KR101458670B1 - Pharmaceutical composition comprising branched chain amino acids as active ingredients and the preparation method thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical liquid suspension composition containing a branched chain amino acid and various drugs as an active ingredient, wherein the active ingredient is scarce, and a process for producing the same.
Specifically, the present invention relates to a pharmaceutical liquid suspension composition containing three branched branched amino acids isoleucine, leucine and valine as an active ingredient, wherein the active ingredient is scarce, and a process for producing the same.
More specifically, the present invention relates to a pharmaceutical composition containing a branched chain amino acid isoleucine, leucine and valine as an active ingredient with controlled particle size distribution, and a combination of a specific thickening agent or a specific thickening agent, a sweetening agent, And a method for preparing the same.

Description

[0001] PHARMACEUTICAL COMPOSITION COMPRISING BRANCHED CHAIN AMINO ACIDS AS ACTIVE INGREDIENTS AND PREPARATION METHOD THEREOF [0002]

The present invention relates to a pharmaceutical liquid suspension composition containing a branched chain amino acid as an active ingredient, wherein the active ingredient is scarce, and a process for producing the same.

Specifically, the present invention relates to a pharmaceutical liquid suspension composition containing three kinds of branched chain amino acids, specifically, isoleucine, leucine and valine as active ingredients, and hiding the active ingredient thereof, and a method for producing the same.

More specifically, the present invention relates to a pharmaceutical composition containing three kinds of branched chain amino acids having controlled particle size distribution, specifically, isoleucine, leucine and valine as an active ingredient, and is characterized by comprising a combination of a specific thickener or a specific thickener To a liquid suspension composition having a dispersing ability and a process for producing the same.

Furthermore, the present invention relates to a process for preparing a liquid suspension composition, characterized in that in the mass production for the commercial use of the liquid suspension composition, the three branching amino acids are introduced in a specific sequence under specific temperature conditions.

The pharmaceutically acceptable liquid suspension composition is used for improving the nutritional status of a patient or a healthy person, and is widely used in medical fields and the like, and is usually dissolved or suspended in a solvent such as water. However, a pharmaceutical liquid suspension composition containing three branched-chain amino acids has a bitter taste, which makes it burdensome for patients taking it.

On the other hand, a suspension containing three branched chain amino acids of isoleucine, leucine and valine has been proposed.

Japanese Laid-Open Patent Publication No. 2002-114674 (published on April 16, 2002) discloses a pharmaceutical suspension containing at least one organic acid as a branched chain amino acid and an acidic agent. However, merely adding an organic acid does not have a sufficient bitter taste masking effect, and therefore, it is difficult to commercialize it.

It is disclosed in U.S. Patent No. 10-2005-0095833 (published October 04, 2005) that, in order to obtain a bitter taste suppressed oral composition, a branched chain amino acid mixture should be taken immediately after preparation of a solution or suspension, It is difficult to expect the same effective efficacy because the amount of water, mixing time, and mixing method are different according to the user as well as troublesome when taking the solution or suspension.

In Registration No. 10-0927254 (registered on November 10, 2009), aloe vera, gum, and acidifier are mixed with three kinds of branched chain amino acids to reduce unpleasant taste and feeling such as bitter taste characteristic of branched chain amino acids, Is formulated into a liquid suspension composition, thereby improving convenience in dosing. However, when used commercially, the suspension is manufactured in a certain volume or weight and sold in pouches, usually in the range of 5 mL to 20 mL (specific gravity of liquid phase 0.8 to 1.2 g / mL). However, in this patent document, the dose of branched chain amino acids is 474 mg of isoleucine, 952 mg of leucine and 572 mg of valine per 20 mL, and 952 mg of isoleucine dose of 1 LIVACT GRANULE as treatment agent, 1,904 mg of leucine and 1,144 mg of valine The amount of use is considerably less than that of This is an example showing that it is difficult to prepare a branched chain amino acid liquid suspension composition for medicines when the three kinds of branched chain amino acids are used in the range of 50 to 150 mesh. In addition, the bitter taste of aloe vera is masked with the bitter taste of amino acids, so there is a technical limitation that it does not fundamentally hide unpleasant taste.

Currently, there are no commercially available liquid suspension preparations containing three kinds of branched chain amino acids.

It is believed that this is because a single dose of three kinds of branched chain amino acids constituting the suspension is large, so that it is considered that the conventional method does not complete the composition of the liquid suspension composition suitable for treatment. This is also the result of not completely solving not only bitter concealment but also foreign matter in the mouth derived from the powder and troubles in mass production process for commercial sale.

Pharmaceutical preparations containing three kinds of branched chain amino acids consisting of isoleucine, leucine and valine as effective ingredients are known as therapeutic drugs effective for liver diseases. These branched chain amino acids have the effect of improving nitrogen balance by correcting the imbalance of plasma amino acid in cirrhotic patients. In addition, it improves the awareness of the ascites and fatigue of liver cirrhosis patients, increases the plasma protein and albumin, improves the protein nutritional status, inhibits muscle protein degradation and hepatic secretion protein depression, and prevents the platelet count from decreasing .

Currently, these three kinds of branched chain amino acids are formulated into granules, which are solid preparations, and are marketed as LIVACT GRANULE. However, in the case of commercially available granules, there is a discomfort due to the bitter taste unique to amino acids upon administration, and granules are uncomfortable in the mouth.

In general, in order to satisfy the requirements such as ensuring the uniformity of the contents and improving the solubility, the granules are often finely pulverized and used. Particularly, in the case of the solid preparation containing the particles of the three kinds of branched chain amino acids , The specific volume of the raw amino acid particles is reduced, and as a result, the volume per volume is large, resulting in a volume in the mouth which is difficult to swallow when taken. The same problem also occurs when formulating into a suspension.

For example, when the active ingredient is pulverized to 50 mu m or less in order to satisfy the requirements of ensuring the uniformity of the content and improving the solubility, the granules thus produced usually have a specific volume of 2.0 mL / g or more, and the amount of the branched chain amino acid is about 4 to 5 g, so that when the granule preparation is pulverized to 50 탆 or less, its volume becomes about 8 to 10 mL, which makes the volume in the mouth large and difficult to swallow very much .

In the case of formulation as a suspension, it is often packaged in a bottle or pouch for ease of taking and carrying. In the case of a pouch package, it is usually commercially available in a volume of 5 mL to 20 mL (specific gravity 0.8 to 1.2 g / mL) When three kinds of chain amino acids (isoleucine, leucine and valine) are undifferentiated, a fluid liquid preparation which can be easily eaten when it is taken is not made to a sufficient concentration, and it should be taken together with water when taking it. It may lead to side effects of bloating, and when a branched-chain amino acid preparation is administered to a liver disease patient who needs to control the water such as plural, the difficulty in controlling the moisture may cause the symptoms of the patient to deteriorate rather. Considering that pharmaceutical preparations containing branched chain amino acids are administered mainly to patients with cirrhosis who require long-term use, such difficulties in taking can cause the patients to stop taking the medication. Therefore, there is an urgent need to improve the dosage of the present granule currently in sale.

In conclusion, the three branched chain amino acids of isoleucine, leucine and valine are difficult to formulate because they have a strong bitter taste and distinctive odor of amino acid, and that they should not be large in dosage while having appropriate fluidity once. And has become a problem in commercial use.

Japanese Patent Application Laid-Open No. 2002-114674 Korean Patent Publication No. 10-2005-0095833 Korean Patent No. 10-0927254

The present invention relates to a liquid suspension composition comprising three branched chain amino acids of isoleucine, leucine and valine, and a process for producing the same, wherein the branched chain amino acid is obtained by mixing an aging agent, a pH adjusting agent and a sweetener, And to provide a liquid suspension composition which alleviates an unpleasant taste and feeling such as a bitter taste of the liquid.

Another object of the present invention is to solve the problems in the mass production process for commercial sale and to formulate three kinds of branched chain amino acids (isoleucine, leucine and valine) into a liquid suspension composition.

As a means for solving the above problems, the present invention provides an orally administrable liquid suspension composition comprising three kinds of branched chain amino acids, isoleucine, leucine and valine, an increasing agent, a pH adjusting agent and a pharmaceutically acceptable additive, Wherein the chain amino acid has a particle size of 35 mesh to 100 mesh.

In addition, in the liquid suspension composition, the thickening agent is selected from the group consisting of hydroxypropylcellulose, microcrystalline cellulose, carboxymethylcellulose sodium, and polyvinylpyrrolidone.

Further, in the liquid suspension composition, the pH adjusting agent is selected from the group consisting of citric acid and anhydrous sodium hydrogen phosphate.

Also, in the liquid suspension composition, a liquid suspension composition characterized by a pH range of 5 to 7 is provided.

In addition, in the above liquid suspension composition, hydroxypropyl cellulose may be added in an amount of 0.2 to 2.0% (w / w) based on the weight of the liquid suspension composition, 1.0 to 3.4% (w / w) of microcrystalline cellulose / carboxymethylcellulose sodium, ), And 2.0 to 4.0% (w / w) based on the weight of the liquid suspension composition of polyvinylpyrrolidone.

Finally, as a method for producing the liquid suspension composition, there is a method of dissolving or suspending a thickening agent selected from the group consisting of hydroxypropyl cellulose, microcrystalline cellulose carboxymethylcellulose sodium and polyvinylpyrrolidone in purified water at room temperature or low temperature ; Adding and dispersing one kind of amino acid selected from isoleucine, leucine and valine to the suspension solution; Adding the remaining two amino acids to the suspension solution at 50 DEG C or lower, raising and lowering the temperature to 70 to 90 DEG C; There is provided a method for preparing an orally administrable liquid suspension composition comprising three kinds of branched chain amino acids of isoleucine, leucine and valine, which comprises the step of adding a preservative, a sweetener and a pH controlling agent to the suspension solution and dissolving .

Since the pharmaceutical liquid suspension composition of the present invention can contain 4g to 5g of three kinds of branched chain amino acids in a volume of about 20mL, it is convenient to take to the patient for therapeutic purposes and provides a liquid suspension composition having a taste with minimal taste . In addition, since there is no process such as coating of the main component which is generally used for scum concealment, it can be easily manufactured at a low cost in a simplified manufacturing method.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a diagram showing a manufacturing process of a production method of the present invention. Fig.
FIG. 2 is a view comparing the aggregation phenomenon according to the manufacturing process.

The composition of the present invention may be used in the form of a liquid suspension containing at least one kind of additive commonly used in the manufacture of medicines such as an acidic agent, a sweetener, a flavoring agent, a binder, a defoamer, a dispersant, a suspending agent, a stabilizer, May be included in an amount suitable for the preparation of the composition.

Branched chain amino acids

The branched chain amino acids contained in the pharmaceutical liquid suspension composition of the present invention include isoleucine, leucine and valine, which are conventionally used in pharmaceuticals and foods. BACKGROUND ART [0002] It has been conventionally known that branched chain amino acids composed of three kinds of amino acids, isoleucine, leucine and valine play an important role as an energy source during exercise and increase the protein. Thus, various pharmaceutical substances containing branched chain amino acids, Have been developed and released.

However, in general, pharmaceuticals and foods containing branched chain amino acids have a unique bitter taste and smell originating from branched chain amino acids, and since the dosage is one dose larger than those of other medicines, foods and the like, It is hard to say that the sense is so good.

On the other hand, the amino acid can be any of an L-isomer, a D-isomer and a DL-isomer, preferably an L-isomer or a DL-isomer, and more preferably an L-isomer. The amino acid can be used in the form of a salt as well as a vitreous body. In the present invention, the amino acid is a concept including both a vitreous body and a salt. Examples of the salt include an acid addition salt and a salt with a base, and it is preferable to select a salt which is acceptable as a medicine of amino acid.

Examples of the acid which forms a pharmaceutically acceptable salt in addition to an amino acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid and phosphoric acid; And organic acids such as acetic acid, lactic acid, citric acid, tartaric acid, maleic acid, fumaric acid, and monomethylsulfuric acid. Examples of the base which forms a salt which is acceptable as a medicine of an amino acid include inorganic bases such as hydroxides or carbonates of metals such as sodium, potassium and calcium, and ammonia; And organic bases such as ethylenediamine, propylenediamine, ethanolamine, monoalkylethanolamine, dialkylethanolamine, diethanolamine, triethanolamine and the like.

The pharmaceutical liquid suspension compositions of the present invention contain three branched amino acids of isoleucine, leucine and valine, preferably in the range of 19% to 21% (w / w) relative to the weight of the pharmaceutical liquid suspension composition.

Incrementer

The pharmaceutical composition of the present invention may contain an increasing agent. Cellulose derivatives such as methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate and the like: starches such as corn starch and wheat starch: synthetic such as polyvinylpyrrolidone, polyvinyl alcohol and acrylic acid polymers Polymers such as natural polymers such as agar, xanthan gum, gum arabic and gelatin, microcrystalline cellulose, cellulose polymer, microcrystalline cellulose, carboxymethylcellulose sodium and the like. On the other hand, according to the study by the present inventors, it was unexpectedly found that the quality of the present solution was not constant depending on the combination of the thickeners. Particularly, as the thickener, polyvinylpyrrolidone, microcrystalline cellulose, carboxymethylcellulose sodium, Hydroxypropylcellulose was used in combination, it was found that the suspension state was excellent. The content of the thickening agent may be within a range in which a conventional liquid suspension composition can be prepared. Preferably, hydroxypropylcellulose is added in an amount of 0.2 to 2.0% (w / w) based on the weight of the liquid suspension composition, microcrystalline cellulose / sodium carboxymethylcellulose (W / w) based on the weight of the liquid suspension composition and 2.0 to 4.0% (w / w) based on the weight of the liquid suspension composition of polyvinyl pyrrolidone.

pH Modulator

The pharmaceutical composition of the present invention may contain a pH adjusting agent. The 9th revision of the Korean Pharmacopoeia discloses a process for preparing disodium hydrogenphosphate citrate buffer which can control pH. Although not limited thereto, a pH adjusting agent such as citric acid and anhydrous sodium hydrogen phosphate is appropriately used to adjust the pH to the range of pH 3.0 to pH 9.0, preferably pH 4.0 to pH 8.0, more preferably pH 5.0 to pH 7. 0 < / RTI >

The three branched-chain amino acids of the present invention show a stable tendency at around pH 5.0 to 7.0, and the bitter taste or unpleasant taste is minimized in the same range.

Acidic

Any acidic agent that can be used is acceptable as long as it can be used in the production of pharmaceuticals. However, ascorbic acid, citric acid (citric acid) and malic acid are preferable from the viewpoint of improving flavor and decreasing bitter taste. There is no particular limitation on the amount of acid to be added, and it can be used alone in an amino acid mixture and may be added together with other additives. Examples of the flavor agent that can be used include an odor improving agent such as apple or strawberry flavor.

Sweetener

The pharmaceutical composition of the present invention may contain a sweetening agent. Examples of the sweetening agent include sugar, glucose, maltose, oligosaccharide, galactose, starch, sorbitol, maltitol, phytonutrients, xylitol, erythritol, hydrogenated starch syrup, mannitol, trehalose, aspartame, acesulfam salt, sucralose, saccharin salt, And may be one or more high sweetening sweeteners selected from the group consisting of tartaric acid, tartaric acid, tartaric acid, neomycin, martin, tomutin mixture, cyclamate salt, tau martin, nahan and extract, licorice extract, stevioside, enzyme treated stevioside, neohesperidin and monelin.

Defoamer

As the antifoaming agent, antifoaming agents such as myristic acid, palmitic acid, simethicone, and silicone antifoaming agents can be appropriately selected from those generally known and the amount to be used may vary depending on the composition of the active ingredient.

Preservative

The liquid suspension compositions of the present invention may contain preservatives commonly used in liquid preparations for safety reasons. Preservatives that can be used include sorbic acid and its salts, benzoic acid and its salts, and p-hydroxybenzoic acid and salts thereof.

Spices

The pharmaceutical compositions of the present invention may also contain flavoring agents. Since the pharmaceutical composition of the present invention is a product to be taken through the oral cavity, it is necessary to add an appropriate flavor. The fragrance may be a natural fragrance, an artificial fragrance or a mixture thereof. Natural spices can be plant leaves, flowers, extracts from fruits and the like, vegetable oils and the like. The vegetable oils may be selected from the group consisting of spearmint oil, cinnamon oil, peppermint oil, lemon oil, clove oil, bay oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil and almond oil. Artificial flavors include artificial synthetic fruit flavors such as lemon, orange, grape, lime and strawberry, and artificial synthetic flavors such as vanilla, chocolate, coffee, cocoa, pine leaf, ginseng, red ginseng and citrus.

Pigment

The pharmaceutical composition of the present invention may contain a pigment suitable for the product. The pigment may be appropriately adjusted in its content as required, and may be added in an amount of 0.1 to 1.0% by weight (w / w) based on the weight of the pharmaceutical liquid suspension composition. The pigment may be a natural or synthetic pigment.

Refreshing agent

The pharmaceutical composition of the present invention may further comprise a refreshing agent. The refreshing agent may be, for example, but is not limited to, l-menthol, WS3, WS23 or quat-t-el. The refreshing agent can appropriately control the content thereof, if necessary, and may be generally added in an amount of 10 wt% (w / w) or less based on the total weight of the pharmaceutical composition.

Bad breath remover

The pharmaceutical composition of the present invention may further include a bad breath removing agent for alleviating the oral odor. The bad breath removing agent may be a metal salt. The metal salt may be, for example, one or more components selected from the group consisting of metal salts of chlorite, capper gluconate, zinc chloride, zinc citrate and zinc gluconate. Another example is an extract of green tea, red ginseng extract, green tea extract, seaweed extract, herbal extract, grapefruit extract, apple extract, time oil, thymol, antibiotic, geraniol, carbachol, citral, hinokitiol, Eucalyptol, catechol, methyl salicylate, and hydrogen peroxide. Such at least one bad breath remover component may be used with the at least one metal salt or independently.

Hereinafter, the method for preparing the composition of the present invention will be described in detail with reference to the following Comparative Examples and Examples, but the scope of the present invention is not limited thereto.

Viscosity measurement:

About 40 mL of the pharmaceutical liquid suspension was placed in a 50 mL centrifuge tube, about 3 cm in inner diameter, and the viscosity was measured using a No. 62 spindle. (BROOKFIELD, model: DV-2 + Pro, USA, measurement method: cup and bob, measurement temperature: room temperature)

Granular classification :

Shaking and classification were carried out for 5 minutes using a standard (TESTING SIEVE, Cheonggye Commercial Company, Korea) and a sieve shaker (Model: CG-211-8, Korea) , And the powder remaining on each of the standard nets and the pan was collected and used. In mass production, manual classification was carried out using separate equipment.

bitter  Rating Score:

The average value of 10 persons aged 25 to 40 years was calculated for the following items.

1: No bitter taste 2: Almost no bitter taste

3: Bitter taste is common 4: Bitter taste is slightly unpleasant

5: Very bitter and very unpleasant

However,

The average value of 10 persons aged 25 to 40 years was calculated for the following items.

1: No foreign object 2: Almost no foreign object

3: A foreign object is common 4: A foreign object is slightly unpleasant

5: Very unpleasant due to strong foreign body

Definition of temperature (Korean Pharmacopoeia 9 revision  Quoting the axiom)

1. Standard temperature is 20 ℃. 2. Normal temperature is 15 ℃ ~ 25 ℃.

3. At room temperature of 1 ~ 30 ℃ 4. At room temperature of 30 ~ 40 ℃

Branched chain amino acids  contain Of the pharmaceutical composition  Produce

Comparative Example 1 :

200 mg of hydroxypropylcellulose, 200 mg of polyvinylpyrrolidone and 200 mg of microcrystalline and carboxymethylcellulose sodium were evenly dispersed in a mixture of 10 g of purified water and 4.8 g of D-sorbitol, and then 3 kinds of branched chain amino acids ( Isoleucine, 1,904 mg of L-leucine and 1,144 mg of L-valine) were added and stirred, and the mixture was heated and maintained at 70 to 90 ° C for 1 hour. Then, 1.6 mg of methyl paraxybenzoate and 0.4 mg Followed by the addition of 120 mg of citric acid and 400 mg of anhydrous sodium hydrogenphosphate to adjust the pH, followed by cooling and drawing with purified water to obtain 20 g of a branched chain amino acid suspension.

The three kinds of branched chain amino acids used in this study were commercial raw materials without any classification. As a result, three kinds of branched chain amino acids were mixed with coarse particles of 18mesh or more and fine particles of 100mesh or less.

The suspension produced through the above process undergoes phase separation and has an unpleasant bitter taste and odor peculiar to amino acids.

Comparative Example  And Example

Comparative Example 2  To 19 , Example 1  To 3

The components other than the three kinds of branched chain amino acids were prepared in the same manner as in Comparative Example 1 and the liquid suspension compositions were prepared in the same manner as in Comparative Example 1 except that the particle size distributions of the three kinds of branched chain amino acids as the main components were measured as TESTING SIEVE, Korea) to prepare a liquid suspension composition for each particle size. In the case of Comparative Example 1, the three main components were used as raw materials sold commercially without separate classification, and in Comparative Examples 2 to 8, only L-isoleucine was classified. In Comparative Examples 9 to 12, L-leucine And in the case of Comparative Examples 13 to 17, L-valine was produced by classification.

In the case of Comparative Example 18, Comparative Example 19, and Examples 1 to 3, the three kinds of branched chain amino acids were separately classified into a ratio of L-isoleucine: L-leucine: L-valine = 1: 2: 1.2 (two decimal places rounded) 20 g of each of the pharmaceutical liquid suspensions was prepared. Suspension, viscosity, bitterness and foreign body sensation of the prepared liquid were evaluated according to the above evaluation criteria.

Surprisingly, as can be seen from Table 1, the three kinds of branched chain amino acids were prepared by using the conventional branched-chain amino acid three kinds of suspension technology (Examples 1 to 3) using a particle size of 35 mesh to 100 mesh The present inventors have found that a pharmaceutical suspending agent for medicines suitable for taking medicines can be prepared by improving the bitterness of the branched chain amino acid itself and improving the foreign body sensation at the same time. It was confirmed that the viscosity at this time was 120 cp to 400 cp.

Example 4  To 17

The liquid suspension composition was prepared in the same process as in Comparative Example 1 (prescription is shown in Table 2), and the particle size of the three kinds of branched chain amino acids was classified using a standard mesh (TESTING SIEVE, Cheonggye Sangyo KK, Korea) Three kinds of branched chain amino acids remaining in 100mesh were prepared to prepare a liquid suspension composition. In order to prepare branched chain amino acid suspensions, as shown in Table 2, one of the groups selected from the group of hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose and microcrystalline cellulose and carboxymethylcellulose sodium Or two or more thickeners were used. Unexpectedly, the quality of the suspension was not constant depending on the combination of thickeners, and as a result, it was found that the suspension state was excellent when PVPK30, AvicelRC591 and HPC-L were used in combination as thickening agents.

Example  18 to 34

The liquid suspension composition was prepared by the same procedure as in Comparative Example 1 (prescription is shown in Table 3), and the particle size of the three branched amino acids was classified using 35 mesh Three kinds of branched chain amino acids remaining in 100mesh were prepared to prepare a liquid suspension composition. The PVPK30, AvicelRC591 and HPC-L selected in Table 2 were prepared as described in Table 3 below to find the appropriate constituent ratio and the suspended state was evaluated.

From the results of a close examination of the test results, it can be seen from Table 3 that PVPK30 as a thickener is 2.0 to 4.0% (w / w) based on the weight of the pharmaceutical liquid suspension, 1.0 to 3.4% (w / w) of AvicelRC591 based on the weight of the pharmaceutical liquid suspension, w) and HPC-L in combination with 0.2 to 2.0% (w / w) based on the weight of the pharmaceutical liquid suspension composition.

Comparative Example 20 ~ Comparative Example 23 , Example 35

For commercial use, mass production at the factory is essential, and the scale of production may be subject to separate scale requirements relating to the circumstances of the manufacturer or the place of purchase or permission.

In general, scale up from laboratory scale to mass production for commercial sale may result in unexpected or unexpected process problems in small laboratory scale.

In the scale-up process for mass production, which is the final step of the present invention, hydroxypropylcellulose, which has been dissolved at room temperature or at low temperature, is heated to a temperature for sterilization of the pharmaceutical liquid suspension composition, There was a phenomenon of re-accumulation. (Figure 2 (a))

When the pharmaceutical liquid suspension in which the aggregation occurs is commercialized as it is, it is difficult to maintain the uniform viscosity of the liquid suspension composition, 2) defective properties, 3) foreign body sensation when taking the product, 4) (Curing, sedimentation, phase separation). Therefore, it is not possible to produce a pharmaceutical liquid suspension composition having excellent commercial properties, and thus a commercially available mass production process has been sought.

As shown in the following Table 4, pharmaceutical liquid suspensions containing three kinds of branched chain amino acids were prepared and compared in the same processes as Comparative Examples 20 to 23 and Example 35 described below, Respectively. In Comparative Examples 20 to 23, hydroxypropyl cellulose, which had been dissolved at room temperature or at low temperature, was reunited during the process due to the specific property of the material itself.

Although the results of Comparative Examples 20 to 23 and the known fact that the hydroxypropylcellulose was aggregated upon heating at high temperature were not at all unexpected, the production process described in Example 35 below solves the problem, A commercially available product can be obtained. 1 to illustrate the manufacturing process of Example 35, and the aggregation phenomenon of hydroxypropylcellulose is shown in FIG. 2 (a), and the preparation of the pharmaceutical liquid suspension composition of Example 35 The process is shown in Figure 2 (b).

The manufacturing methods of Comparative Examples 20 to 23 and Example 35 are shown below. Three kinds of branched chain amino acids used herein were raw materials classified into 35 mesh to 100 mesh. The scope of the present invention is not limited to the range of Comparative Examples and Examples, and a similar effect can be obtained even when a relatively small amount of particles larger than 35 mesh or smaller than 100 mesh are mixed. However, it is most preferable to use the amino acid having a particle size ranging from 35 mesh to 100 mesh as described above.

Comparative Example 20

Production process 1 of Table 4

72 kg of D-sorbitol and 130 kg of purified water having a temperature of 50 ° C or higher which had been previously warmed were added to a cleaned preparation tank, and 4 kg of hydroxypropylcellulose, 8 kg of polyvinylpyrrolidone and 9 kg of microcrystalline cellulose carboxymethylcellulose sodium were added thereto while stirring and stirred . A lump occurred in the preparation tank. Addition of three kinds of branched chain amino acids (L-isoleucine 14.280 kg, 28.560 kg and 17.160 kg) does not disintegrate the agglomerated lumps and the process can no longer be carried out. The heat-up process is closely related to agglomeration, but it is a process that must be done due to the industrial nature to be manufactured under sterile conditions.

Comparative Example 21

Production process 1 of Table 4

To the cleaned preparation tank, 130 kg of purified water at room temperature or low temperature and 72 kg of D-sorbitol are added, and while stirring, 4 kg of hydroxypropyl cellulose, 8 kg of polyvinyl pyrrolidone and 9 kg of microcrystalline cellulose carboxymethyl cellulose sodium are added and stirred.

Production process 2 of Table 4

Set the temperature to 90 ± 5 ℃ and raise the temperature. A lump phenomenon starts to occur at a temperature in the vicinity of 45 to 50 DEG C of the liquid preparation in the preparation tank. Addition of three kinds of branched chain amino acids (L-isoleucine 14.280 kg, 28.560 kg and 17.160 kg) does not disintegrate the agglomerated lumps and the process can no longer be carried out.

Comparative Example 22

Production process 1 of Table 4

130 kg of purified water at room temperature or low temperature and 72 kg of D-sorbitol are added to the prepared preparation tank, and 4 kg of hydroxypropyl cellulose and 9 kg of microcrystalline cellulose · carboxymethyl cellulose sodium are added thereto while stirring.

Production process 2 of Table 4

Set the temperature to 90 ± 5 ℃ and raise the temperature.

Production process 3 of Table 4

8 kg of polyvinylpyrrolidone is added to the above preparation tank and stirred. (Around 40 DEG C) The lump phenomenon starts to occur at a temperature of 45 to 50 DEG C in the preparation liquid in the preparation tank. Addition of three kinds of branched chain amino acids (L-isoleucine 14.280 kg, 28.560 kg and 17.160 kg) does not disintegrate the agglomerated lumps and the process can no longer be carried out.

Comparative Example 23

Production process 1 of Table 4

130 kg of purified water at room temperature or low temperature and 72 kg of D-sorbitol are added to the prepared preparation tank, and 4 kg of hydroxypropyl cellulose and 9 kg of microcrystalline cellulose · carboxymethyl cellulose sodium are added thereto while stirring.

Production process 2 of Table 4

One of the branched chain amino acids is added to the above preparation tank and stirred.

Production process 3 of Table 4

Set the temperature to 90 ± 5 ℃ and raise the temperature.

Production process 4 of Table 4

Two kinds of branched chain amino acids are added in the vicinity of the temperature of the preparation liquid in the above preparation tank at 50 to 70 ° C and stirred. A lump phenomenon starts to occur at a temperature of the preparation liquid in the preparation tank near 70 to 90 占 폚.

Example 35

Production process 1 of Table 4

To the cleaned preparation tank, 130 kg of purified water at room temperature or low temperature and 72 kg of D-sorbitol are added, and while stirring, 4 kg of hydroxypropyl cellulose, 8 kg of polyvinyl pyrrolidone and 9 kg of microcrystalline cellulose carboxymethyl cellulose sodium are added and stirred.

Production process 2 of Table 4

One branching amino acid (L-isoleucine) is added to the preparation tank and stirred.

Production process 3 of Table 4

Two kinds of branched chain amino acids (L-leucine, L-valine) are added to the above preparation tank and stirred. (50 DEG C or less)

Production process 4 of Table 4

Set the temperature to 90 ± 5 ℃ and raise the temperature. Even if the temperature of the preparation liquid in the preparation tank is raised up to 90 DEG C, no aggregation phenomenon occurs. When the order of the three kinds of branched chain amino acids to be added to the above-mentioned production steps 2 and 3 is reversed, the same pharmaceutical phase liquid pharmaceutical suspension composition can be obtained.

The present invention relates to a pharmaceutical composition containing a branched chain amino acid isoleucine, leucine and valine as an active ingredient with controlled particle size distribution as described in the above embodiments, and a combination of a specific thickening agent or a specific thickening agent, Sweeteners, and pharmaceutical liquid suspension compositions in a volume suitable for the patient to take, while concealing bitter and foreign sensations by controlling a certain range of pH. The present invention also provides a preferred process for the preparation of pharmaceutical liquid suspension compositions which can be commercialized under sterile conditions by solving the buildup of thickening agents that occur in mass production for commercial use.

The pharmaceutical composition of the present invention and the method for producing the same can constitute a pharmaceutical liquid suspension composition having improved taste and volume which is easy to be administered to patients in the form of a liquid suspension composition containing various amino acids having a bitterness , And can be produced on an industrial scale.

Claims (6)

Three branched chain amino acids such as isoleucine, leucine and valine; Increasing agent; A pH control agent and a pharmaceutically acceptable excipient, wherein the branched chain amino acid has a particle size of 35 mesh to 100 mesh,
Wherein the pH of said composition is between 5 and 7,
Wherein said composition comprises at least 4 g of said three branched chain amino acids in a volume of 20 ml,
A thickening agent selected from the group consisting of hydroxypropylcellulose, microcrystalline cellulose, carboxymethylcellulose sodium, and polyvinylpyrrolidone. delete The liquid suspension composition according to claim 1, wherein the pH adjusting agent is selected from the group consisting of citric acid and anhydrous sodium hydrogen phosphate. delete 2. The liquid suspension composition according to claim 1, wherein the hydroxypropylcellulose is 0.2 to 2.0% (w / w) based on the weight of the liquid suspension composition, 1.0 to 3.4% (w / w) Vinylpyrrolidone in an amount of 2.0 to 4.0% (w / w) based on the weight of the liquid suspension composition. Dissolving or suspending an enhancer selected from the group consisting of hydroxypropylcellulose, microcrystalline cellulose, carboxymethylcellulose sodium and polyvinylpyrrolidone in purified water at room temperature or low temperature;
Adding and dispersing one kind of amino acid selected from isoleucine, leucine and valine to the suspension solution;
Adding the remaining two amino acids to the suspension solution at 50 DEG C or lower, raising and lowering the temperature to 70 to 90 DEG C;
Adding a preservative, a sweetener, and a pH adjusting agent to the suspension solution and dissolving
Or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The method of claim 1,

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