KR100970664B1 - Manufacturing Process of Gel Including L-ornithine-L-aspartate and Gel thereof - Google Patents

Abstract

The present invention relates to a method for preparing a gel agent containing L-ornithine-L-aspartate (L-ornithine-L-aspartate) used as a therapeutic agent for liver disease, and the gel agent, specifically, carboxymethyl Provided are a method for producing an L-ornithine-L-aspartate-containing gel using sodium cellulose and a gel. The gel containing L-ornithine-L-aspartate of the present invention as a main pharmacological component can be directly administered by a patient, compared to conventional injections, and can prevent a problem in which patient discomfort increases rapidly even after repeated administration. The stability is also remarkably improved. In addition, there is an advantage that can be treated in the case of hepatic brain disease patients and elderly patients who do not have the ability to swallow the existing powder.

L-ornithine-L-aspartate, sodium carboxymethylcellulose, liver disease, gel

Description

Manufacturing method of gel containing L-ornithine-L-aspartate and its gel {Manufacturing Process of Gel Including L-ornithine-L-aspartate and Gel etc}

The present invention relates to a method for preparing a gel agent containing L-ornithine-L-aspartate (L-ornithine-L-aspartate) used as a therapeutic agent for liver disease, and the gel agent, specifically, carboxymethyl Provided are a method for producing an L-ornithine-L-aspartate-containing gel using sodium cellulose and a gel.

L-ornithine-L-aspartate is a stable salt of two naturally occurring amino acids, ornithine and aspartic acid. Hepatic encephalopathy, cirrhosis, It has been used for liver diseases associated with chronic hepatitis, hyperammonemia (Henglein-Ottermann D: Ther Gegenw, 1976; 115: 1504-1518, M.ting D, Reikowski J: Therapiewoche, 1980; 30: 5990-5996, Reikowski J, M.ting D: Witzstrock, Baden-Baden, 1982; 153-156, Fleig, WE, Kircheis, G., Spengler, U., Zeuzem, ST, G¨ ortelmeyer, R., and The German-Austrian-Swiss Multicenter Study Group J. Hepatol .: 1999; 30 (Suppl. 1): 65.

As a mechanism for the treatment of liver disease, glutamate synthetase stimulation by aspartate (H.ussinger D: J Parenteral Enter Nutr, 1990; 14 (4, suppl.): 56S-62S, Stoll B, H Ussinger D: Eur J Biochem, 1991; 195: 121-129, Stoll B, H.ussinger D: Eur J Biochem, 1989; 181: 709-716, H.ussinger D, Stoll B, Stehle T, Gerok W: Eur J Biochem, 1989; 185: 181-187, H.ussinger D: Biochem J, 1990; 267: 281-290, H.ussinger D, Gerok W: Chem Biol Interact, 1984; 48: 191, Kaiser S, Gerok W, H.ussinger D: Eur J Clin Invest, 1988; 18: 535-542, H.ussinger D, Meijer AJ, Gerok W, Sies H: Academic Press, London 1988; 337-377 7-10), ornithine Stimulation of carbamoyl phosphatase synthetase by (Banko G, Z.llner H: Int J Biochem, 1985; 17: 503-507, Zieve L, Lyftogt C, Raphael D: Metab Brain Dis, 1986; 1 25-35, Cohen NS, Chung CW, Rijman L: J Biol Chem, 1980; 255: 10248-55) and muscles with ornithine and aspartate Proteolytic inhibition (Leweling H, Kortsik C, Gladisch R, Staedt U, Hagm.ller E, Holm E: Progress in Hepatic Encephalopathy and Metabolic Nitrogen Exchange. CRC Press, Boca Raton 1991; 377-389, Cynober L. Nutrition, 1991; 5: 313-322, Wernermann J: Ann Surg, 1987; 206: 674-678, Hammarquist F, Wernermann J, Ali R, Vinnars E: Br J Surg, 1990; 2: 214-218 28. Stauch S, R.sch W :. Aspekte der Diagnose und Behandlung. Univ.-Verl. Jena 1992; 89-98, Nilius R, Kircheis G: Aspekte der Diagnose und Behandlung. Univ.-Verl. Jena 1992; 99-117).

In other words, L-ornithine-L-aspartate is broken down into ornithine and aspartic acid in the human body, and they act on the TCA cycle of hepatocytes, promoting energy production and normalizing liver function. Furthermore, ornithine promotes the urea cycle and converts ammonia generated in the body into urea, and aspartic acid, which is essential for nucleic acid synthesis, is involved in nucleic acid synthesis and rejuvenates damaged liver cells, thereby treating liver disease. Effect.

However, L-ornithine-L-aspartate, compared with conventional powder or injection formulations, injections are difficult to administer directly to the general public, which requires the intervention of a medical professional, and the discomfort of patients due to repetitive prescription may be rapidly increased. In addition, there is a problem that accompanied the stability problems depending on the expiration date. In addition, powdered powder has a problem that treatment is difficult because hepatic encephalopathy patients and elderly patients have no swallowing ability.

The present invention has been made to solve the above problems, and an object thereof is to provide a method for preparing L-ornithine-L-aspartate-containing gel using sodium carboxymethylcellulose.

Moreover, another object of this invention is to provide the gel agent manufactured by the said manufacturing method.

In order to achieve the object as described above, a method for preparing a gel containing L-ornithine-L-aspartate of the present invention as an active ingredient,

(A) dissolving 0.4 to 0.6 parts by weight of preservative and 1.0 to 1.6 parts by weight of buffer based on 100 parts by weight of L-ornithine-L-aspartate in 57 to 87 parts by weight of water;

(B) dissolving 100 parts by weight of L-ornithine-L-aspartate in 110 to 176 parts by weight of water and then dissolving it in the mixture of step (A); And

(C) mixing 12 to 20 parts by weight of sucrose and 5.4 to 8.5 parts by weight of sodium carboxymethylcellulose and dissolving it in the mixture of step (B).

Characterized in that it comprises a.

In addition, the step (B) is each of the L- ornithine-L- aspartate divided into 2 to 5 parts divided into the same ratio as the split ratio of the L- ornithine-L- aspartate After dissolution, it is preferred to dissolve in the mixture of step (A).

In the step (C), the sucrose and sodium carboxymethylcellulose divided into 2 to 5 parts are preferably mixed, and then dissolved in the mixture of the step (B) sequentially.

In addition, it is preferable to further include 1.6 to 2.4 parts by weight of the sweetener in the step (A).

Further, after step (A) and before step (B), it is preferable to further dissolve 10-30 parts by weight of sucrose in the mixture of step (A).

Further, separately from the further dissolved sucrose, 30 to 50 parts by weight of sucrose, which is integrally or divided into 2 to 4 parts, is dissolved in 55 to 88 parts by weight of water, which is divided in the same ratio as that of the sucrose, respectively. It is preferable to add further after making it.

Further, after step (B) and before step (C), it is preferable to further include dissolving 0.08 to 0.12 parts by weight of the colorant in 6 to 10 parts by weight of water and then dissolving it in the mixture of step (B). .

Further, after step (C), it is preferred to further comprise dissolving 5.5 to 8.7 parts by weight of the flavoring agent in the mixture of step (C).

It is also preferred to add 7.5 to 11.5 parts by weight of water to the mixture of step (B) after step (B) and before step (C).

Also, after step (C), it is preferable to add 11 to 17 parts by weight of water to the mixture of step (C).

In addition, the water is preferably boiled and cooled to 60 to 80 ℃.

In addition, it is preferable to further include the step of filtering the mixture of step (A), water in which the sucrose is dissolved, or water in which the L-ornithine-L-aspartate is dissolved.

On the other hand, the gel agent containing L- ornithine-L- aspartate of the present invention as an active ingredient is characterized in that it was prepared by the above method.

In addition, the gel containing L- ornithine-L- aspartate of the present invention as an active ingredient

100 parts by weight of L-ornithine-L-aspartate;

5.4 to 8.5 parts by weight of sodium carboxymethylcellulose;

0.4 to 0.6 parts by weight of preservative;

1.0 to 1.6 parts by weight of buffer;

Sucrose 12 to 20 parts by weight; And

250 to 400 parts by weight of water

It may be to include.

In addition, the gel of the present invention preferably further comprises 40 to 60 parts by weight of sucrose.

In addition, the gel of the present invention preferably further comprises 1.6 to 2.4 parts by weight of the sweetener.

In addition, the gel of the present invention preferably further comprises 0.08 to 0.12 parts by weight of colorant and 5.5 to 8.7 parts by weight of flavoring agent.

In addition, the preservative is preferably potassium sorbate.

In addition, the buffer is preferably tartaric acid.

In addition, the sweetener is preferably aspartame.

In addition, the colorant is preferably yellow No. 5 prescribed by the Korea Food and Drug Administration.

In addition, the flavoring agent is preferably an orange essence.

The gel containing L-ornithine-L-aspartate of the present invention as a main pharmacological component can be directly administered by a patient, compared to conventional injections, and can prevent a problem in which patient discomfort increases rapidly even after repeated administration. The stability is also remarkably improved. In addition, there is an advantage that can be treated in the case of hepatic brain disease patients and elderly patients who do not have the ability to swallow the existing powder.

Hereinafter, preferred embodiments of the present invention will be described in detail. In addition, many specific details such as specific components are described in the following description, which is provided to help a more general understanding of the present invention, and the present invention may be practiced without these specific details. It is self-evident to those who have knowledge. In the following description of the present invention, a detailed description of known functions and configurations incorporated herein will be omitted when it may make the subject matter of the present invention rather unclear.

The method for preparing a gel comprising L-ornithine-L-aspartate of the present invention as an active ingredient is based on 100 parts by weight of L-ornithine-L-aspartate, and is preferably 0.4 to 0.6 parts by weight and buffer 1.0. To 1.6 parts by weight dissolving in 57 to 87 parts by weight of water.

It is preferable to use the water cooled to 60 to 80 ℃ boiled water, it is more preferable to increase the dissolution efficiency to the stirring after adding the preservative and buffer.

The preservative may be used as long as it is a general preservative disclosed in the pharmacopoeia, and potassium sorbate is particularly preferable in the present invention.

The buffer can be used as long as it is a general buffer disclosed in the pharmacopoeia, tartaric acid is particularly preferred in the present invention.

Separately, 100 parts by weight of L-ornithine-L-aspartate is dissolved in 110 to 176 parts by weight of water, and then mixed with an aqueous solution of the preservative and the buffer.

It is more preferable to filter the aqueous solution of the L-ornithine-L-aspartate and the aqueous solution such as the preservative before mixing with each other. In this case, it is preferable that the pore diameter of the filter medium is 5 to 20 µm.

Furthermore, the L-ornithine-L-aspartate is divided into 2 to 5 parts, rather than dissolving all 100 parts by weight in the water at once, and the split ratio of such L- ornithine-L-aspartate It is preferable to dissolve in water divided in equal proportions, respectively.

High concentrations of L-ornithine-L-aspartate in large volumes of water make it difficult to determine whether all L-ornithine-L-aspartates are completely dissolved. In addition, the filtration process can be performed more simply.

Next, 12 to 20 parts by weight of sucrose and 5.4 to 8.5 parts by weight of sodium carboxymethylcellulose are mixed and then added to a mixed aqueous solution such as L-ornithine-L-aspartate.

Sodium carboxymethylcellulose, which is used for the preparation of the gel of the present invention, simplifies the administration of L-ornithine-L-aspartate, even at low temperatures in an aqueous solution of L-ornithine-L-aspartate, the main pharmacological component of the present invention. It has the advantage of being well dissolved and rapidly swelling and not affected by pH.

In addition, dissolving the carboxymethyl cellulose alone in an aqueous solution such as L- ornithine-L- aspartate will inevitably cause losses such as blowing due to the finely divided properties of the carboxymethyl cellulose sodium, agglomeration upon contact with water There is a problem in that the melting efficiency is sharply reduced.

Therefore, in the present invention, by mixing the carboxymethyl cellulose sodium with sucrose to dissolve, it is possible to prevent the loss, such as flying and to improve the dissolution efficiency.

Furthermore, as in the case of L-ornithine-L-aspartate, rather than dissolving the entire mixture of sodium carboxymethylcellulose and sucrose in the water at once, it is divided into 2 to 5 parts and then sequentially It is more preferable to dissolve each.

On the other hand, it is preferable that the gel containing L- ornithine-L-aspartate of the present invention as an active ingredient further comprises a sweetening agent together with the preservatives and buffers in order to reduce the rejection. The amount of the sweetener added is preferably 1.6 to 2.4 parts by weight based on 100 parts by weight of the L-ornithine-L-aspartate, and there is no limitation in the use of the sweetener used in the pharmaceutical composition. This is preferred.

Further, it is more preferable to further include sucrose in the gel of the present invention in order to increase such effects. Specifically, 10 to 30 parts by weight of sucrose may be added before the addition of the L-ornithine-L-aspartate. It is preferable to add to aqueous solution of.

In addition, it is preferable to further add 30 to 50 parts by weight of sucrose, which is divided into two or four parts in one piece, or 55 to 88 parts by weight of water, each divided by the same ratio as the split ratio of sucrose, and then further add. .

The addition of the sucrose by dividing is for the same purpose as the dividing and adding of the L-ornithine-L-aspartate.

On the other hand, it is preferable to add 0.08-0.12 weight part of coloring agents to 6-10 weight part of water, and to add to the gel of this invention. If the colorant disclosed in the pharmacopoeia is not limited to use, it is more preferable to use the yellow No. 5 prescribed in the Korea Food and Drug Administration according to the color of the aqueous solution of L- ornithine-L- aspartate of the present invention. In addition, the point of addition of the colorant is more preferably before addition of sodium carboxymethylcellulose after addition of L-ornithine-L-aspartate of the present invention.

Furthermore, it is preferable to add 7.5-11.5 weight part of water to aqueous solution, such as said L-ornithine-L-aspartate, before adding the said coloring agent. In particular, the water to perform the function of washing the container used in each step of the present invention, it can be effective to reduce the burden of the subsequent washing step as well as the efficient use of the residual raw material.

Moreover, it is preferable to add 5.5-8.7 weight part of flavoring agents to aqueous solution, such as said L-ornithine-L-aspartate, similarly to the said coloring agent. There is no particular limitation on the flavoring agent, but according to the color expressed in the L-ornithine-L-aspartate and the colorant, it is more preferable to use an orange essence in the present invention. The addition time of the flavoring agent is more preferably after addition of the carboxymethyl cellulose sodium of the present invention.

Further, it is preferable to add 11 to 17 parts by weight of water to an aqueous solution such as L-ornithine-L-aspartate before adding the flavoring agent. In particular, the water to perform the function of washing the container used in each step of the present invention, it can be effective to reduce the burden of the subsequent washing step as well as the efficient use of the residual raw material.

In addition, an aqueous solution such as a preservative of the present invention, water in which the sucrose is dissolved, or water in which the L-ornithine-L-aspartate is dissolved are further subjected to a filtration step before mixing with other components. More preferable in terms of prevention.

EMBODIMENT OF THE INVENTION Hereinafter, the Example of this invention is described.

Example

Example  1: L-ornithine-L- Aspartate  contain Gel  Manufacturing (1)

130 L of purified water was heated to 100 ° C, cooled to 75 ° C, poured into a 200L preparation tank, and 0.9 kg of potassium sorbate and 2.4 kg of tartaric acid were added thereto, followed by stirring. This was filtered through a 10 μm filter medium and poured into a 1500 L preparation tank. Separately, 130 L of purified water was heated to 100 ° C., cooled to 75 ° C., poured into a 200 L preparation tank, 90 kg of L-ornithine-L-aspartate was added thereto, followed by stirring. After filtration, it was poured into 1500 L of the preparation tank. Then, 130 L of purified water was heated to 100 ° C, cooled to 75 ° C, poured into a 200L preparation tank, 90 kg of L-ornithine-L-aspartate was added and stirred, and then passed through a 10 μm media. After filtration, it was poured into 1500 L of the preparation tank. Then, 17 L of purified water was also heated to 100 ° C., cooled to 75 ° C., rinsed and poured into the 200 L preparation tank, filtered through a 10 μm filter medium, and poured into the 1500 L preparation tank. On the other hand, after 15 kg of sucrose and 6.3 kg of sodium carboxymethylcellulose were mixed, the process of adding to the 1500 L preparation tank was repeated twice. Finally, 25 kg of purified water was poured into the 1500 L preparation tank to prepare a gel containing L-ornithine-L-aspartate of the present invention. Here, the 1500-L preparation tank kept stirring.

Example  2: L-ornithine-L- Aspartate  contain Gel  Manufacturing (2)

Following the same procedure as in Example 1, 3.6 kg of aspartame and 45 kg of sucrose were dissolved together with the potassium sorbate and tartaric acid, and heated to 100 ° C. before addition of L-ornithine-L-aspartate, followed by 75 130 liters of purified water cooled to ℃ was poured into 200 liters of the preparation tank, 45 kg of sucrose was added thereto and stirred, and the aqueous sucrose solution filtered through a 10 μm media was poured into the 1500 liters of the preparation tank.

Example  3: L-ornithine-L- Aspartate  contain Gel  Manufacture (3)

After the same process as in Example 1, but before the addition of sodium carboxymethyl cellulose heated to 100 ℃ and dissolved in 180 l of yellow No. 5 (KFDA) in 15 L of purified water cooled to 75 ℃ and then the 1500 Pour into a liter preparation tank, and separately 25 liters of purified water were added to the 1500 liter preparation tank, and then 12.96 kg of orange essence was added to the 1500 liter preparation tank.

Example  4: L-ornithine-L- Aspartate  contain Gel  Manufacture (4)

The same process as in Example 2, but before the addition of sodium carboxymethyl cellulose heated to 100 ℃ and then dissolved in 180 l of yellow No. 5 (KFDA) in 15 ℓ of purified water cooled to 75 ℃ and then the 1500 Pour into a liter preparation tank, and separately 25 liters of purified water were added to the 1500 liter preparation tank, and then 12.96 kg of orange essence was added to the 1500 liter preparation tank.

Test Example  1: evaluation of preference

The 50-person sensory test group having the age distribution of Table 1 was subjected to a nine-step evaluation method for the degree of preference for the L-ornithine-L-aspartate-containing gel of the present invention, and the results are shown in Table 2 below. Each number in Table 2 represents the number of heads of sensory testing groups who made the assessment.

age 10-19 20-29 30-39 40-49 50-59 60-69 Number of people 3 6 8 15 11 7

Symbol haha weight river bed Medium Medium slander Up and down In mourning Imagination Example 1 One 5 14 16 11 3 Example 2 2 5 8 18 10 7 Example 3 3 10 13 17 5 2 Example 4 3 6 13 19 9

As can be seen in Table 2, Example 2, which additionally added sucrose and sweetener, exhibited higher palatability compared to Example 1, which was not added thereto, and further added a coloring agent and a flavoring agent. Example 4 showed the highest acceptability.

Test Example  2: long-term preservation test

36 months test for appearance, pH, content, preservative, mass deviation, microbial limit, precipitation to test whether the L-ornithine-L-aspartate-containing gel of Example 4 is changed physicochemically during distribution The results are shown in Table 3.

As can be seen in Table 3, the L- ornithine-L- aspartate-containing gel agent of the present invention is stable enough during the distribution period, such as no precipitation, no decrease in content, and no microorganisms. appear.

In the above description of the preferred embodiment of the present invention, the present invention is not limited to the specific embodiments described above, those skilled in the art various modifications without departing from the gist of the present invention Of course it is possible. Accordingly, the scope of the present invention should not be construed as being limited to the above-described embodiments, but should be determined by equivalents to the appended claims, as well as the following claims.

Claims (17)

(A) 0.4 to 0.6 parts by weight of potassium sorbate, 1.0 to 1.6 parts by weight of tartaric acid, 1.6 to 2.4 parts by weight of aspartame and 10 to 30 parts by weight of sucrose, based on 100 parts by weight of L-ornithine-L-aspartate, Dissolved in 87 parts by weight, separately from the dissolved sucrose, 30 to 50 parts by weight of sucrose, integrally or divided into 2 to 4 parts, 55 to 88 parts by weight of water divided in the same ratio as the split ratio of sucrose Further dissolving in and further adding to each other; (B) 100 parts by weight of the L-ornithine-L-aspartate divided into 2 to 5 parts by weight of 110 to 176 parts by weight, respectively, divided by the same ratio as the split ratio of the L-ornithine-L-aspartate After dissolving, dissolving in the mixture of step (A), dissolving 0.08 to 0.12 parts by weight of yellow No. 5, 6 to 10 parts by weight of water and then further dissolving in the mixture of step (A), water Adding 7.5 to 11.5 parts by weight to the mixture of step (A); And (C) 12 to 20 parts by weight of sucrose divided into 2 to 5 parts and 5.4 to 8.5 parts by weight of carboxymethylcellulose sodium, respectively, were mixed, and then sequentially dissolved in the mixture of step (B) and orange essence 5.5 to 8.7 parts by weight are further dissolved in the mixture of step (B), and 11 to 17 parts by weight of water is added to the mixture of step (B). Method for producing a gel comprising L- ornithine-L-aspartate as an active ingredient, characterized in that it comprises a. delete delete delete delete delete delete delete delete delete delete delete delete 100 parts by weight of L-ornithine-L-aspartate; 5.4 to 8.5 parts by weight of sodium carboxymethylcellulose; 0.4 to 0.6 parts by weight of potassium sorbate; 1.0 to 1.6 parts by weight of tartaric acid; Sucrose 52 to 80 parts by weight; Aspartame 1.6 to 2.4 parts by weight; Korea Food and Drug Administration Yellow No. 5 0.08 to 0.12 parts by weight; 5.5 to 8.7 parts by weight of orange essence; And 250 to 400 parts by weight of water Gel comprising the L- ornithine-L-aspartate as an active ingredient, characterized in that it comprises a. delete delete delete