JP2534139B2 - Oral amino acid preparation for renal failure - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel oral amino acid preparation for renal failure.

Conventional technology and its problems During chronic renal failure, catabolism of body proteins is enhanced, resulting in metabolic disorders such as sugars, lipids, proteins and electrolytes. The therapeutic methods include drug therapy, dialysis therapy, kidney transplantation, etc., but dietary therapy is considered to be an extremely important therapeutic method with the recent progress in research on metabolic disorders during renal failure. That is, dietary therapy for patients with chronic renal insufficiency, which is considered to be a wasting syndrom, suppresses the increase in body protein catabolism by nutritional treatment and exerts a preventive therapeutic effect on the progression of renal insufficiency. Is expected to do.

The most common diet is a low-protein diet, which is a treatment that attempts to suppress the progression of renal failure by reducing the accumulation of nitrogen compounds (ureas), which are the final protein products. Is. However, patients prone to malnutrition (protein malnutrition) by protein restriction, Jiorudano (Giordano) [JLab.Clin.Med., 62 , 231
(1963)] proposes supplementation of essential amino acids in the above-mentioned low protein diet therapy in order to correct this drawback. This aims at supplementing essential amino acids under a high-calorie, low-protein diet, and at the same time, reusing urea accumulated in the body for assimilation of body proteins to improve nutritional status and suppress progression of renal failure. Based on this idea, oral amino acid preparations for renal failure were marketed,
Mainly Rose et al. [J. Biol. Chem., 223 , 107 (196
5)] has been developed, which has an amino acid composition conforming to the required amount of essential amino acids for normal persons, and is commercially available, for example, as "Amiyu granules" (Morishita Pharmaceutical Co., Ltd.).

In recent years, metabolic abnormalities under various pathological conditions have been studied in detail, and abnormalities of protein / amino acid metabolism in renal failure have been clarified. As a result, criticism that the amino acid composition based on the essential amino acid requirement proposed by Rose et al. Is not necessarily optimal for amino acid supplementation in patients with renal failure, and the anabolic action of urea on body protein is quantitatively determined. It has also been pointed out that its nutritional role is poor.

Furthermore, some experts have suggested that taking "Amiyu granules" may cause adverse effects such as acidosis.

Conventionally, oral amino acid preparations have a problem of difficulty in taking them because the amino acid itself has a unique odor and taste. Therefore, various studies have been conducted on the taste masking of oral amino acid preparations, and attempts have been made, for example, to coat oils and fats, natural waxes and waxes, and to add flavors and sweeteners.

However, conventional oral amino acid preparations are not completely satisfactory because they have a problem that they cause discomfort such as nausea, tingling, stomach upset, etc. even after the peculiar odor and taste are masked. It was

On the other hand, very recently, an amino acid transfusion for renal failure, which does not show adverse effects such as hyperammonemia, hepatic steatosis, and encephalopathy, has been developed, and has received attention due to its excellent effect (see JP-A-6-307822). . However, this was developed only for infusion, and its prescription as an oral preparation has not been studied.

Generally, chronic renal insufficiency patients, especially patients in the conservative therapy period, can orally ingest, and thus oral supplementation of amino acids is preferable to infusion. Therefore, the above-mentioned taste, the problem of discomfort and the problem of adverse effects are eliminated, and the drawbacks of a low-protein diet are corrected, the nutritional condition is improved, and the amino acid preparation for oral use having a medicinal effect such as the suppression of the progression of the disease state is obtained. Development has long been awaited.

Means for Solving the Problems As a result of intensive studies conducted by the present inventors, the inventors found a truly preferable amino acid composition for oral use for patients with renal failure, and used a specific granulating agent and enteric coating agent in appropriate amounts. By formulating, all the above problems can be solved, and the present invention has been completed.

That is, the present invention contains at least the following amino acids,
A mixture containing amino acids having a free amino acid equivalent composition ratio in the following range is granulated by adding 1 to 10 g of cellulose and / or a derivative thereof to 100 g of the mixture, and the granulated product is 5 to 100 g of the mixture. The present invention relates to an oral amino acid preparation for renal failure, which is coated with 30 g of a methacrylic acid copolymer. L-amino acid Composition range (g / 100g) Leucine 18.0 to 29.6 Isoleucine 10.8 to 18.0 Valine 13.0 to 21.6 Methionine 3.6 to 12.0 Lysine 6.2 to 10.8 Threonine 3.6 to 7.1 Tryptophan 3.2 to 5.4 Phenylalanine 1.5 to 10.8 Tyrosine 0.3 to 2.0 Histidine 3.3 to 7.1 Arginine 5.4 to 9.0 Cysteine or cystine 1.1 to 2.0 The amino acid preparation of the present invention essentially has the above amino acid composition, and further has L-alanine, L-proline, L-serine, L-aspartic acid and L-glutamic acid. At least one selected from the above can be blended.

Based on the above composition, the oral amino acid preparation for renal failure of the present invention is applied to an orally ingestible chronic renal insufficiency patient, particularly a patient in the conservative therapy stage, to improve nutritional status by supplementing a protein source. The diet can prevent patients from becoming malnourished. Further, the oral amino acid preparation of the present invention can exert effects such as lowering of BUN, improvement of subjective symptoms, suppression of progression of pathological condition, and none showing adverse effects such as acidosis. Further, the oral amino acid preparation of the present invention does not have an unpleasant taste, and is irritated after administration,
There is no feeling of burning or stomach upset.

The preferred composition of amino acids in the oral amino acid preparation of the present invention is as follows. L-amino acid Composition range (g / 100g) Leucine 20.2 to 27.2 Isoleucine 12.2 to 16.5 Valine 14.8 to 19.8 Methionine 4.0 to 10.0 Lysine 7.0 to 9.9 Threonine 4.0 to 6.5 Tryptophan 3.6 to 5.0 Phenylalanine 5.0 to 8.5 Tyrosine 0.8 to 2.0 Histidine 3.7 to 6.5 Arginine 6.1 to 8.3 Cysteine or cystine 1.2 to 1.8 In addition to the amino acid preparation of the present invention, L-alanine and L
-Proline, L-serine, L-aspartic acid and L-
When blending at least one selected from glutamic acid, the blending amount thereof is preferably selected from the following range with respect to 100 g of the amino acid composition. L-amino acid Composition range (g) Alanine 3.1 to 5.9 Proline 5.9 to 11.1 Serine 4.7 to 11.1 Aspartic acid 1.2 to 2.3 Glutamic acid 1.2 to 2.3 Each amino acid constituting the oral amino acid preparation for renal failure of the present invention is a crystalline amino acid. Although these are usually used in the form of free amino acids, they are not particularly limited to the free form and can be used in various forms such as salts, esters, N-acyl derivatives and peptides. Examples of the salts include metal salts such as sodium salts and potassium salts, mineral salts such as hydrochlorides and sulfates, organic acid salts such as acetates, lactates and malates. Specific examples include L-lysine hydrochloride, L-lysine acetate, L-lysine malate, L-arginine hydrochloride, L-histidine hydrochloride monohydrate and the like. Examples of the forms of the ester, N-acyl derivative and peptide include L-methionine methyl ester, N-acetyl-L-tryptophan, L-alanyl-L-tyrosine, L-alanyl-L-leucine and the like. When each amino acid is used in a form other than the above free amino acids, the amount of each amino acid used is determined so that the amount converted into the free amino acid falls within the above specific range.

In the oral amino acid preparation of the present invention, the above-mentioned various forms of amino acids or derivatives thereof are blended as free amino acids within the above-mentioned specific range, and cellulose and / or
Or 1 to 10 derivatives thereof per 100 g of the amino acid mixture.
g, preferably 1 to 7 g, added, granulated and classified, and then methacrylic acid copolymer is added to the above amino acid mixture 10
It is produced by coating 5 to 30 g, preferably 10 to 30 g per 0 g. As the granulation method, any of various methods commonly used in the field of formulation, such as a wet method and a dry method, can be applied. As the coating method, a general method such as rolling coating or fluidized bed coating can be used.

Cellulose and its derivatives used for the above granulation, various substances that have been conventionally generally used as a binder, typically, for example, crystalline cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxy. Propyl methyl cellulose phthalate and the like are included. Specific examples thereof include commercially available products such as "HPC-L" (Nippon Soda Co., Ltd.) and "HPC.EF-G" (Shin-Etsu Chemical Co., Ltd.).

As the methacrylic acid copolymer used as the coating agent, a copolymer of methacrylic acid and methyl methacrylate or ethyl acrylate is preferable. Specific examples thereof include those developed by Reem Pharma of West Germany, marketed as "Eudragit" (registered trademark), and widely used as an enteric coating agent.

As described above, based on the combined use of cellulose (or a derivative thereof) and methacrylic acid copolymer as the binder and the coating agent, the preparation of the present invention can mask the odor and taste peculiar to amino acids, and also cause sickness after administration. It has the advantage of being able to suppress gastrointestinal symptoms such as skin irritation and burning, and also being stable in terms of formulation.

In the coating step during preparation of the preparation of the present invention, if necessary, triethyl citrate, macrogol 6000, cetanol, plasticizer such as triacetin, polyoxyethylene curing castor infusion, dispersant such as polysorbate 80, talc,
A lubricant such as magnesium stearate can also be used in combination.

Furthermore, if necessary, a flavoring agent such as fruit essence, a stabilizer such as sodium bisulfite, anhydrous citric acid and the like can be appropriately added to the oral amino acid preparation for renal failure of the present invention.

The dose of the amino acid preparation of the present invention is generally 1 adult per day.
About 5 to 15 g per person is a standard, and it can be appropriately increased or decreased according to the disease state, nutritional condition, age, weight, etc. of the patient to whom it is administered.

Examples Hereinafter, in order to further clarify the present invention, a production example of the oral amino acid preparation for renal failure of the present invention will be given as an example, and then a test example will be given.

Example 1 Amount of L-amino acid (g) Leucine 305 Isoleucine 172 Valine 191 Methionine 57 Lysine acetate 134 (95 as lysine) Threonine 67 Tryptophan 48 Phenylalanine 95 Tyrosine 10 Histidine 67 Arginine 86 Cystine 19 Centrifugal fluidized granulator (CF -Granulator / manufactured by Freund Sangyo Co., Ltd., using 90 g of Nonpareil 101 (Freund Sangyo Co., Ltd .; main component = granulated sugar) as a core, gradually adding each amino acid mixture having the above composition, hydroxypropyl cellulose "HPC-L" (Nippon Soda Co., Ltd.) 75 g of an ethanol solution (5%) was sprayed and granulated to prepare elementary granules. After drying the obtained elementary granules, a methacrylic acid copolymer "Eudragit L100" (Higuchi Shokai) 175 g and triethyl citrate 17.5 g in a 1: 1 ethanol / dichloromethane solution (methacrylic acid copolymer 5
%) To the elementary granules by spraying and drying to prepare coated granules. The obtained coated granules were packaged to produce 500 oral amino acid preparations of the present invention.

Example 2 L-amino acid amount (g) Leucine 300 Isoleucine 175 Valine 200 Methionine 55 Lysine acetate 134 (95 as lysine) Threonine 65 Tryptophan 50 Phenylalanine 95 Tyrosine 10 Histidine 65 Arginine 85 Cystine 20 Each amino acid of the above composition, Nonpareil 101 90g, hydroxypropyl cellulose "HPC-L" (Nippon Soda Co., Ltd.) 7
Example 1 from 5 g of an ethanol solution (5%) and a methacrylic acid copolymer “Eudragit L100” (Higuchi Shokai) 175 g and 17.5 g of triethyl citrate in a 1: 1 ethanol / dichloromethane solution (5% methacrylic acid copolymer). Similarly, 500 oral amino acid preparations of the present invention were produced.

Example 3 Amount of L-amino acid (g) Leucine 300 Isoleucine 175 Valine 200 Methionine 55 Lysine acetate 134 (95 as lysine) Threonine 65 Tryptophan 50 Phenylalanine 95 Tyrosine 10 Histidine 65 Arginine 85 Cystine 20 To each amino acid mixture of the above composition, 40 g of hydroxypropyl cellulose "HPC EF-G" (manufactured by Shin-Etsu Chemical Co., Ltd.) was mixed, 320 g of ethanol was added, the mixture was stirred and kneaded, and granulated by an extrusion granulator (disc pelleter / manufactured by Fuji Paudal). After that, elementary granules were prepared by sizing with a spherical granulator (Marumerizer / Fuji Paudal). After drying the obtained granules, 30% methacrylic acid copolymer liquid "Eudragit L30D-55" (Higuchi Shokai) 650 g, "Macrogol 6000"
A suspension of 20 g, talc 20 g and water 650 g was coated while spraying using a fluidized bed coating device (manufactured by Gran Grat / Grat) and dried to prepare coated granules. The obtained coated granules were packaged to produce 500 oral amino acid preparations of the present invention.

Example 4 Amount of L-amino acid (g) Leucine 200 Isoleucine 120 Valine 160 Methionine 40 Lysine hydrochloride 100 (80 as lysine) Threonine 40 Tryptophan 40 Phenylalanine 80 Tyrosine 4 Histidine 52 Arginine 60 Cystin 12 Alanine 40 Proline 76 Serine 76 Aspartic acid 16 Glutamic acid 16 Each amino acid of the above composition, 100 g of nonpareil 101, hydroxypropyl cellulose “HPC · EF-G (Shin-Etsu Chemical Co., Ltd.) 60 g ethanol solution (5%) and methacrylic acid copolymer“ Eudragit L100 ”(Higuchi Shokai) 240 g In the same manner as in Example 1, 500 packets of the oral amino acid preparation of the present invention was produced from a solution of 24 g of triethyl citrate and 1: 1 ethanol / dichloromethane (methacrylic acid copolymer 5%).

Example 5 Amount of L-amino acid (g) Leucine 200 Isoleucine 120 Valine 160 Methionine 40 Lysine hydrochloride 100 (80 as lysine) Threonine 40 Tryptophan 40 Phenylalanine 80 Tyrosine 4 Histidine 52 Arginine 60 Cystine 12 Alanine 40 Proline 76 Serine 76 Aspartic acid 16 Glutamic acid 16 Each amino acid of the above composition, hydroxypropyl cellulose “HPC-L” (manufactured by Nippon Soda Co., Ltd.) 100 g ethanol solution (10%), 30% methacrylic acid copolymer solution “Eudragit L30D-55” (Higuchi Shokai) 730 g , "Macro Goal 60
20 "of 00", 40 g of talc and 730 g of water were used to prepare 500 oral amino acid preparations of the present invention in the same manner as in Example 3.

Example 6 L-amino acid amount (g) Leucine 215 Isoleucine 138 Valine 154 Methionine 46 Lysine / hydrochloride 96 (77 as lysine) Threonine 54 Tryptophan 38 Phenylalanine 69 Tyrosine 8 Histidine / hydrochloride monohydrate 52 (38 as histidine) Arginine / hydrochloride 84 (69 as arginine) cystine 22 90 g of each amino acid having the above composition, nonpareil 101 90 g, hydroxypropylcellulose “HPC-L” (manufactured by Nippon Soda Co., Ltd.) 3
Example 1 using 7 g of an ethanol solution (5%), a methacrylic acid copolymer “Eudragit L100” (Higuchi Shokai) 146 g and a 1: 1 ethanol / dichloromethane solution of 24 g of triethyl citrate (methacrylic acid copolymer 5%). Similarly, 400 oral amino acid preparations of the present invention were produced.

Test Example 1 Using a 5-week-old Wistar rat, 75% of the left kidney was excised under Nembutal anesthesia, and two weeks later, the right kidney was excised again under Nembutal anesthesia. Two weeks after that, the serum creatinine in each group was divided into two groups (one group consisting of 9 animals) and subjected to the following tests.

That is, one group was fed with the adjusted feed containing the pulverized product of the amino acid preparation of the present invention of Example 1 (hereinafter referred to as “the present invention group”).
), And the other group was fed with a conditioned feed containing a crushed commercial amino acid preparation for renal failure (Amu Granules; Morishita Pharmaceutical Co., Ltd.) (hereinafter referred to as "comparative group").

 The composition of each feed is shown in Table 1.

Each group was allowed to freely ingest the above feed and water for 28 days, and changes in body weight and nitrogen balance were measured. Weight is 14 before starting the experiment
Measurements were made on the day and 28th day, and nitrogen balance was determined from the 19th to 21st day of the experiment by controlling the test animals in individual metabolic cages.

 The food intakes of both groups during the test were the same.

 The results are shown in Table 2.

As is clear from Table 2, the group of the present invention has better weight gain and nitrogen balance, and the nutritional effect of the amino acid preparation of the present invention is better than that of the comparative group.

Test Example 2 With respect to the amino acid preparations of the present invention of Examples 1 and 4, and the same commercially available oral amino acid preparation for renal failure (Amu granules: Morishita Pharmaceutical Co., Ltd.) used in Test Example 1, the feeling of ingestion by 25 test subjects was examined. A comparison was made. The results are shown in Table 3.

As is clear from Table 3, the amino acid preparation of the present invention comprises:
It can be said that the gastrointestinal symptoms after taking the drug are significantly superior to those on the market. Further, it can be said that the masking degree of bitterness at the time of taking is equal to or higher than that of a commercial product.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication location A61K 47/38 A61K 47/38 B (72) Inventor Mitsuo Nakayama Nakashima Takashima, Naruto-cho, Naruto City, Tokushima Prefecture 129-28 (72) Inventor Yuichi Kono Seven pieces of Iwaji, Nara, Municipal Government, Naruto City, Tokushima Prefecture 19-1 (72) Hideki Kobata 208-16 (72) Shimohonjo, Myojin, Seto-cho, Naruto City, Tokushima Prefecture Tatsuo Mochi 117, Miyanonishi, Kitahama, Narato-cho, Tokushima Prefecture (72) Inventor, Takashi Fujimoto 26-1, Uechi, Nakamura, Kitajima-cho, Itano-gun, Tokushima Prefecture (56) Reference JP-A-63-307822 (JP, A)

Claims (1)

(57) [Claims] Claims: 1. A mixture containing at least the following amino acids and having an amino acid equivalent composition ratio within the following range is granulated by adding 1 to 10 g of cellulose and / or its derivative to 100 g of the mixture. An oral amino acid preparation for renal failure, which is obtained by coating the granulated product with 5 to 30 g of a methacrylic acid copolymer per 100 g of the above mixture. L-amino acid Composition range (g / 100g) Leucine 18.0 to 29.6 Isoleucine 10.8 to 18.0 Valine 13.0 to 21.6 Methionine 3.6 to 12.0 Lysine 6.2 to 10.8 Threonine 3.6 to 7.1 Tryptophan 3.2 to 5.4 Phenylalanine 1.5 to 10.8 Tyrosine 0.3 to 2.0 Histidine 3.3 to 7.1 Arginine 5.4-9.0 Cysteine or cystine 1.1-2.0