 50 parts by weight of the stabilizer, and pH adjuster 0.001 It is -1 weight part and 0.5-20 weight part of water.

In the following embodiment relates to a process for obtaining the contents of the transparent soft capsule liquid formulation, the amount of the content is in the range of 200 ~ 300mg in consideration of the soft capsule manufacturing and packaging process. The following examples are intended for the specification of the manufacturing method raised by the present invention and are not intended to limit the scope of the present invention to the examples.

Example 1

Basic Efficacy Group Clear liquid  Produce

200 g of polyethylene glycol (PEG400 (DOW)), 30 g of polyoxyethylene sori-bitan fatty acid ester (Tween-20 (Duksan)), 16.75 g of docuate sodium (Merk Eprova AG), 5 g of bisacryl (DISHMAN), citric acid ( Deoksan) 5g 256.75g, 256.75mg 1000 capsules manufacturing

First, polyethylene glycol (PEG) and polyoxyethylene-sorbitan fatty acid ester (Tween) are mixed and heated to 60 ° C. After 30 minutes, all of the solution is dissolved to make a clear solution. Add 5g of citric acid and bisacryl and stir well to obtain a colorless and transparent solution. At this time, the pH of this liquid was 4.67. This solution was produced in a capsule capsule size 6 Oval through a soft capsule maker.

Experimental results of the disintegration of the capsule film and the change of the content of bisacyl and dosytate sodium and the leaching of the contents under the accelerated conditions of the prepared capsule are shown in Table 1 and FIG. 1. In the following, both the content test and the leakage test were conducted under a constant temperature and humidity condition of 40 ° C and 75% relative humidity.

<Table 1>

division first 2 months 4 months 6 months Visacodil 99.7 98.1 96.1 95.3 Docusate sodium 99.7 98.7 98.1 97.1 Leakage Ratio (%) 0 0 0 0 Disintegration time 6 minute, 20 seconds 7 minute, 30 seconds 9 minute, 10 seconds 11 minute, 10 seconds

Example 2

Basic Efficacy Group  And preparation of mixed liquor

In the solution preparation method of Example 1, 0.5 g of potassium hydroxide (ducksan) was mixed instead of citric acid, and then 10 g of urdexoxiccholic acid (Daewoong) was added to make 262.25 g of the system, thereby preparing 1000 capsules at 262.25 mg per capsule. PH at this time was 4.44. Experimental results for the disintegration of the capsule film and the content of bisaccordyl, sodium docetate, urethanexisocholic acid, leaching of the contents under the accelerated conditions are shown in Table 2 and FIG.

<Table 2>

division first 2 months 4 months 6 months Visacodil 99.6 98.7 98.1 97.5 Docusate sodium 99.7 98.9 98.5 98.1 Ursodexisocholic acid 99.5 98.7 98.2 98.2 Leakage rate (%) 0 0 0 0 Disintegration time 6 minute, 20 seconds 8 minute, 20 seconds 9 minute, 10 seconds 11 minute, 10 seconds

Example 3

Basic Efficacy Group and Vitamin Mixture Preparation

Example 3-1

Hydrochloric acid  mix

The contents were prepared by mixing 1 g of potassium hydroxide instead of citric acid in the basic solution of Example 1. At the same time, 3 g of DSM NUTRITIONAL PROGUCTS GMBH is completely dissolved in 9 g of water and then mixed into the base solution. A total of 264.75 g was obtained to prepare 1000 capsules of 264.75 mg for each capsule. PH at this time was 8.61. Experimental results of the disintegration of the capsule coating and the content of bisacyl, sodium docetate, hydrochloric acid, and leaching of the contents under accelerated conditions are shown in Table 3-1 and FIG. 3. In the case of chiamine hydrochloride, the content change occurs even in the general formulation, and the standard can be met by adding an excess of 20%.

<Table 3-1>

division first 2 months 4 months 6 months Visacodil 99.5 99.1 98.5 97.2 Docusate sodium 99.8 98.9 98.5 98.1 Ursodexisocholic acid 99.1 99.1 98.5 97.2 Hydrochloric acid 99.0 97.9 95.1 93.8 Leakage rate (%) 0 0 0 0 Disintegration time 6 minute, 10 seconds 7 minute, 50 seconds 9 minute, 30 seconds 10 minute, 50 seconds

Example 3-2

Pyridoxine hydrochloride  mix

When preparing the basic solution of Example 1, 3 g of pyridoxine hydrochloride (WUXUE XUNDA Co., Ltd.) was completely dissolved in 20 g of water, and mixed with the basic solution, 279.75 g of a pale yellow transparent solution was obtained. 1000 capsules were prepared using 279.75 mg of each capsule. PH at this time was 3.29. Experimental results for the disintegration of the capsule film and the content of bisaccordyl, sodium docetate, pyridoxine hydrochloride, leaching of the contents under the accelerated conditions are shown in Tables 3-2 and 4. In the case of pyridoxine hydrochloride, the content change also occurs in general formulations, which can usually be met by 20% overdosage.

<Table 3-2>

division first 2 months 4 months 6 months Visacodil 99.7 99.1 98.2 98.1 Docusate sodium 99.9 99.2 98.1 97.9 Ursodexisocholic acid 99.8 99.7 99.2 98.7 Hydrochloric acid 99.0 97.7 95.8 93.9 Leakage rate (%) 0 0 0 0 Disintegration time 6 minute, 20 seconds 7 minute, 10 seconds 8 minutes 50 seconds 11 minute, 10 seconds

Example 3-3

Of calcium pantothenate  mix

In the basic solution of Example 1, a basic solution containing 0.4 g of potassium hydroxide was prepared instead of citric acid. At the same time, 5 g of calcium pantothenate (SAKURA Co., Ltd.) was completely dissolved in 20 g of water and mixed with the base liquid to obtain a total of 277.25 g of a clear liquid. PH at this time was 5.11. This prepared 1000 capsules of 277.25 mg of soft capsule. Experimental results for the disintegration of the capsule film and the content of bisaccordyl, sodium docetate, pyridoxine hydrochloride, leaching of the contents under accelerated conditions, and the leaching of the contents are shown in Tables 3-3 and 5. In the case of calcium pantothenate, the content changes also occur in general formulations, which can usually be met by 20% overdosage.

<Table 3-3>

division first 2 months 4 months 6 months Visacodil 99.5 98.9 98.7 97.5 Docusate sodium 99.8 99.7 99.1 98.9 Ursodexisocholic acid 99.9 99.8 98.9 98.7 Calcium Pantothenate 99.0 97.6 95.2 93.0 Leakage rate (%) 0 0 0 0 Disintegration time 6 minute, 10 seconds 7 minute, 10 seconds 8 minute, 20 seconds 10 minutes

Example 4

Basic Efficacy Group  Combination of liquids, formal preparations and vitamins

200 g of PEG400, 30 g of Tween 20, and 16.75 g of sodium docuate are mixed and stirred while heating to 60 ° C. to form a clear solution. 10 g of ursode Soycholic acid is added to this mixed solution. 1 g of potassium hydroxide is added to 20 g of water, and 3 g of chiamine hydrochloride, 3 g of pyridoxine hydrochloride, and 5 g of calcium pantothenate are mixed well. This solution is mixed and mixed well to obtain 298.75 g of a pale yellow transparent solution. PH at this time is 4.63. This capsule was filled with 298.75 mg of each capsule to prepare 1000 capsules. Experimental results for the disintegration of the capsule film and the content of bisaccordyl, sodium dosytate, ursodesoxic acid, chiamine hydrochloride, pyridoxine hydrochloride, calcium pantothenate, and leaching of the contents under accelerated conditions are shown in Table 4. And as shown in FIG.

<Table 4>

division first 2 months 4 months 6 months Visacodil 99.7 99.5 99.1 98.9 Docusate sodium 99.8 99.7 99.2 99.1 Ursodexisocholic acid 99.8 99.8 99.7 99.1 Hydrochloric acid 98.9 97.2 95.3 93.3 Pyridoxine hydrochloride 98.7 97.3 95.4 93.5 Calcium Pantothenate 98.5 97.1 94.9 93.1 Leakage rate (%) 0 0 0 0 Disintegration time 6 minute, 30 seconds 7 minute, 20 seconds 8 minute, 10 seconds 10 minute, 10 seconds

As described above, the present invention is based on the stimulant and infiltrate and adds a suit or vitamin thereto, and by appropriately adjusting the hydrophilic solvent, nonionic or cationic surfactant, stabilizer and pH adjusting agent. By preparing a transparent solution, the solution does not damage the film of the capsule even if the content of the active ingredient is kept stable and is manufactured as a soft capsule. In the case of a capsule solid, there is a risk that the necessary deviation of elapsed time, that is, the disintegration and dissolution time, may vary depending on the excipient and the process used. Precisely control the maximum drug expression time of constipation patients Has the advantage that it can.

Claims (13)

Per 1 part by weight of irritant, Mixing 1 to 80 parts by weight of the hydrophilic solvent and 0.05 to 100 parts by weight of the surfactant; Heating the mixture to 50-70 ° C., adding 0.5-8 parts by weight of the infiltrating agent and stirring for 20-30 minutes; When the transparent liquid is made in the above step, stirring by adding 1 part by weight of irritant and 0.001 to 1 part by weight of pH adjusting agent; Soft capsule manufacturing method of laxative transparent liquid, characterized in that the capsule is produced through. Per 1 part by weight of irritant, 1 to 80 parts by weight of a hydrophilic solvent and 0.05 to 100 parts by weight of a surfactant are mixed and stirred by adding 0.5 to 8 parts by weight of an invasive laxative to the mixture, and then stirred by adding 1 part by weight of an irritant laxative and 0.001 to 1 part by weight of a pH adjusting agent. Soft capsule of the laxative clear liquid, characterized in that. Per 1 part by weight of irritant, 1 to 80 parts by weight of hydrophilic solvent, 0.05 to 100 parts by weight of surfactant, 0.5 to 8 parts by weight of infiltrant laxative, 1 part by weight of irritant laxative, and 0.001 to 1 part by weight of pH adjusting agent. . The method of claim 1, The capsule is a soft capsule manufacturing method of a laxative transparent liquid formulation, characterized in that it can be prepared by adding one or more selected from 0.01 to 10 parts by weight of urodexisocholic acid or 0.01 to 25 parts by weight of dehydrocholine acid as a formal formulation. The method of claim 1, The capsule is a soft capsule of a laxative clear liquid, characterized in that it can be prepared by adding at least one selected from 0.01 to 2 parts by weight of chiamine hydrochloride, 0.01 to 5 parts by weight of pyridoxine hydrochloride, and 0.01 to 3 parts by weight of calcium pantothenate. Manufacturing method. The method of claim 1, Hydrophilic solvents include polyethylene glycol (PEG200 to PEG6000), castor oil, corn oil, cottonseed oil, ethyl oleate, glycerin monostearate, glycofurol Isopropyl Palmitate, Lecithin, Mineral Oil, Polyoxyethylene Alkyl Ether, Sesame Oil, Soy Bean Oil, Sunflower Oil Oil), triacetin (Triacetin) is a soft capsule manufacturing method of a laxative transparent liquid, characterized in that at least one selected from. The method of claim 1, Surfactants include polyoxyethylene sorbitan fatty acid esters (Tween 20-80), cetrimide, glycerin monooleate, and polyoxyethylene caster oil glycosides, poloxamers, and labrafils. , Soft capsule manufacturing method of the laxative transparent liquid agent, characterized in that at least one selected from the span. The method of claim 1, Infiltrating laxative is a soft capsule manufacturing method of a laxative clear liquid, characterized in that at least one selected from docusate sodium, choras, supak, polosacol. The method of claim 1, Irritant laxative is a soft capsule manufacturing method of a laxative transparent liquid agent, characterized in that at least one selected from bisacyl, phenolphthalein, dantron. The method of claim 1, pH adjusting agent is a soft capsule manufacturing method of a laxative transparent liquid agent, characterized in that at least one selected from an acidifying agent or an alkalizing agent. delete The method of claim 10, The acidifying agent is a laxative clear liquid, characterized in that at least one selected from citric acid, acetic acid, hydrochloric acid, ascorbic acid, edetic acid, fumaric acid, lactic acid, malic acid, phosphoric acid, propionic acid, sodium ascorbate, taric acid Soft capsule manufacturing method. The method of claim 10, As an alkalizing agent, soft capsules of a laxative transparent liquid agent, characterized in that at least one selected from diethanolamine, potassium citrate, potassium hydroxide, sodium bicarbonate (heavy bath), sodium citrate dihydrate, triethanolamine, sodium hydroxide Way.

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