JP2003221329A - Dry syrup containing branched amino acids - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a dry syrup excellent in suspensibility, whose taste and comfortableness on swallowing are improved, which can maintain an excellent suspensibility when suspended, and which contains three branched amino acids such as isoleucine, leucine, and valine as the effective ingredients. <P>SOLUTION: The dry syrup for medical use contains only the three branched amino acids such as isoleucine, leucine, and valine as the main agents, at least one suspending agent selected from the group consisting of xanthan gum, polyvinyl alcohol, cellulose derivatives, gelatin, agar, tragacanth powder, sodium alginate, and a carboxyvinyl polymer, and surface active agents. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical dry syrup containing isoleucine, leucine and valine as active ingredients. The dry syrup agent in the present invention means a dry solid agent which is used by dissolving or suspending at the time of use, among the syrup agents described in the Japanese Pharmacopoeia.

[0002]

2. Description of the Prior Art Isoleucine, leucine and valine
A pharmaceutical preparation containing a branched chain amino acid as an active ingredient is an effective therapeutic agent for cirrhosis. However, the formulation currently on the market has a drawback that it is difficult to take because the dose is about 5 g in terms of granules, which is a remarkably large amount as compared with a general formulation and the bitterness is strong.

[0003] On the other hand, it is also known to use a drug that is administered at a large dose once as a suspending agent that does not require water at the time of administration and that is easy to pass through the throat. However, in the case of commercially available suspensions, the suspension concentration of the active ingredient is about 10% or less due to technical problems, etc., except for enteral nutrients containing some protein degradation products. It is usually used (sucralfate, aluminum hydroxide / magnesium hydroxide).

The present inventors provide a pharmaceutical suspending agent which contains particles of three types of branched chain amino acids of isoleucine, leucine and valine as an active ingredient in a high suspension concentration and is excellent in stability and easy to take. Therefore, the viscosity of the suspending agent is 3
A pharmaceutical suspending agent characterized by having an HLB of ˜15,000 mPa · sec and an HLB of 3 to 40 was proposed. But,
Since the suspension is a liquid, it has problems such as being heavy, bulky, not suitable for transportation and storage, poor in chemical stability, and difficult to maintain suspension.

Since the dry syrup which is suspended or dissolved at the time of use is a dry solid agent, it has advantages such as being lightweight and compact, excellent in transportation and storage, excellent in chemical stability, and needing to be suspended only at the time of use. . But isoleucine,
In the case of a pharmaceutical preparation containing only particles of three kinds of branched chain amino acids consisting of leucine and valine as an active ingredient, it is very difficult to suspend because the branched chain amino acids have water repellency.

[0006] In addition, it is necessary to reduce the amount of suspended water because many patients have a limited amount of water, although the active ingredient for a single dose is 4 g, which is very large compared to the usual preparations. The concentration of 10% is close to the upper limit of the concentration of usual suspending agents
(W / V) is exceeded. At this concentration, the suspension will precipitate, making it difficult to maintain dispersibility. Even if the suspension concentration can be increased, the viscosity of the suspension will increase and the fluidity will decrease, making it difficult to take.

Furthermore, it is desirable to avoid the use of commonly used saccharides, because they cause coloration due to the Maillard reaction with amino acids. For the reasons described above, no dry syrup preparation containing particles of three types of branched chain amino acids of isoleucine, leucine and valine as active ingredients in high concentration has been developed so far.

[0008]

The object of the present invention is to provide three types of branched chain amino acids, isoleucine, leucine and valine, which have improved flavor and drinking comfort and can maintain good suspendability when suspended. An object of the present invention is to provide a dry syrup preparation containing particles as an active ingredient and having an excellent suspending property.

[0009]

[Means for Solving the Problems] In order to solve the above problems, the inventors of the present invention have made extensive studies, and as a result, suspended the active ingredient particles of three kinds of branched chain amino acids of isoleucine, leucine and valine. It was found that the above problems can be solved by preparing a dry syrup preparation in which an agent and a surfactant coexist, and the present invention has been completed.

In the present invention, the basic composition is a mixture of particles of three types of branched chain amino acids, which are the main drug, isoleucine, leucine and valine, a suspending agent and a surfactant, which are suspended at the time of use. The present invention relates to a pharmaceutical dry syrup preparation which is a solid preparation to be taken as an oral administration, and further includes the following respective inventions.

(1) Isoleucine, leucine and valine are used as the main ingredients of only three kinds of branched chain amino acids, which are selected from the group consisting of xanthan gum, polyvinyl alcohol, cellulose derivatives, gelatin, agar, powdered tragacanth, sodium alginate and carboxyvinyl polymer. A pharmaceutical dry syrup containing at least one suspending agent and a surfactant.

(2) The cellulose derivative as the suspending agent is at least one selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, carmellose sodium, and crystalline cellulose. The dry syrup preparation for medical use according to (1), wherein

(3) The surfactant is polysorbate 20, polysorbate 60, polysorbate 80, sorbitan fatty acid ester, polyoxy hydrogenated castor oil 20,
The dry syrup preparation for medical use according to (1) or (2), which is at least one selected from the group consisting of polyoxy hydrogenated castor oil 60, sodium lauryl sulfate and polyoxyl stearate 40.

(4) The suspending agent is xanthan gum and / or polyvinyl alcohol, and the surfactant is polysorbate 80 (1) to (3).
The pharmaceutical dry syrup according to any one of 1.

(5) The suspension concentration of the branched chain amino acid is 1
1-70% (W / V) (1)-
The dry syrup preparation for medical use according to any one of (4).

(6) The suspension concentration of the branched chain amino acid is 1
5 to 60% (W / V) (1) to
The dry syrup preparation for medical use according to any one of (4).

(7) The dry syrup preparation for medicine according to any one of (1) to (6), which contains isoleucine particles and leucine particles each having a particle size adjusted to 20 to 700 μm.

(8) The pharmaceutical dry syrup preparation according to any one of (1) to (6), which contains isoleucine particles and leucine particles each having a particle size adjusted to 50 to 500 μm.

(9) The mass ratio of the above-mentioned three kinds of branched chain amino acids is isoleucine / leucine / valine = 1 / 1.9 to
The pharmaceutical dry syrup preparation according to any one of (1) to (8), which is 2.2 / 1.1 to 1.3.

(10) Containing at least one selected from sweeteners, acidulants, aromatics and colorants (1) to
The dry syrup preparation for medical use according to any one of (9).

(11) The sweetener is aspartame,
At least 1 selected from artificial sweeteners such as saccharin and sugar alcohols such as erythritol and mannitol
The dry syrup preparation for medical use according to any one of (1) to (10), which is a seed.

(12) The pharmaceutical dry syrup according to any one of (1) to (11), wherein the sour agent is at least one selected from citric acid, malic acid, acetic acid, tartaric acid, ascorbic acid and the like. Agent.

[0023]

BEST MODE FOR CARRYING OUT THE INVENTION The dry syrup preparation of the present invention is a dry solid preparation of the syrup preparations described in the Japanese Pharmacopoeia, which is dissolved or suspended before use.

The active ingredient (main drug) in the dry syrup preparation of the present invention is three kinds of branched chain amino acids consisting of isoleucine, leucine and valine. Isoleucine is a particle which is generally produced by a fermentation method and has a particle size of 1 mm or less, which satisfies the Japanese Pharmacopoeia standard, but is not limited thereto. It is preferably adjusted to a particle size of 20 to 700 μm, more preferably 50 to 500 μm.

Leucine is a particle having a particle size of 1 mm or less, which is generally produced by a fermentation method or an extraction method, and satisfies the standard of the Japanese Pharmacopoeia, but is not limited thereto. It is preferably adjusted to a particle size of 20 to 700 μm, more preferably 50 to 500 μm. The bitterness of both amino acids can be reduced by adjusting the particle size of isoleucine and leucine within the above range.

As valine, particles which are generally produced by a fermentation method or a synthetic method and have a particle size of 1 mm or less and which satisfy the Japanese Pharmacopoeia standard are used, but the valine is not limited thereto. . There is no particular restriction on the grain size of valine as long as it meets the standards of the pharmacopoeia.

There are no particular restrictions on the method of adjusting the particle size of the three types of branched chain amino acid particles consisting of isoleucine, leucine and valine, and the usual grinding method is employed. As a crusher that can be used for crushing, an impact type (high-speed rotation type) crusher such as a hammer mill or a tumbler type (medium type) such as a ball mill
A fluid type (air flow type) pulverizer such as a pulverizer and a jet mill may be used.

The mixing ratio of the three kinds of branched chain amino acids consisting of isoleucine, leucine and valine in the present invention is a mass ratio, isoleucine / leucine / valine = 1 / 1.9.
~ 2.2 / 1.1-1.3 is suitable.

In selecting the suspending agent used in the dry syrup preparation of the present invention, attention should be paid to the following points. First, since a branched chain amino acid having water repellency is dispersed at a high concentration of 10% or more, a suspending agent having a high suspending ability is required. Secondly, it is necessary to select a suspending agent that does not cause coloration due to reaction with a branched chain amino acid.

The suspending agent used in the dry syrup of the present invention is at least one selected from the group consisting of xanthan gum, polyvinyl alcohol, cellulose derivatives, gelatin, agar, tragacanth powder, sodium alginate and carboxyvinyl polymer. It is preferable.

Sucrose fatty acid ester, which is often used as a suspending agent in many dry syrups, gives a good suspended state of the above-mentioned branched chain amino acid particles, but due to the fact that it is a saccharide, It is thought to cause a Maillard reaction and causes coloration during storage.

Further, as a suspending agent often used,
There is crystalline cellulose-carmellose sodium. Maximum oral use of this suspension is 300 per day
mg (Pharmaceutical Additives 2000 edition). Since the pharmaceutical preparation of the present invention is administered three times a day, the limit of the single use amount of the present suspension is up to 100 mg, but this amount is insufficient in suspending property. When crystalline cellulose / carmellose sodium is formulated within the range of the maximum use precedent, it is effective to use methyl cellulose and the like together, but coloration occurs during storage and the stability is not sufficient.

Further, the commonly used polyvinylpyrrolidone has a very poor suspension property with respect to the above-mentioned three kinds of branched chain amino acids. Similarly, gum arabic and carrageenan cause coloration on storage.

The cellulose derivative used in the dry syrup of the present invention is preferably hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, carmellose sodium, crystalline cellulose and the like.

Since the branched chain amino acid in the dry syrup preparation of the present invention has water repellency, a surfactant is effective for improving wettability. As the surfactant, polysorbate 20, polysorbate 60, polysorbate 8
0, sorbitan fatty acid ester, polyoxy hydrogenated castor oil 20, polyoxy hydrogenated castor oil 60, sodium lauryl sulfate and polyoxyl 40 stearate.

The suspension concentration of amino acid particles when the dry syrup preparation of the present invention is suspended is 11 to 70% (W / V).
It is preferably 15 to 60% (W / V).

The dry syrup agent of the present invention is a high speed stirring granulator, a fluidized bed granulator, a planetary mixer, a dry compression granulator, a crushing granulator, an extrusion granulator, a tumbling granulator, a sprayer. It can be produced by using any of the dry granulator and coating granulator, and as long as a uniform granulated product can be obtained, regardless of the granulation mechanism or model, a high-speed stirring granulator, extrusion Granulators are preferred.

The extrusion granulation method is a method of granulating by extruding a powder having plasticity from a screen having a large number of holes, a pre-extrusion granulator, a disc pelleter granulator, a ring die. Type granulators, basket type granulators, oscillating type granulators, cylinder type granulators and the like are used.

The high-speed agitation granulation method is a method in which water or a binder solution is added to or sprayed on powder, and shearing, rolling, and consolidation are performed by the rotation of a stirring blade to perform granulation.
A horizontal stirred granulator is used. The fluidized bed granulation method is a granulation method performed by spraying water or a binder liquid while flowing the powder, and aggregating the powder, a fluidized bed granulator, a stirring fluidized bed granulator, A rolling fluidized bed type granulator and a stirring rolling fluidized bed type granulator are used.

The dry pressing granulation method is a method of compressing and molding powder without using water or a binder liquid, and includes roll press, briquetting machine, single-shot tableting machine, rotary tableting machine. Is used. The rolling granulation method is a method of rolling powder to granulate, and a drum type granulator, a plate type granulator, a vibrating granulator, and a disc rotary granulator are used.

A binder may be used in the production of the dry syrup preparation of the present invention. As a binder,
Any starch that can be used for medicinal purposes such as corn starch, wheat starch and the like, synthetic polymers such as acrylic acid polymers and the like that meet the Japanese Pharmacopoeia or pharmaceutical additive standards can be used without particular limitation. . Also, the amount used may be in a range that allows normal granulation.

The dry syrup preparation of the present invention includes a sweetener,
Sour agents, fragrances, colorants and the like can be added. The use of sugars such as sucrose is 3 of isoleucine, leucine and valine.
It is desirable to avoid it because it causes coloration due to the Maillard reaction with certain amino acids. As sweeteners, aspartame, artificial sweeteners such as saccharin and sugar alcohols such as erythritol, mannitol, etc., citric acid, malic acid, acetic acid, tartaric acid, ascorbic acid, etc. as acidulants, menthol, peppermint, etc. as aromatic agents, colorants As such, food dyes such as Food Red No. 2 can be used.

[0043]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

The particle size of the branched chain amino acid used in the dry syrup preparation of each example can be measured as follows. Using a laser diffraction / scattering particle size distribution analyzer (LA-910, manufactured by Horiba, Ltd.), a proper amount of 2-propanol was put in a circulation tank, stirred, and circulated while being irradiated with ultrasonic waves, and then a blank measurement (at the time of measurement, Sound wave OFF).
Then, a proper amount of 2-propanol is put into the circulation tank, and the amino acid sample for measurement is put so that the transmittance becomes about 85%. The particles are circulated while stirring and irradiating with ultrasonic waves, and the particle size is measured after stopping the ultrasonic waves. The median diameter used the median diameter.
The particle size of the branched chain amino acid used in each Example and Comparative Example is shown in Table 1, and the formulation is shown in Table 2.

[0045]

[Table 1]

[0046]

[Table 2]

Example 1 The specified amounts of the components of Example 1 shown in Table 2 above were weighed and the components other than polysorbate 80 were uniformly mixed with a stirring granulator (Fukae Industry Co., Ltd., High Speed Mixer). Then, the thing which melt | dissolved the polysorbate 80 in distilled water was added, and it granulated, it dried using the tray dryer and the granulated material was obtained. After sieving with a 1400 μm sieve, the sieved product was forcedly sieved with a 1400 μm sieve and thoroughly mixed with the sieved product to obtain a dry syrup preparation of the present invention.

Example 2 The specified amount of each component of Example 2 shown in Table 2 above was weighed out, and the components other than polysorbate 80 were uniformly mixed with a stirring granulator (Fukae Industry Co., Ltd., High Speed Mixer). Then, the thing which melt | dissolved the polysorbate 80 in distilled water was added, and it granulated, it dried using the tray dryer and the granulated material was obtained. After sieving with a 1400 μm sieve, the sieved product was forcedly sieved with a 1400 μm sieve and thoroughly mixed with the sieved product to obtain a dry syrup preparation of the present invention.

Comparative Example 1 The designated amounts of the respective components of Comparative Example 1 shown in Table 2 above were weighed and uniformly mixed with a stirring granulator (Fukae Kogyo KK, high speed mixer), and then distilled water was added. Then, granulation was performed and dried using a tray dryer to obtain a granulated product. 1400
After sieving with a μm sieve, the sieved product was forcedly sieved with a 1400 μm sieve and thoroughly mixed with the sieved product to obtain a dry syrup preparation of the present invention.

Comparative Example 2 The specified amounts of the components of Comparative Example 2 shown in Table 2 above were weighed and uniformly mixed with a stirring granulator (Fukae Kogyo Co., Ltd., High Speed Mixer), and then distilled water was added. Then, granulation was performed and dried using a tray dryer to obtain a granulated product. 1400
After sieving with a μm sieve, the sieved product was forcedly sieved with a 1400 μm sieve and thoroughly mixed with the sieved product to obtain a dry syrup preparation of the present invention.

Comparative Example 3 The specified amounts of the components of Comparative Example 3 shown in Table 2 above were weighed out, and the components other than polysorbate 80 were uniformly mixed with a stirring granulator (Fukae Kogyo Co., Ltd., High Speed Mixer). Then, the thing which melt | dissolved the polysorbate 80 in distilled water was added, and it granulated, it dried using the tray dryer and the granulated material was obtained. After sieving with a 1400 μm sieve, the sieved product was forcedly sieved with a 1400 μm sieve and thoroughly mixed with the sieved product to obtain a dry syrup preparation of the present invention.

Comparative Example 4 The designated amounts of the respective components of Comparative Example 4 shown in Table 2 above were weighed and uniformly mixed with a stirring granulator (Fukae Kogyo KK, high speed mixer), and then distilled water was added. Then, granulation was performed and dried using a tray dryer to obtain a granulated product. 1400
After sieving with a μm sieve, the sieved product was forcedly sieved with a 1400 μm sieve and thoroughly mixed with the sieved product to obtain a dry syrup preparation of the present invention.

Comparative Example 5 The specified amount of each component of Comparative Example 5 shown in Table 2 above was weighed and uniformly mixed with a stirring granulator (Fukae Kogyo Co., Ltd., High Speed Mixer), and then distilled water was added. Then, granulation was performed and dried using a tray dryer to obtain a granulated product. 1400
After sieving with a μm sieve, the sieved product was forcedly sieved with a 1400 μm sieve and thoroughly mixed with the sieved product to obtain a dry syrup preparation of the present invention.

Experimental Example 1 With respect to the dry syrup preparations (4 g of branched chain amino acid) obtained in the above Examples and Comparative Examples, sensory evaluation was carried out using 6 adult male panelists while ensuring blindness. The dry syrup is suspended in 20 ml of water and taken, and the suspended state, ease of administration, bitterness of the branched chain amino acid after administration and the residual taste of the branched chain amino acid (bitterness after 1 minute of administration) Was evaluated according to the following criteria.

[0055] ◎: Good or not at all ○: I do not care much △: Slightly annoying or slightly bitter ×: Difficult to drink or bitter

Experimental Example 2 The dry syrup agent (4 g of branched chain amino acid) obtained in the above Examples and Comparative Examples was air-tightly packaged in an aluminum laminate bag and stored at 40 ° C. for 4 weeks. It was observed with the naked eye. Colored state ◯: No coloration Δ: Slightly colored X: Colored, change in suspension property ○: No change Δ: Slightly reduced ×: Reduction Table 3 shows the results of Experimental Example 1 and Experimental Example 2 together.

[0057]

[Table 3]

As is clear from Tables 1 to 3, the dry syrup preparations of Examples 1 and 2 in which the suspending agent and the surfactant are used in combination are in good suspension and easy to take. However, while the other evaluation items also showed good results, the dry syrup preparations of Comparative Examples 1 and 2 in which no surfactant was used had an insufficient suspension state. In addition, polyvinylpyrrolidone (Comparative Example 3) had a very poor suspension property. In addition, a dry syrup formulation containing sucrose palmitate (Comparative Example 4) and crystalline cellulose / carmellose sodium (Comparative Example 5), which are commonly used suspending agents, was colored during storage. Furthermore, the dry syrup preparation using crystalline cellulose / carmellose sodium (Comparative Example 5) also showed a decrease in suspension property.

[0059]

From the above results, the pharmaceutical suspension prepared from the dry syrup containing only isoleucine, leucine and valine as the active ingredient provided by the present invention has a good taste and a pleasant throat, It is clear that the suspension and stability when turbid are also good.

Front page continuation (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/34 A61K 47/34 47/36 47/36 47/38 47/38 47/44 47/44 47/46 47 / 46 (72) Inventor Kunikazu No. 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa Ajinomoto Co., Inc. Pharmaceutical Research Laboratories (72) Inventor Haruo Orita 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa In-house Pharmaceutical Research Institute (72) Inventor Masahisa Ozaki 1-1 1-1 Kawasaki-ku, Kawasaki-shi, Kanagawa Ajinomoto Incorporated Pharmaceutical Research Center F-term (reference) 4C076 AA22 AA29 BB01 CC16 CC21 DD01 DD46 DD61 EE06F EE08F EE23F EE30F EE31F EE32F EE36F EE41 EE42F EE53 EE58F FF52 4C206 AA02 FA53 MA03 MA05 MA10 MA28 MA29 MA43 MA63 MA72 NA09 ZA75 ZC21

Claims (9)

[Claims] 1. Three of isoleucine, leucine and valine.
Xanthan gum is the only active ingredient of branched-chain amino acids,
Polyvinyl alcohol, cellulose derivative, gelatin,
A medicinal dry syrup containing at least one suspending agent and a surfactant selected from the group consisting of agar, powdered tragacanth, sodium alginate and carboxyvinyl polymer. 2. The cellulose derivative as the suspending agent is hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, carmellose sodium,
The dry syrup preparation for medicine according to claim 1, which is at least one selected from the group consisting of crystalline cellulose. 3. The surfactant is polysorbate 2
At least one selected from the group consisting of 0, polysorbate 60, polysorbate 80, sorbitan fatty acid ester, polyoxy hydrogenated castor oil 20, polyoxy hydrogenated castor oil 60, sodium lauryl sulfate, and polyoxyl stearate 40. The pharmaceutical dry syrup preparation according to 1 or 2. 4. The pharmaceutical dry syrup according to any one of claims 1 to 3, wherein the suspending agent is xanthan gum and / or polyvinyl alcohol, and the surfactant is polysorbate 80. . 5. The suspension concentration of the branched chain amino acid is 11 to 11.
It is 70% (W / V), It is characterized by the above-mentioned.
The pharmaceutical dry syrup according to any one of 1. 6. The suspension concentration of the branched chain amino acid is 15 to
It is 60% (W / V), It is characterized by the above-mentioned.
The pharmaceutical dry syrup according to any one of 1. 7. The dry syrup preparation for medical use according to any one of claims 1 to 6, which contains isoleucine particles and leucine particles each having a particle size adjusted to 20 to 700 μm. 8. The dry syrup preparation for medical use according to any one of claims 1 to 6, which contains isoleucine particles and leucine particles having a particle size adjusted to 50 to 500 μm. 9. The mass ratio of the three types of branched chain amino acids is
Isoleucine / leucine / valine = 1 / 1.9 to 2.2
/1.1-1.3, The dry syrup preparation for medical use according to any one of claims 1 to 8.