KR102303835B1 - Aqueous flowable liquid composition and preparing methode thereof - Google Patents

Abstract

The present invention relates to a process for preparing an aqueous, flowable liquid composition for treating gastritis, gastroesophageal reflux, esophagitis, reflux esophagitis, heartburn, dyspepsia and/or peptic ulcer. In addition, the present invention relates to an aqueous, flowable liquid composition and pharmaceutical composition prepared by the above preparation method.

Description

Aqueous flowable liquid composition and method for preparing the same

The present invention relates to a process for preparing an aqueous, flowable liquid composition for treating gastritis, gastroesophageal reflux, esophagitis, reflux esophagitis, heartburn, dyspepsia and/or peptic ulcer. In addition, the present invention relates to an aqueous, flowable liquid composition and pharmaceutical composition prepared by the above preparation method.

Gastroesophageal reflux disease is a condition in which uncomfortable symptoms or complications are caused by the contents of the stomach refluxed into the esophagus. have.

As one of the drugs for the treatment of gastroesophageal reflux disease, a formulation that forms a carbonated gelatinous foam or raft gel floating in gastric contents upon contact with gastric acid is known. The formulation may firstly prevent reflux of gastric contents by forming a floating gel in the stomach in contact with gastric acid, and secondly, by regurgitating the floating gel prior to gastric contents, it can be protected from irritation of the esophageal mucosa.

Liquid or solid preparations comprising, for example, sodium alginate, sodium hydrogen carbonate or potassium hydrogen carbonate, and calcium carbonate are known. This formulation is marketed under the trade names GAVISCON (Reckitt & Colman Product Ltd.) and GAVISCON ADVANCE, and is described in British Patent No. 1,524,740 and International Patent Publication No. 95/11668. The formulation relieves gastroesophageal reflux disease by allowing low-viscosity alginic acid to form cross-links with calcium, a polyvalent metal ion, in the stomach, and at the same time, carbonic acid produced from bicarbonate and carbonate floats the alginate gel.

Currently marketed gaviscon solutions contain carbomer as a suspending agent. When the gaviscon composition remains in the stomach, it helps the composition to float and prevents reflux of gastric acid into the esophagus. do. Carbomers are high molecular weight synthetic polymers of acrylic acid crosslinked with pentaerythritol or allyl esters of sucrose. Carbomer shows viscosity by forming a gel between pH4 and pH10 due to its molecular properties, but has a characteristic that the viscosity drops at low pH (pH3 or less) or high pH (pH10 or more). When manufacturing a viscous liquid formulation using these characteristics, it is a general manufacturing method to disperse the carbomer in water, add an alkalizing agent to gel, and then add the remaining additives.

However, when the carbomer is gelled with an alkalizing agent, the fluidity of the carbomer is lost due to a sharp increase in viscosity. Therefore, it is impossible to mix carbomer and additives with a general stirrer, and the inconvenience of having to carry out the carbomer dispersion process and the main ingredient dispersion process in separate containers follows, which inevitably complements the equipment (manufacturing container supplementation, stirrer). supplementation, etc.)

In the present invention, various methods were considered in order to overcome the difficulties of the above manufacturing process, and as a result, the present invention was completed by establishing an optimal manufacturing process.

An object of the present invention is to provide a method for preparing a gastroretentive solution for treating gastritis, gastroesophageal reflux, esophageal reflux, reflux esophagitis, heartburn, indigestion and/or peptic ulcer, and to provide a gastroretentive solution prepared using the same will be.

In particular, the present invention enables the progress of the entire manufacturing process in one container by appropriately maintaining the fluidity of the carbomer in the manufacture of a gastroretentive liquid preparation using carbomer, and ensures uniformity of quality, and formulation An object of the present invention is to provide a method for preparing a liquid preparation capable of improving stability and a gastroretentive liquid preparation prepared using the same.

More specifically, one object of the present invention is to provide a method for preparing an aqueous, flowable liquid composition for the treatment of gastritis, gastroesophageal reflux, esophagitis, reflux esophagitis, heartburn, dyspepsia and/or peptic ulcer.

Another object of the present invention is to provide an aqueous, flowable liquid composition and pharmaceutical composition prepared by the above preparation method.

Another object of the present invention is to provide a composition comprising alginate, carbonate, calcium carbonate, carbomer, and a preservative, and having improved preservation and taste.

The conventional method for preparing a gaviscon liquid formulation is as follows:

Dispersing the carbomer in deionized water in the first container and neutralizing it with sodium hydroxide (no fluidity. The viscosity is at least 10,000 cps to tens of thousands of cps or more);

mixing sodium bicarbonate, a preservative (eg, methylparaben, propylparaben), and a sweetener (eg, sodium saccharin) with deionized water in a second container;

a step of putting calcium carbonate in a second container to completely mix and disperse it, and adding sodium alginate thereto and stirring until completely dissolved;

adding the contents of the second container to the contents of the first container and stirring until completely dispersed;

adding a flavoring agent (eg, peppermint oil) and adjusting the volume by further addition of deionized water; and

The process of stirring the mixture until it is completely dispersed.

However, the present inventors have found that when the carbomer is gelled with an alkalizing agent as described above, there is a problem in that the fluidity of the carbomer is lost due to a rapid increase in viscosity. If the fluidity of the carbomer is lost, it is impossible to mix the carbomer and the additive with a general stirrer, and the carbomer dispersion process and the main ingredient dispersion process are each carried out in separate containers, which inevitably leads to a manufacturing vessel It requires supplementation of equipment such as supplementation of the agitator or supplementation of the stirrer, which causes an increase in production cost. In addition, in the process of transferring and mixing the mixture prepared in two containers to one container, it is difficult to secure uniform quality, and there is a problem of exposure to contamination by microorganisms.

Accordingly, the present invention provides a liquid preparation method capable of enabling the entire manufacturing process to proceed in one container, ensuring uniformity of quality, and improving formulation stability, and a gastroretentive liquid prepared using the same do.

The present inventors found that if a part of the additive is first added before the alkalizing agent is added to the carbomer dispersion, a part of the gelation is disturbed by the additive in the carbomer dispersion, which properly maintains the fluidity of the carbomer to facilitate the subsequent process. It was confirmed that it was possible to proceed more easily. In addition, as the fluidity of the carbomer can be maintained in this way, it was confirmed that the entire process can be performed in one container, thereby reducing production costs, securing uniformity of quality, and preventing microbial contamination. .

Accordingly, in one aspect, the present invention relates to a method for preparing an aqueous, flowable liquid composition comprising the steps of:

A process of adding and mixing at least one selected from the group consisting of a preservative and alginate to the carbomer;

adding and mixing an alkalizing agent, and

A process of adding and mixing at least one selected from the group consisting of carbonate, alginate and hydrogen carbonate.

Among the above manufacturing methods, in the process of adding and mixing at least one selected from the group consisting of a preservative and alginate to the carbomer, 0.5 to 2.5% (w/v) of the total input amount of alginate can be added and mixed. have.

In addition, the total input amount of alginate in the entire process may be 1.0 to 10.0% (w/v) of the total input amount.

In the case of preservatives, according to the Preservative Power Test Method of the Korean Pharmacopoeia, 10% or less of the number of inoculated bacteria after 14 days for bacteria, the same level as or less than the level after 14 days after 28 days, and the same level as the number of inoculated bacteria after 14 days for fungi or less, and after 28 days, it includes adding and mixing in an amount equal to or less than the number of inoculated bacteria.

For example, when using parabens as a preservative, it may contain more than 0.2% (w/v) to less than 0.5% (w/v) of parabens, and more preferably 0.25% (w/v) or more. ~ 0.45% (w / v) or less may be included.

According to the above preparation method, the pH of the mixture after the step of adding and mixing at least one selected from the group consisting of a preservative and alginate to the carbomer is pH3.0-5.0, and the viscosity is preferably 100-1000 CPS .

In addition, it is preferable that the pH of the mixture after the step of adding and mixing the alkalizer is pH4.5 to 6.5 and the viscosity is 1000 to 2000 CPS.

After the step of adding and mixing at least one selected from the group consisting of carbonate, alginate and hydrogen carbonate, the pH of the mixture is preferably pH 7.0 to 8.0, and the viscosity is preferably 500 to 1000 CPS.

In one embodiment of the above preparation method, the present invention relates to a method for preparing an aqueous, flowable liquid composition comprising the following steps:

a first step of dispersing the carbomer in deionized water;

A second process of adding and mixing a preservative to the result of the first process,

A third process of adding and mixing alginate in the mixture of the second process;

A fourth step of adding and mixing an alkalizing agent to the mixture of the third step,

A fifth step of adding and mixing carbonate to the mixture of the fourth step;

A sixth step of adding and mixing alginate in the mixture of the fifth step, and

A seventh step of adding and mixing bicarbonate into the mixture of the sixth step.

In addition, optionally, at least one selected from the group consisting of a sweetener and a flavoring agent may be mixed with the mixture of the second process.

In addition, optionally, an eighth step of adding and mixing at least one selected from the group consisting of a sweetener and a flavoring agent and deionized water to the mixture of the seventh step may be further included.

In the above, the second process and the third process may be performed simultaneously or their order may be changed from each other.

In the above, the fifth to seventh processes, or the fifth to eighth processes may be performed simultaneously or their order may be changed.

In another aspect, the present invention provides an aqueous, flowable liquid composition prepared by the above method.

Hereinafter, the manufacturing process will be described in more detail.

1st process

The first step is a step of dispersing the carbomer in deionized water.

Carbomers are high molecular weight synthetic polymers of acrylic acid crosslinked with pentaerythritol or allyl esters of sucrose. Carbomer shows viscosity by forming a gel at pH 4-10 due to its molecular properties, but has a characteristic that the viscosity drops at low pH (pH3 or less) or high pH (pH10 or more).

In the present invention, carbomer can be used as a suspending agent, and commercially available carbomer is Acrypol, Acritamer, Acrylic acid polymer, Carbomera, Carboxy polymethylene, polyacrylic acid, Carboxyvinyl polymer, Pemulen, Tego Carbomer, Carbopol 934P or Carbopol 974P (BF Goodrich), etc. It can be illustrated, but is not limited thereto .

The concentration of carbomer is preferably 0.2 to 1.5% (w/v) or 0.5 to 1.0% (w/v), and when the concentration range is exceeded, there is a difficulty in the manufacturing process, and Since the viscosity is too high, difficulties may occur when taking it, and if it is less than the concentration range, a problem of poor stability of properties may occur.

2nd process

The second process is a process of adding and mixing a preservative to the resultant of the first process.

In the present invention, the preservative may be used to prevent contamination by microorganisms or subsequent deterioration. Examples of the preservative include, but are not limited to, parabens such as alkylparabens (methyl, ethyl, propyl or butyl para-hydroxybenzoate, etc.) or salts thereof. More specifically, methylparaben, propylparaben, ethylparaben, butylparaben or salts thereof may be exemplified, and one or two or more preservatives may be used together.

Preservatives have a characteristic irritating taste (bitter taste, severe irritation to the tongue, oral cavity, and esophagus), so it is desirable to mask the characteristic irritating taste in order to increase the convenience of taking.

In order to be able to mask the unique taste of a preservative with a sweetener, etc., and to be able to express its preservative power against microorganisms, the preservative is "according to the Korean Pharmacopoeia's preservative power test standard, when each preparation is inoculated with bacteria or fungi, in the case of bacteria, If less than 10% of the number of inoculated bacteria after 14 days and less than or equal to the level after 14 days after 28 days, and in the case of fungi, the same level as or less than the number of inoculated bacteria after 14 days and the same level as the number of inoculated bacteria after 28 days It is appropriate to be contained on the basis of "or less than this".

In a specific embodiment of the present invention, when considering both the expression of preservative power and the functional aspect for irritating taste masking, parabens as a preservative may be used in an amount of more than 0.2% (w/v) to less than 0.5% (w/v). In this case, it was confirmed that the preservative power was expressed, and the stimulant taste peculiar to the preservative was reduced, thereby satisfying both the preservative power and the sensuality. In addition, it was confirmed that it is more preferable to include parabens as a preservative in an amount of 0.25% (w/v) or more to 0.45% (w/v) or less. If the content is out of the above range, for example, if the content of the preservative is higher than the above range, it will eventually cause the use of an excessive sweetener, and the sweetness may be too strong, so there is a problem that may give a rejection to taking it. It is possible, but there is a possibility that the preservation power will not be expressed or problems such as microbial contamination may occur.

In this process of adding a preservative, a sweetener may be optionally added together to mask the taste of the preservative. The sweetener is used for the purpose of enhancing the convenience of taking by masking the characteristic irritating taste (bitter taste, severe irritation to the tongue, mouth, and esophagus) of the preservative. Examples of the sweetener include acesulfame, sucralose, stevia, stevioside, polydextrose, refined sucrose, xylitol, erythritol, high fructose, aspartame, sorbitol, saccharin, fructose, licorice extract, and the like, but is not limited thereto.

The high sweetener (acesulfame, sucralose, stevioside, etc.) may be used in an amount of 0.01 to 0.1% (w/v) or 0.04 to 0.08% (w/v) based on the total input amount. A larger amount of general sweeteners such as refined white sugar or high fructose can be added.

3rd process

A 3rd process is a process of injecting|throwing-in and mixing an alginate in the mixture of a 2nd process. As a preferred example, alginate may be added as much as 0.5 to 2.5% (w/v) of the total input amount.

Alginic acid is a viscous natural polysaccharide obtained from natural seaweed, and contains units of β-D-mannuronic acid (named as N units) and α-L-guluronic acid (named units as G). Alginic acid is soluble in water and its physical properties vary depending on pH, but it has the characteristic of selectively forming a gel at pH 3.5 or less.

In the present invention, alginic acid exists as a liquid in the composition, reacts with bicarbonate and carbonate in an aqueous environment in the oral cavity to form a foam and is absorbed. to form

Preferably, the alginic acid may be low-viscosity alginic acid. For example, the preferred viscosity of alginic acid may be used at 25° C. and a viscosity of 300 to 700 mPasec in a 10% w/v solution state, but is not limited thereto.

Also preferably, alginic acid is used in the form of an alginate. As the alginate, any metal salt or non-metal salt may be used, and more preferably, an alkali metal salt may be used. For example, sodium alginate, potassium alginate, magnesium alginate, triethanolamine alginate, or propylene glycol alginate may be used, but is not limited thereto. Preferably, sodium alginate can be used.

In the present invention, for the purpose of preventing gelation of the carbomer and securing fluidity, a part of the alginate is first added to the carbomer dispersion before reacting the carbomer with the alkalizing agent. More specifically, after the alginic acid is primarily input in the third process, the remaining amount may be secondary in the sixth process. It is preferable that the total input amount of alginate is 1.0 to 10.0% (w/v) of the total input amount of the composition, Of these, 0.5 to 2.5% (w/v) or 1.0 to 1.7% (w/v) of the total input amount of the composition is first added in the third step, and the remaining amount is added in the sixth step.

In a specific embodiment of the present invention, when the amount of alginate trisalt added in the third process exceeded 2.5% (w/v), the final product showed a viscosity lower than the target viscosity, which resulted in the stability of the formulation (precipitation property, layer separation phenomenon, etc.) was shown. In addition, when the input amount of trisalt alginate in the third process was less than 0.5% (w/v), the carbomer did not exhibit fluidity, which caused difficulties in the subsequent process. Therefore, it has been experimentally confirmed that the alginate input in the third process is most appropriate in 0.5 to 2.5% (w/v), more preferably 1.0 to 1.7% (w/v) of the total input amount of the composition. The remaining alginate is preferably added after the alkalizing agent is added.

4th process

A 4th process is a process of injecting|throwing-in and mixing an alkalinizing agent to the mixture of a 3rd process.

In the present invention, the alkalizing agent may be sodium hydroxide, potassium hydroxide, magnesium hydroxide, ammonium, sodium acetate, and the like, but is not limited thereto, and sodium hydroxide may be preferably used. It is also possible to use one or more alkalizing agents.

It is preferable to use the alkalizer in an amount of 0.3 to 0.5% (w/v) or 0.3 to 0.4% (w/v) with respect to the total amount of the input. If it is out of the above range, there may be a problem in that the properties of the suspension become unstable due to a decrease in viscosity, such as layer separation.

In the conventional method for producing a gastroretentive liquid formulation using carbomer, when the carbomer is gelled with an alkalizing agent, the viscosity rapidly increases from at least 10,000 CPS to tens of thousands of CPS, and the fluidity of the carbomer is lost. In the present invention, before the fourth step of adding the alkalizing agent to the carbomer dispersion, the step of adding the preservative and the alginate is preceded, and after the alkalizing agent is added in the fourth step, the pH of the mixture is pH4.5~ 6.5 and the viscosity was 1000~2000 CPS. Accordingly, rapid gelation can be prevented, and thus, the fluidity of the carbomer is maintained.

5th process

A 5th process is a process of injecting|throwing-in and mixing carbonate in the mixture of a 4th process.

An alkali metal salt or an alkaline earth metal salt can be illustrated as an example of a carbonate. More specifically, sodium carbonate, potassium carbonate, calcium carbonate, or magnesium carbonate may be exemplified, but the present invention is not limited thereto, and it is possible to use one or two or more carbon salts. Preferably, calcium carbonate can be used.

6th process

A 6th process is a process of injecting|throwing-in and mixing an alginate in the mixture of a 5th process.

As described above, for the purpose of preventing gelation of the carbomer and securing fluidity, in the third process, which is a step before reacting the carbomer with the alkalizing agent, 0.5 to 2.5 of alginate is added to the total amount of the composition in the carbomer dispersion. % (w/v) or 1.0 to 1.7% (w/v) is added, and 0.5 to 9.5% (w/v), 0.7 to 8.3% (w/v) of the total input amount of alginate in the sixth step ), or 1.5 to 7.5% (w/v), the total input amount of alginate is preferably 1.0 to 10.0% (w/v) of the total input amount of the composition, for example, about 5% (w/v). do.

7th process

A 7th process is a process of injecting|throwing-in and mixing bicarbonate in the mixture of a 6th process.

Examples of the hydrogen carbonate salt include alkali metal salts or alkaline earth metal salts. More specifically, sodium hydrogen carbonate or potassium hydrogen carbonate may be exemplified, but the present invention is not limited thereto, and it is possible to use one or two or more hydrogen carbonate salts. Preferably, sodium hydrogen carbonate can be used.

In the present invention, carbonate and bicarbonate react with gastric acid to generate carbon dioxide (carbon dioxide), which prevents the gas from being trapped in the alginate gel and escaping, thereby suspending the gel. In addition, when sodium bicarbonate is used, it can also serve to neutralize gastric acid because it is basic. In addition, when calcium carbonate is used, the gel can be appropriately cut to widen the specific surface of the composition, and thus it can also serve to increase the antacid power.

Therefore, as an example, carbonate and bicarbonate salt can be used in an amount sufficient to provide a suitable volume of carbon dioxide (carbon dioxide) for suspending the suspended gel produced with alginic acid upon contact with gastric acid in the gastric environment. .

For example, hydrogen carbonate may generally be included in the composition of the present invention at 1.5 to 3.0% (w/v), preferably between 2.0 and 2.5% (w/v), the carbonate being 3.0 to 5.0 in the composition of the present invention. % (w/v), preferably 3.0 to 3.5% (w/v) may be included. If the bicarbonate and carbonate are out of the numerical range, sufficient carbon dioxide is not generated and the antacid power is not sufficiently expressed, so that the medicinal effect does not appear properly.

In addition, the weight ratio of bicarbonate to carbonate in the composition of the present invention may be 30:70 to 50:50, preferably 40:60 to 35:65.

8th process

The eighth process is an optional process, and is a process of adding and mixing at least one selected from the group consisting of a sweetener and a flavoring agent and deionized water to the mixture of the seventh process.

In the present invention, the flavoring agent is a natural or artificial extract, for example, apple, banana, cherry, cinnamon, cranberry, grape, honeydew, honey, kiwi, lemon, lime, orange, peach, mint, peppermint, spearmint, An extract of pineapple, raspberry, tangerine, watermelon, or raspberry may be used, but is not limited thereto. Preferably, peppermint oil may be used.

The flavoring agent is 0.01 to 1.0% (w/v) or 0.01 to 0.1% (w/v) based on the total amount It can be exemplified using

In the manufacturing method established in the present invention, various problems may occur when the order of each manufacturing process is changed. In the present invention, the order of input of the raw materials to be input to each process is in consideration of the pH of the mixed solution after the input, which is related to the stability of the main ingredient showing the medicinal effect. For example, when calcium carbonate or sodium hydrogen carbonate is first added to the mixture of the second process, carbon dioxide is generated from calcium carbonate and sodium hydroxide by a neutralization reaction in an acidic pH condition. Therefore, the carbon dioxide content in the formulation is lowered and the quality is deteriorated.

For example, after completion of the second process, the pH of the mixture is preferably pH2.0 to 3.0, and the viscosity is preferably 100 to 1000 CPS.

As another example, after completion of the third process, the pH of the mixture is pH3.0 to 5.0, and the viscosity is preferably 100 to 1000CPS.

As another example, after completion of the fourth process, the pH of the mixture is preferably pH 4.5 to 6.5, and the viscosity is preferably 1000 to 2000 CPS.

As another example, after completion of the fifth process, the pH of the mixture is preferably pH 6.0 to 7.5, and the viscosity is preferably 500 to 1000 CPS.

As another example, after completion of the sixth process, the pH of the mixture is preferably pH 7.0 to 8.0, and the viscosity is preferably 500 to 1000 CPS.

The aqueous, flowable liquid composition of the present invention may be in suspension, for example. In addition, it may be formulated as a syrup, an oral solution, a lemonade, an elixirs, and the like.

The composition of the present invention may further include one or more pharmaceutically acceptable solvents or additives, and according to specific forms, surfactants, solubilizers, pH adjusters, buffers which are conventional additives used in the manufacture of oral preparations. , viscosity modifier, emulsifier It may additionally contain, but is not limited to these.

In the present invention, the aqueous, flowable liquid composition prepared as described above can be used to treat gastritis, gastroesophageal reflux, esophageal reflux, reflux esophagitis, heartburn, dyspepsia and/or peptic ulcer. Accordingly, the present invention provides a pharmaceutical composition comprising the aqueous, flowable liquid composition.

When the composition of the present invention is used as a pharmaceutical composition, it is apparent to those skilled in the art that a suitable total daily amount can be determined by a treating physician within the scope of sound medical judgment. Preferably, the dosage of the pharmaceutical composition may be used 4 times a day in the range of 10 to 80 mL, and 10 to 20 mL at a time may be divided and administered after meals and before bedtime. However, for the purposes of the present invention, a specific therapeutically effective amount for a particular patient depends on the type and extent of the response to be achieved, the specific composition, including whether other agents are used, if necessary, the specific composition, the patient's age, weight, general health, It is preferable to apply differently depending on various factors including sex and diet, administration time, administration route and secretion rate of the composition, treatment period, drugs used together with or concurrently with a specific composition, and similar factors well known in the pharmaceutical field.

In addition, the aqueous liquid composition of the present invention can be used as a carrier for targeted delivery or sustained release of a pharmaceutically active ingredient because it can deliver or sustained release of a pharmaceutically active substance to a target by absorption through the gastrointestinal mucosa. have. A pharmaceutically active ingredient may be a substance that is absorbed into the body through mucous membranes such as esophageal mucosa, gastric mucosa, in particular intestinal mucosa, for example, as an active ingredient suitable for targeted delivery in the stomach or through the stomach, a topical antibacterial agent , H2-antagonists, pro-kinetic agents (eg, cisaprid), carbenoxolone, sucralfate, local anesthetics, proton pump inhibitors, or anticholinergics. Accordingly, the present invention provides a composition for targeted delivery comprising said aqueous, flowable liquid composition. In addition, the present invention provides a composition for sustained release comprising the aqueous fluid liquid composition.

In addition, the present invention provides a composition comprising an alginate, a carbonate, a calcium carbonate, a carbomer and a preservative, and having improved preservation and taste.

Preferably, the preservative may be parabens. Examples of the parabens include, but are not limited to, alkyl parabens (methyl, ethyl, propyl or butyl para-hydroxybenzoate, etc.) or salts thereof. More specifically, methylparaben, propylparaben, ethylparaben, butylparaben or salts thereof may be exemplified, and one or two or more preservatives may be used together.

The preservative is 10% or less of the number of inoculated bacteria after 14 days in the case of bacteria according to the Korean Pharmacopoeia preservative test method, the same as or less than the level after 14 days after 28 days, and the same level as the number of inoculated bacteria after 14 days in the case of fungi or less, and after 28 days, it may be included in an amount equal to or less than the number of inoculated bacteria.

In a specific embodiment of the present invention, when considering both the expression of preservative power and the functional aspect for irritating taste masking, parabens as a preservative may be used in an amount of more than 0.2% (w/v) to less than 0.5% (w/v). In this case, it was confirmed that the preservative power was expressed, and the stimulant taste peculiar to the preservative was reduced, thereby satisfying both the preservative power and the sensuality. In addition, it was confirmed that it is more preferable to include parabens as a preservative in an amount of 0.25% (w/v) or more to 0.45% (w/v) or less. If the content is out of the above range, for example, if the content of the preservative is higher than the above range, it will eventually cause the use of an excessive sweetener, and the sweetness may be too strong, so there is a problem that may give a rejection to taking it. It is possible, but there is a possibility that the preservation power will not be expressed or problems such as microbial contamination may occur.

In addition, in this process of adding a preservative, a sweetener may be selectively added together to mask the taste of the preservative. The sweetener is used for the purpose of enhancing the convenience of taking by masking the characteristic irritating taste (bitter taste, severe irritation to the tongue, mouth, and esophagus) of the preservative. Examples of the sweetener include acesulfame, sucralose, stevia, stevioside, polydextrose, refined sucrose, xylitol, erythritol, high fructose, aspartame, sorbitol, saccharin, fructose, licorice extract, and the like, but is not limited thereto.

The high sweetener (acesulfame, sucralose, stevioside, etc.) may be used in an amount of 0.01 to 0.1% (w/v) or 0.04 to 0.08% (w/v) based on the total input amount. A larger amount of general sweeteners such as refined white sugar or high fructose can be added.

Through the improvement of the manufacturing process of the present invention, the following effects can be expected.

First, the production cost can be greatly reduced. Two different containers are needed for the preparation of gaviscon suspension: one for dispersing the viscosity modifier Carbomer and one for dissolving the active ingredient. Therefore, equipment supplementation is required, and a lot of manpower and power are consumed because each container has to be worked separately. However, in the improved manufacturing process, since all operations are carried out in one container, there is no need to supplement equipment, and since manpower and power consumption can be minimized, production costs can be greatly reduced.

Second, it is possible to secure the uniformity of quality between lots. In the case of manufacturing according to the conventional manufacturing process, some loss of the main component or carbomer occurs in the process of transferring the mixture prepared in two containers to one container and mixing, which causes a difference in viscosity and content between lots, making it difficult to secure uniformity. it becomes difficult On the other hand, if the improved manufacturing process is applied, since additives are sequentially added from one container, the difference in content and viscosity between lots can be reduced and uniformity can be easily secured.

Third, it is possible to secure formulation stability from microbial contamination. When the process is carried out in two containers, it is necessary to mix each prepared mixture with each other, and in the process of transporting the mixture, it is inevitably exposed to contamination by microorganisms. In the improved manufacturing process, there is no need to transport the mixture, and since each process can be carried out without external exposure as much as possible, it is possible to prevent deterioration of the preparation due to microbial contamination in advance.

Through the improvement of the manufacturing process of the present invention, it is possible to achieve the effect of reducing production cost, securing uniformity of quality between lots, and securing formulation stability from microbial contamination.

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

<Comparative Example 1>

Disperse 8.84 g of carbomer in 800 mL of deionized water, 2.8 g of methylparaben, 0.4 g of propylparaben, 0.2 g of acesulfame potassium, 0.4 g of sucralose, 32.5 g of calcium carbonate, 21.3 g of sodium hydrogen carbonate and 50.0 g of sodium alginate. were added one by one and melted. Here, 3.53 g of sodium hydroxide was added to neutralize, 0.3 g of peppermint flavor A-971126 was added, and the volume was adjusted to 1000 mL with purified water.

<Comparative Example 2>

In the first container, 8.84 g of carbomer was dispersed in 300 mL of deionized water, and sodium hydroxide was added thereto to neutralize the gel. In the second container, 21.3 g of sodium bicarbonate, 2.8 g of methylparaben, 0.4 g of propylparaben, 0.2 g of acesulfame potassium and 0.4 g of sucralose were mixed with 600 mL of deionized water. 32.5 g of calcium carbonate was added thereto and thoroughly mixed and dispersed, and 50.0 g of sodium alginate was added and stirred until completely dissolved. The contents of the second vessel were added to the contents of the first vessel and stirred until completely dispersed. Here, 0.3 g of peppermint flavor A-971126 was added, and deionized water was added to adjust the volume to 1000 mL.

<Comparative Example 3>

In the first container, 8.84 g of carbomer was dispersed in 400 mL of deionized water, 20.0 g of calcium carbonate and 25.0 g of sodium alginate were added thereto and mixed, followed by neutralization by adding 3.53 g of sodium hydroxide. In the second container, 2.8 g of methylparaben, 0.4 g of propylparaben, 0.2 g of acesulfame potassium and 0.4 g of sucralose were added to 400 mL of deionized water and mixed. 12.5 g of calcium carbonate, 25.0 g of sodium alginate, and 21.3 g of sodium hydrogen carbonate were added thereto and stirred until completely dissolved. The contents of the second vessel were added to the contents of the first vessel and stirred until completely dispersed. Here, 0.3 g of peppermint flavor A-971126 was added, and deionized water was added to adjust the volume to 1000 mL.

<Examples 1 to 3 and Comparative Examples 4 to 9>

Carbomer was dispersed in 800 mL of deionized water, and methylparaben, propylparaben, acesulfame potassium, and sucralose were added thereto and mixed. Sodium alginate was added thereto as much as the contents of Tables 1 and 2, stirred and mixed, and then sodium hydroxide was added and neutralized. Calcium carbonate was added to this mixture, thoroughly mixed and dispersed, and the remaining amount of sodium alginate was added to dissolve completely. Sodium bicarbonate was added thereto and completely dissolved, then peppermint flavor A-971126 was added, and deionized water was added to adjust the volume to 1000 mL.

<Comparative Examples 10-19>

Carbomer was dispersed in 800 mL of deionized water, and preservatives (methylparaben, ethylparaben, propylparaben, butylparaben, potassium sorbate or sodium benzoate), acesulfame potassium, and sucralose were added thereto and mixed. Sodium alginate was added thereto and mixed by stirring, followed by neutralization by adding sodium hydroxide. Calcium carbonate was added to this mixture, thoroughly mixed and dispersed, and the remaining amount of sodium alginate was added to dissolve completely. The total input amount of sodium alginate was set to 5% (w/v). Sodium bicarbonate was added thereto and completely dissolved, then peppermint flavor A-971126 was added, and deionized water was added to adjust the volume to 1000 mL.

process Raw material Example 1
(g) Example 2
(g) Example 3
(g) Comparative Example 4 (g) Comparative Example 5
(g) Comparative Example 6
(g) Mix 1 Carbomer 8.84 8.84 8.84 8.84 8.84 8.84 methylparaben 2.8 2.8 2.8 2.8 2.8 2.8 Propylparaben 0.4 0.4 0.4 0.4 0.4 0.4 acesulfame potassium 0.2 0.2 0.2 0.2 0.2 0.2 sucralose 0.4 0.4 0.4 0.4 0.4 0.4 Mix 2 sodium alginate 5.0 12.5 25.0 0.0 37.5 50.0 sodium hydroxide 3.53 3.53 3.53 3.53 3.53 3.53 Mix 3 calcium carbonate 32.5 32.5 32.5 32.5 32.5 32.5 mix 4 sodium alginate 45.0 37.5 25.0 50.0 12.5 0.0 mix 5 sodium bicarbonate 21.3 21.3 21.3 21.3 21.3 21.3 Mix 6 Peppermint flavor 0.3 0.3 0.3 0.3 0.3 0.3

process Raw material Comparative Example 7 (g) Comparative Example 8
(g) Comparative Example 9
(g) Mix 1 Carbomer 8.84 8.84 8.84 methylparaben 4.0 2.0 1.3 Propylparaben 0.6 0.3 0.2 acesulfame potassium 0.2 0.2 0.2 sucralose 0.4 0.4 0.4 Mix 2 sodium alginate 12.5 12.5 12.5 sodium hydroxide 3.35 3.35 3.35 Mix 3 calcium carbonate 32.5 32.5 32.5 mix 4 sodium alginate 37.5 37.5 37.5 mix 5 sodium bicarbonate 21.3 21.3 21.3 Mix 6 Peppermint flavor 0.3 0.3 0.3

Experimental example 1. Confirmation of stability by changing the order of adding additives

As a result of the preparation as described above, in Comparative Example 1, since calcium carbonate and sodium hydrogen carbonate were added under a low pH condition, carbon dioxide gas was generated, resulting in a content decrease problem. In Comparative Example 2, it was impossible to stir because the additive was added while the carbomer was completely gelled. In addition, in the case of Comparative Example 3, there was a problem in that calcium carbonate and sodium alginate were agglomerated into lumps under a low pH condition and were not released. In the case of Examples 1 to 3, the fluidity of the carbomer was appropriate for the subsequent process.

Experimental example 2. alginate Confirmation of stability according to content

In addition, as a result of the preparation as described above, in Comparative Example 4, the fluidity of the carbomer was low and stirring was not possible, and in Comparative Examples 5 to 6, the viscosity of the final product was low, so there was a problem in stability (precipitation and layer separation). . In the case of Examples 1 to 3, the fluidity of the carbomer was appropriate for the subsequent process.

Experimental example 3. Confirmation of stability and taste masking effect according to preservatives

3-1. preservative preservative exam

The preservation test is based on the standard of the preservation test method among the general test methods of the Korean Pharmacopoeia. When bacteria or fungi are inoculated into each preparation, in the case of bacteria, it is less than 10% of the number of inoculated bacteria after 14 days, and after 28 days, it is the same as the level after 14 days. Preservative power was considered to be expressed when the level was equal to or lower than the number of inoculated bacteria after 14 days or less, and when the number was equal to or lower than the number of inoculated bacteria after 28 days.

As the strains used, Escherichia coli (ATCC 9637), Pseudomonas aeruginosa (ATCC 29336), and Staphylococcus aureus (ATCC 6538) were used as bacteria, and Aspergillus niger (ATCC 16404), Candida albicans (ATCC 10231) were used as fungi. did. Bacteria were cultured in Tryptic Soy Agar medium, and fungi were cultured in Sabouraud Dextrose Agar medium.

In the case of potassium sorbate 0.2% (w/v) E. coli P. aeruginosa S. aureus A. niger C. albicans day live cell count 130,141 129,443 109,267 1,355 106,170 percentage 100% 100% 100% 100% 100% 14 days live cell count multiplication multiplication multiplication multiplication multiplication percentage 100%< 100%< 100%< 100%< 100%< 28 days live cell count multiplication multiplication multiplication multiplication multiplication percentage 100%< 100%< 100%< 100%< 100%< Judgment incongruity incongruity incongruity incongruity incongruity

In the case of sodium benzoate 0.06% (w/v) E. coli P. aeruginosa S. aureus A. niger C. albicans day live cell count 120,442 130,512 124,745 1,302 114,456 percentage 100% 100% 100% 100% 100% 14 days live cell count multiplication multiplication multiplication multiplication multiplication percentage 100%< 100%< 100%< 100%< 100%< 28 days live cell count multiplication multiplication multiplication multiplication multiplication percentage 100%< 100%< 100%< 100%< 100%< Judgment incongruity incongruity incongruity incongruity incongruity

In the case of methylparaben 0.2% (w/v) E. coli P. aeruginosa S. aureus A. niger C. albicans day live cell count 122,326 153,209 135,798 2,078 147,535 percentage 100% 100% 100% 100% 100% 14 days live cell count 11,402 multiplication 12,578 multiplication 119 percentage 9.32% 100%< 9.26% 100%< 0.08% 28 days live cell count 1,385 multiplication 289 multiplication 0 percentage 1.13% 100%< 0.21% 100%< 0% Judgment fitness incongruity fitness incongruity fitness

In the case of ethylparaben 0.2% (w/v) E. coli P. aeruginosa S. aureus A. niger C. albicans day live cell count 119,823 157,285 129,267 1,892 125,932 percentage 100% 100% 100% 100% 100% 14 days live cell count 1,180 multiplication 297 multiplication 4,125 percentage 0.92% 100%< 0.23% 100%< 3.27% 28 days live cell count 1,098 multiplication 245 multiplication 3,517 percentage 0.91% 100%< 0.19% 100%< 2.79% Judgment fitness incongruity fitness incongruity fitness

In the case of propylparaben 0.2% (w/v) E. coli P. aeruginosa S. aureus A. niger C. albicans day live cell count 118,221 148,723 130,854 1,774 105,821 percentage 100% 100% 100% 100% 100% 14 days live cell count 1,674 multiplication 6,551 1,492 4,557 percentage 1.42% 100%< 5.01% 84.10% 4.31% 28 days live cell count 1,723 multiplication 398 1,407 3,912 percentage 1.46% 100%< 0.31% 79.31% 3.69% Judgment fitness incongruity fitness fitness fitness

In the case of butylparaben 0.2% (w/v) E. coli P. aeruginosa S. aureus A. niger C. albicans day live cell count 122,598 148,717 118,784 1,626 134,264 percentage 100% 100% 100% 100% 100% 14 days live cell count 1,385 multiplication 168 1,283 105 percentage 1.13% 100%< 0.14% 78.91% 0.08% 28 days live cell count 1,264 multiplication 175 1,154 85 percentage 1.03% 100%< 0.15% 70.97% 0.06% Judgment fitness incongruity fitness fitness fitness

When methylparaben and propylparaben are 0.15% (w/v) E. coli P. aeruginosa S. aureus A. niger C. albicans day live cell count 116,473 162,193 123,420 1,663 136,206 percentage 100% 100% 100% 100% 100% 14 days live cell count 1,305 multiplication 114 1,400 56 percentage 1.12% 100%< 0.13% 85.6% 0% 28 days live cell count 1,340 multiplication 0 1,200 0 percentage 1.15% 100%< 0% 72.2% 0% Judgment fitness incongruity fitness fitness fitness

When methylparaben and propylparaben are 0.1% (w/v) E. coli P. aeruginosa S. aureus A. niger C. albicans day live cell count 100,840 186,577 105,607 1,293 113,017 percentage 100% 100% 100% 100% 100% 14 days live cell count 1,714 multiplication 3,066 1,100 487 percentage 1.7% 100%< 2.9% 85.1% 0.4% 28 days live cell count 1,340 multiplication 40 1,200 707 percentage 1.33% 100%< 0.04% 92.8% 0.6% Judgment fitness incongruity fitness fitness fitness

When methylparaben and propylparaben are 0.04% (w/v) E. coli P. aeruginosa S. aureus A. niger C. albicans day live cell count 101,707 186,963 114,357 1,327 131,397 percentage 100% 100% 100% 100% 100% 14 days live cell count 3,439 multiplication 33,253 2,100 2,184 percentage 3.38% 100%< 29.1% 158.3% 1.7% 28 days live cell count 6,663 multiplication 55,550 1,900 13,483 percentage 6.6% 100%< 48.6% 143.2% 10.3% Judgment fitness incongruity incongruity incongruity fitness

When methylparaben and propylparaben are 0.01% (w/v) E. coli P. aeruginosa S. aureus A. niger C. albicans day live cell count 133,943 132,049 156,037 1,330 116,013 percentage 100% 100% 100% 100% 100% 14 days live cell count multiplication multiplication multiplication multiplication multiplication percentage 100%< 100%< 100%< 100%< 100%< 28 days live cell count multiplication multiplication multiplication multiplication multiplication percentage 100%< 100%< 100%< 100%< 100%< Judgment incongruity incongruity incongruity incongruity incongruity

When methylparaben and propylparaben are 0.46% (w/v) E. coli P. aeruginosa S. aureus A. niger C. albicans day live cell count 109,170 143,077 118,313 1,377 129,807 percentage 100% 100% 100% 100% 100% 14 days live cell count 0 0 0 53 0 percentage 0% 0% 0% 3.8% 0% 28 days live cell count 0 0 0 9 0 percentage 0% 0% 0% 0.65% 0% Judgment fitness fitness fitness fitness fitness

When methylparaben and propylparaben are 0.32% (w/v) E. coli P. aeruginosa S. aureus A. niger C. albicans day live cell count 100,447 149,637 102,240 1,333 130,940 percentage 100% 100% 100% 100% 100% 14 days live cell count 0 0 15 1,100 0 percentage 0% 0% 0.02% 82.5% 0% 28 days live cell count 0 0 0 204 0 percentage 0% 0% 0% 15.3% 0% Judgment fitness fitness fitness fitness fitness

When methylparaben and propylparaben are 0.23% (w/v) E. coli P. aeruginosa S. aureus A. niger C. albicans day live cell count 109,510 173,870 134,603 1,340 124,130 percentage 100% 100% 100% 100% 100% 14 days live cell count 209 27 177 1,150 0 percentage 0.2% 0.02% 0.13% 85.6% 0% 28 days live cell count 0 8 7 333 0 percentage 0% 0.01% 0.01% 24.9% 0% Judgment fitness fitness fitness fitness fitness

3-2. preservative preservative and taste masking effect test

Preservatives have a characteristic irritating taste (bitter taste, severe irritation to the tongue, oral cavity, and esophagus), and thus masking of this characteristic irritating taste is required in order to increase the convenience of taking.

Accordingly, for the formulations of Examples 1 to 3 and Comparative Examples 7 to 19, the preservative power and masking effect according to the content of the preservative were checked. The preservation test is based on the standard of the preservation test method among the general test methods of the Korean Pharmacopoeia. When bacteria or fungi are inoculated into each preparation, in the case of bacteria, it is less than 10% of the number of inoculated bacteria after 14 days, and after 28 days, it is the same as the level after 14 days. Preservative power was considered to be expressed when the level was equal to or lower than the number of inoculated bacteria after 14 days or less, and when the number was equal to or lower than the number of inoculated bacteria after 28 days.

purpose of mixing Raw material name Example 1 ~3 comparative example 7 comparative example 8 comparative example 9 mass
(g/100 mL ) ratio
(w/v%) mass
(g/100 mL ) ratio
(w/v%) mass
(g/100 mL ) ratio
(w/v%) mass
(g/100 mL ) ratio
(w/v%) chief ingredient sodium alginate 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 chief ingredient sodium bicarbonate 2.13 2.13 2.13 2.13 2.13 2.13 2.13 2.13 chief ingredient calcium carbonate 3.25 3.25 3.25 3.25 3.25 3.25 3.25 3.25 thickener Carbomer 0.884 0.884 0.884 0.884 0.884 0.884 0.884 0.884 preservative methylparaben 0.28 0.28 0.40 0.40 0.20 0.20 0.13 0.13 preservative Propylparaben 0.04 0.04 0.06 0.06 0.03 0.03 0.02 0.02 sweetener acesulfame potassium 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 sweetener sucralose 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 flavoring agent Peppermint flavor 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 pH regulator sodium hydroxide 0.353 0.353 0.353 0.353 0.353 0.353 0.353 0.353 solvent Purified water appropriate amount - appropriate amount - appropriate amount - appropriate amount - retention test results preservation power preservation power It meets the criteria for the retention test, but there is a possibility of contamination No preservation power Sensory evaluation (taste) Reduction of irritation (taste) characteristic of preservatives Preservative-specific irritation (taste) presence - -

purpose of mixing Raw material name comparative example 10 comparative example 11 comparative example 12 comparative example 13 mass
(g/100 mL ) ratio
(w/v%) mass
(g/100 mL ) ratio
(w/v%) mass
(g/100 mL ) ratio
(w/v%) mass
(g/100 mL ) ratio
(w/v%) chief ingredient sodium alginate 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 chief ingredient sodium bicarbonate 2.13 2.13 2.13 2.13 2.13 2.13 2.13 2.13 chief ingredient calcium carbonate 3.25 3.25 3.25 3.25 3.25 3.25 3.25 3.25 thickener Carbomer 0.884 0.884 0.884 0.884 0.884 0.884 0.884 0.884 preservative methylparaben 0.20 0.20 - - - - - - preservative ethylparaben - - 0.20 0.20 - - - - preservative Propylparaben - - - - 0.20 0.20 - - preservative Butylparaben - - - - - - 0.20 0.20 sweetener acesulfame potassium 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 sweetener sucralose 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 flavoring agent Peppermint flavor 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 pH regulator sodium hydroxide 0.353 0.353 0.353 0.353 0.353 0.353 0.353 0.353 solvent Purified water appropriate amount - appropriate amount - appropriate amount - appropriate amount - retention test results No preservation power No preservation power No preservation power No preservation power Sensory evaluation (taste) No pungent taste characteristic of preservatives No pungent taste characteristic of preservatives No pungent taste characteristic of preservatives No pungent taste characteristic of preservatives

purpose of mixing Raw material name comparative example 14 comparative example 15 comparative example 16 comparative example 17 mass
(g/100 mL ) ratio
(w/v%) mass
(g/100 mL ) ratio
(w/v%) mass
(g/100 mL ) ratio
(w/v%) mass
(g/100 mL ) ratio
(w/v%) chief ingredient sodium alginate 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 chief ingredient sodium bicarbonate 2.13 2.13 2.13 2.13 2.13 2.13 2.13 2.13 chief ingredient calcium carbonate 3.25 3.25 3.25 3.25 3.25 3.25 3.25 3.25 thickener Carbomer 0.884 0.884 0.884 0.884 0.884 0.884 0.884 0.884 preservative methylparaben 0.50 0.50 - - - - - - preservative ethylparaben - - 0.50 0.50 - - - - preservative Propylparaben - - - - 0.50 0.50 - - preservative Butylparaben - - - - - - 0.50 0.50 sweetener acesulfame potassium 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 sweetener sucralose 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 flavoring agent Peppermint flavor 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 pH regulator sodium hydroxide 0.353 0.353 0.353 0.353 0.353 0.353 0.353 0.353 solvent Purified water appropriate amount - appropriate amount - appropriate amount - appropriate amount - retention test results fitness fitness fitness fitness Sensory evaluation (taste) Irritation to the mouth and throat by preservatives is too strong, and masking with sweeteners is impossible Irritation to the mouth and throat by preservatives is too strong, and masking with sweeteners is impossible Irritation to the mouth and throat by preservatives is too strong, and masking with sweeteners is impossible Irritation to the mouth and throat by preservatives is too strong, and masking with sweeteners is impossible

purpose of mixing Raw material name comparative example 18 comparative example 19 mass
(g/100 mL ) ratio
(w/v%) mass
(g/100 mL ) ratio
(w/v%) chief ingredient sodium alginate 5.00 5.00 5.00 5.00 chief ingredient sodium bicarbonate 2.13 2.13 2.13 2.13 chief ingredient calcium carbonate 3.25 3.25 3.25 3.25 thickener Carbomer 0.884 0.884 0.884 0.884 preservative Potassium Sorbate 0.20 0.20 - - preservative sodium benzoate - - 0.06 0.06 sweetener acesulfame potassium 0.02 0.02 0.02 0.02 sweetener sucralose 0.04 0.04 0.04 0.04 flavoring agent Peppermint flavor 0.03 0.03 0.03 0.03 pH regulator sodium hydroxide 0.353 0.353 0.353 0.353 solvent Purified water appropriate amount - appropriate amount - retention test results microbial growth
inadequate retention microbial growth
inadequate retention Sensory evaluation (taste) Preservative-specific irritation (taste) presence Preservative-specific irritation (taste) presence

3-3. according to preservatives preservative and overall taste masking test results

According to the Korea Food and Drug Administration notice (No. 2012-137, 2012. 12. 28, Regulations on drug product approval, notification, and review), the allowable range of benzoic acids (benzoic acid, sodium benzoate) among preservatives used for oral use is 0.06 % (w/v) or less, the allowable range of sorbic acids (sorbic acid, potassium sorbate, sodium sorbate) is 0.2% (w/v) or less. However, as a result of the experiment, in the case of benzoic acids and sorbic acids, although the preservation power test was conducted at the maximum allowable range concentration according to the notification of the Food and Drug Administration, the preservation power was not expressed (Tables 3 and 4), and the sensory taste was very unpleasant. It was confirmed to be inappropriate by showing (Comparative Examples 18 and 19 in Table 19).

Next, when parabens are included in the composition of the present invention by 0.2% (w/v) or less, there was a certain effect on taste improvement, but there was a problem in that the preservation power was not expressed (Tables 5 to 12; Comparative Example 9; Comparative Examples 10-13 in Table 17).

In addition, when parabens are included in 0.5% (w/v) or more, preservative power is expressed, but irritation to the mouth and throat by the preservative is too strong in terms of sensuality, and even if a sweetener is used, it is impossible to mask the irritating taste. (Comparative Examples 14 to 17 in Table 18). In addition, in this case, in order to mask the irritating taste of the preservative, the use of an excessive sweetener was ultimately induced, and the sweetness was too strong, and there was a problem in that it could give a reluctance to take it.

As a result, when considering both the expression of preservative power and the sensory aspect for irritating taste masking in the composition of the present invention, parabens as a preservative are reduced to more than 0.2% (w/v) and less than 0.5% (w/v). When used, the preservative power is expressed (Tables 13 to 15), and the irritating taste peculiar to the preservative is reduced (Examples 1 to 3 of Table 16), and it was confirmed that both the preservative power and the sensory property can be satisfied. However, in the case of Comparative Example 7 containing 0.46% (w / v) parabens, there was a limit in masking the irritating taste peculiar to the preservative, and in Comparative Example 8 containing 0.23% (w / v) parabens Although the preservation ability was expressed, there was a possibility that the problem of microbial contamination occurred. Therefore, in order to effectively express the preservative power against microorganisms and to mask the unique taste of the preservative, it is more preferable to include parabens in an amount of 0.25% (w/v) or more to 0.45% (w/v) or less as a preservative. was confirmed to be

Claims (29)

A process of adding and mixing at least one selected from the group consisting of a preservative and alginate to the carbomer;
adding and mixing an alkalizing agent, and
Including a step of adding and mixing at least one selected from the group consisting of carbonate, alginate and hydrogen carbonate,
The carbomer is a high molecular weight synthetic polymer of acrylic acid crosslinked with allyl ester of sucrose or pentaerythritol,
A process for preparing an aqueous, flowable liquid composition.
The method according to claim 1, wherein the carbomer is 0.2 to 1.5% (w/v) of the total input amount.
The method according to claim 1, wherein the alginate is sodium alginate, potassium alginate, magnesium alginate, triethanolamine alginate or propylene glycol alginate.
According to claim 1, wherein in the process of adding and mixing at least one selected from the group consisting of a preservative and alginate to the carbomer, 0.5 to 2.5% (w/v) of the total amount of alginate is added and mixed A manufacturing method that makes
The method according to claim 1, wherein the total input amount of alginate is 1.0 to 10.0% (w/v) of the total input amount.
The method according to claim 1, wherein the preservative is parabens including methylparaben, propylparaben, ethylparaben and butylparaben.
The method according to claim 1, wherein the preservative is 10% or less of the number of inoculated bacteria after 14 days in the case of bacteria according to the Korean Pharmacopoeia preservative test method, the same as or less than the level after 14 days after 28 days, and 14 days in the case of fungi A manufacturing method in which the content is equal to or less than the number of inoculated bacteria after 28 days, and the content is added and mixed at the same level or lower than the number of inoculated bacteria after 28 days.
The method according to claim 1, wherein the alkalizing agent is sodium hydroxide, potassium hydroxide, magnesium hydroxide, ammonium or sodium acetate.
The method according to claim 1, wherein the carbonate is sodium carbonate, potassium carbonate, calcium carbonate or magnesium carbonate.
The method according to claim 1, wherein the hydrogen carbonate salt is sodium hydrogen carbonate or potassium hydrogen carbonate.
The method according to claim 1, wherein after the step of adding and mixing at least one selected from the group consisting of a preservative and an alginate to the carbomer, the pH of the mixture is pH3.0 to 5.0 and the viscosity is 100 to 1000 CPS.
The method according to claim 1, wherein the pH of the mixture after the step of adding and mixing the alkalizer is pH 4.5 to 6.5 and the viscosity is 1000 to 2000 CPS.
The method according to claim 1, wherein after the step of adding and mixing at least one selected from the group consisting of carbonate, alginate and hydrogen carbonate, the pH of the mixture is pH 7.0 to 8.0 and the viscosity is 500 to 1000 CPS.
The method according to claim 1, further comprising the step of adding and mixing at least one selected from the group consisting of a sweetener and a flavoring agent.
15. The method of claim 14, wherein the sweetener is acesulfame, sucralose, stevia, stevioside, polydextrose, refined sucrose, xylitol, erythritol, fructose liquid, aspartame, sorbitol, saccharin, fructose or licorice extract.
15. The method of claim 14, wherein the flavoring agent is apple, banana, cherry, cinnamon, cranberry, grape, honeydew, honey, kiwi, lemon, lime, orange, peach, mint, peppermint, spearmint, pineapple, raspberry, tangerine, Watermelon, or an extract of raspberries.
According to claim 1,
a first step of dispersing the carbomer in deionized water;
A second process of adding and mixing a preservative to the result of the first process,
A third process of adding and mixing alginate in the mixture of the second process;
A fourth step of adding and mixing an alkalizing agent to the mixture of the third step,
A fifth step of adding and mixing carbonate to the mixture of the fourth step;
A sixth step of adding and mixing alginate in the mixture of the fifth step, and
Including a seventh process of adding and mixing bicarbonate to the mixture of the sixth process,
A process for preparing an aqueous, flowable liquid composition.
The method according to claim 17, wherein in the third step, alginate is added in an amount of 0.5 to 2.5% (w/v) of the total input amount and mixed.
The method according to claim 17, wherein the total content of sodium alginate input to the third process and sodium alginate input to the sixth process is 1.0 to 10.0% (w/v) of the total input amount.
The method according to claim 17, wherein the preservative is 10% or less of the number of inoculated bacteria after 14 days for bacteria, the same as or less than the level after 14 days after 28 days, and 14 days for fungi according to the Korean Pharmacopoeia preservative test method A method of manufacturing that is included in an amount equal to or less than the number of inoculated bacteria after 28 days and at the same level as or less than the number of inoculated bacteria after 28 days.
The method according to claim 17, wherein the pH of the mixture after completion of the third process is pH3.0 to 5.0 and the viscosity is 100 to 1000 CPS.
The method according to claim 17, wherein the pH of the mixture after completion of the fourth process is pH 4.5 to 6.5 and the viscosity is 1000 to 2000 CPS.
The method according to claim 17, wherein the pH of the mixture after completion of the sixth process is pH 7.0 to 8.0 and the viscosity is 500 to 1000 CPS.
The method according to claim 17, further comprising a step of adding and mixing at least one selected from the group consisting of a sweetener and a flavoring agent to the mixture of the second step or the seventh step.
The method of claim 1 , wherein the composition is used to treat gastritis, gastroesophageal reflux, esophageal reflux, reflux esophagitis, heartburn, dyspepsia or peptic ulcer.
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