Aqueous solution for parenteral nutrition

 

(57) Abstract:

The invention relates to the field of pharmaceutical industry and relates to aqueous solution for parenteral nutrition mammals. The invention lies in the fact that it contains the following set of amino acid based on 100 g/l of amino acids: isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, arginine, histidine, alanine, aminouksusnoy acid (glycine, asparagine, aspartic acid, acetyl cysteine, glutamic acid, ornithine, Proline, serine, tyrosine in the form of acetyltyrosine, taurine, following electrolytes: sodium, potassium, magnesium, calcium, zinc, phosphate, chloride, acetate, citric acid, malate, lactate, glycerol, gluconate and not necessarily the solution of carbohydrates and/or fat emulsion. The invention provides for obtaining an aqueous solution for parenteral nutrition mammals, which would satisfy the requirements of the concept, which consists in using an excess of reason. 9 C.p. f-crystals, 1 table.

The present invention relates to aqueous solution intended for parenteral nutrition of mammals.

In EP I described the drug for infusion intended for use as a source pit is to variants of amino acid composition.

Similarly, in DE 4316326C1 describes the different variants of the amino acid composition for total parenteral nutrition by intravenous injection.

In DE 3916903 A1 as well as DE 4316326 C1 described aqueous composition for parenteral nutrition, which, in particular, different specific variant amino acid composition.

In R. Zander in Infusionsther. Transfusionsmed. 1993; 20: 217-235 outlined a concept concerning the use of certain bases in solutions for infusion. Thus, in particular, the concept consists in using an excess of bases (a measure of metabolic acidosis) (IO, mmol/l and the potential of IO, mmol/l) needed to be able to identify signs of potential changes in the pool of HCO-3after infusion and metabolism of solutions for infusion. This also applies to a derivative of blood, which can occur transfusion acidosis or alkalosis, and to the hemodialysis and peritoneal dialysis, when in the course of treatment must take into account the possibility of acidosis and alkalosis. The above variants of the amino acid composition of the solutions, which go on sale, do not satisfy the requirements of the concept, which consists in the use of the RA for parenteral nutrition mammals, which would satisfy the requirements of the specified framework.

The specified task according to the first variant embodiment of the invention is solved by an aqueous solution for parenteral nutrition mammals, including:

(a) the following set of amino acids, the number of which is specified in terms of 100 g/l amino acids, g/l:

Isoleucine 4,0-5,5

Leucine 8,0-10,0

Lysine 6,0-8,0

Methionine 4,0-6,0

Phenylalanine 4,0-6,0

Threonine 4,0-6,0

Tryptophan 1,0-2,0

Valine 6,0-8,0

Arginine 10,0-12,0

Histidine 1,5-3,5

Alanine 9,0-12,0

Aminouksusnoy acid (glycine) 11,0-16,0

Asparagine 0-1,0

Aspartic acid 5,5-8,0

Acetylcysteine 0-2,5

Glutamic acid 6,0-10,0

Ornithine 0-1,0

Proline 4,0-6,0

Serine 1,0-3,0

Tyrosine 0,1-0,5

(Acetyltyrosine) 0-2,0

Taurine 0-4

b) the next set of electrolytes, mmol/l:

Sodium 0-100,0

Potassium 0-80,0

Magnesium 0-8,0

Calcium 0-8,0

and/or

Zinc 0-0,08

Phosphate 0-20,0

Chloride 0-120,0

Acetate 0-120,0

Gluconate 0-120,0

C) optional solution of carbohydrates (sugar) and/or fat emulsion.

Parenteral nutrition should provide the body with all the components necessary for growth and tissue formation. Amino acids play a significant role as they are the basic components for protein synthesis. To ensure optimal absorption of amino acids requires the introduction of an additional energy source. Part of this problem can be solved by the optional use of carbohydrates. Since glucose can be used directly, it is the preferred carbohydrate, which is usually chosen, but at the same time instead of glucose or its partial replacement can be used xylitol.

However, the prior art known to the application and other carbohydrates.

The electrolyte is injected to maintain metabolic and physiological functions. Adding them allows you to comply with the requirements that must be met used for parenteral nutrition aqueous solution.

After intravenous infusion components of the solution according to the present invention very quickly involved in the metabolism due to the specific is minislot used for protein synthesis, the rest are decomposed according to the following scheme: the amino groups are separated in the transamination and carbon fragment or oxidized to CO2in the Krebs cycle, or used by the liver as a substrate for gluconeogenesis. The amino group resulting from the decomposition of protein in muscle tissue, transported to the liver where it is synthesized urea. The ingredients of the aqueous solution are naturally occurring compounds or intermediates of metabolism, and their concentration after appropriate infusion close to physiological levels.

The total amino acid content may vary depending on the needs of the patient, which they should be entered. Thus, the total content of amino acids in aqueous solutions of the present invention may range from 20 to 180 g/L. However, this should not happen deviations from the above composition. Hence, these amounts can be divided into smaller or increased to obtain a higher or lower concentration.

In yet another preferred embodiment of the present invention the pH value renno preferably, to pH values of aqueous solutions was in the range of from 4.8 to 6.5.

Use at least 20 wt.% the branched chain amino acids is particularly preferred. In W. Hartig Moderne in Infusionstherapie, Parenterale Ernahrung, VEB Johann Ambrosius Barth, 1989, pp. 451-455, described is the preferred choice of amino acids according to Rose. In the table on page 451 in respect of essential amino acids only indicated that the number of the branched chain amino acids such as isoleucine, leucine and valine, is of 40.9%. In relation to the preferred solution of amino acids indicated that the content of essential amino acids is 42%. In this number the content of branched chain amino acids is 17.2 wt.%

On the other hand, according to the present invention serves to significantly increase the number of branched chain amino acids compared to the above described example of the composition of the Rose (about 18 wt.%). This change led to the approximation of the composition of amino acids to that characteristic of the protein of eggs, for which it assumes full bioavailability.

In this regard it is important not only the amount of branched chain amino acids, but also their relative content in CPA (in particular limit) on the solubility of amino acids as such due to their relatively poor solubility. According to well-known authors of the invention the information in this field does not exist or is unavailable another such solution of amino acids, in which the concentration of amino acids would be at least 15 wt.%, moreover, the number of branched chain amino acids would reach 20 wt.% or more relative to the total content of amino acids. Thus, the number of branched amino acids is particularly important for amino acid solutions that contain their most preferred concentration, such as 16 or 18% (by weight of the amino acids).

Also taken into account that the potential excess of the basis of the applied solution of amino acids does not exceed 20 mmol/day when using the maximum recommended dose of amino acids 2 g of protein/kg body weight/day.

By selecting the composition of the electrolytes (chloride, acetate, malate, citrate in the case of containing the electrolyte solution), and by using only the salts of amino acids (lysine/lysine acetate, but also can be used aspartate, glutamate and Pyroglutamate) it was found that the potential excess grounds should preferably be from -10 to +10 mmol/l in the final product. For containing the electrolyte VRLA not containing electrolytes options offer an aqueous solution the ability to control the excess of reason is limited to what these solutions do not contain chlorides, and, therefore, the potential excess of bases in these solutions varies preferably in the range from -15 to -8 mmol/l Relative to the negative excess reason not containing electrolytes options offered aqueous solution does not cause any problems if the concrete does not contain electrolytes solution of amino acids is part of therapeutic treatment.

Not containing electrolytes amino acid solutions should be mixed with solutions of electrolytes to balance consumption of electrolytes by the patient during treatment. Formulations of the compositions were selected mainly based on the experience gained for the known solutions of amino acids, which go on sale for many years. A specific set of amino acids, proposed according to the present invention, is the result of years of clinical experiments with solutions coming into the market, while in the claimed invention in addition to the amino acid composition was taken into account physiological aspect of excess reason, the aspect associated with galenovye forms, and the stability of the product. Given the high solubility of aminotic the significant extent to vary. For example, the same basic solution may be the basis of a 10% aqueous solution (corresponding to 100 g/l of amino acids to meet other concentrations of 3, 5, 8 and even 16 to 18%).

In the case when an aqueous solution according to the invention contains amino acids and carbohydrates are of type glucose in the same container, as a rule, there is a reaction between these components, which mainly depends on the temperature and oxygen content. The so-called reaction Maillard causes staining of the final product in yellow color. This is especially true for selling full parenteral solutions. Therefore, these solutions prepared in aseptic conditions without the usual heat sterilization at temperatures above 121°C.

The reaction between glucose and amino acids leads to the formation of products of Maillard (condensation products, painted in yellow/brown color), resulting in decreases in the concentrations of some valuable amino acids in solution. This phenomenon is widely described in the literature. In this regard, it is important to know the influence of physiological salts (phosphate, glycerol, acetate, chloride, citrate, lactate and malate) on the kinetics of interaction in the above reacts the only means. Studies in this regard have not previously carried out or was carried out very rarely, accordingly, there are practically no publications on this topic. Various solutions of the present invention is optimized from the point of view of the abundance of grounds, but also from the point of view of the kinetics of the above reaction Maillard.

The excess basis (as a measure of metabolic alkalosis) can be calculated as follows.

The excess basis (IO) - (TC + 24), where TC denotes the acid titration (the number of mmol/l NaOH required to reach pH 7,4), 24 mmol/l of Na bicarbonate in the blood; the potential of IO (the pot. IO) = (TE + t), where TE denotes the metabolic effect (metabolism of R-COOH>CO2), for example, TE = (concentration of acetate) + (lactate concentration) + 2 (concentration of malate) + 3 (concentration of citrate).

In another preferred embodiment, the aqueous solution according to the invention is distinguished by the following set of amino acids, the number of which is specified in terms of 100 g/l amino acids, g/l:

Isoleucine 4,7-5,3

Leucine Is 8.5-9.5

Lysine 6,5-7,5

Methionine 4,0-5,0

Phenylalanine 4,5-5,5

Threonine 4,0-5,0

Tryptophan 1,5-1,7

ª acid (glycine) 11,0-12,0

Asparagine 0-0,5

Aspartic acid 5,5-6,0

Acetylcysteine 0,2-1,0**

Glutamic acid 6,0-8,0

Ornithine 0-0,5

Proline 5,0-6,0

Series 2.0 To 3.0

Tyrosine 0,3-0,5

(acetyltyrosine) 0-2,0

Taurine 0-2,5

Note: ** sensitive to oxidation, so the dose may depend on the technology of cooking, as well as from the container.

Similarly, another variant implementation of the present invention is distinguished by the following set of electrolytes, mmol/l::

Sodium 25,0-75,0

Potassium 20,0-30,0

Magnesium 20,0-30,0

Calcium 0-4,0

Zinc 0-0,04

Phosphate 5,0-15,0

Chloride* 25,0-75,0

Acetate* 25,0-75,0

Citric acid 1,0-3,0

Malate 0-40,0

Lactate 0-5,0

Glycyrrhizinate 5-30,0

and/or

Gluconate 25-120,0

In the context of the present description the term "mammals", obviously, applies to all mammals, in particular man.

A variant embodiment of the invention is shown in the table.

1. Aqueous solution for parenteral nutrition mammal, comprising (a) after the Qing 4,0-5,5

Leucine 8,0-10,0

Lysine 6,0-8,0

Methionine 4,0-6,0

Phenylalanine 4,0-6,0

Threonine 4,0-6,0

Tryptophan 1,0-2,0

Valine 6,0-8,0

Arginine 10,0-12,0

Histidine 1,5-3,5

Alanine 9,0-12,0

Aminouksusnoy acid (glycine) 11,0-16,0

Asparagine 0-1,0

Aspartic acid 5,5-8,0

Acetylcysteine 0-2,5

Glutamic acid 6,0-10,0

Ornithine 0-1,0

Proline 4,0-6,0

Serine 1,0-3,0

Tyrosine* 0,1-0,5

*as acetyltyrosine 0-2,0

Taurine 0-4

and b) the next set of electrolytes, mmol/l:

Sodium 0-100,0

Potassium 0-80,0

Magnesium 0-8,0

Calcium 0-8,0

and/or

Zinc 0-0,08

Phosphate 0-20,0

Chloride 0-120,0

Acetate 0-120,0

Citric acid 0-10,0

Malate 0-80,0

Lactate 0-10,0

Glycyrrhizinate 0-30,0

and/or

Gluconate 0-120,0

C) optionally a solution of a carbohydrate and/or fat emulsion.

2. The solution on p. 1, characterized in that the content of amino acids in it varies from 20 to 180 g/L.

3. The solution on p. 1, characterized in that its value is branched chain.

5. The solution on p. 1, characterized in that it contains at least 42 wt.% essential amino acids.

6. The solution on p. 1, characterized in that it contains at least 24% of precursors selected from the group including Asp, Glu and/or Arg.

7. The solution on p. 1, characterized in that the potential excess reason is from -10 to + 10 mmol/L.

8. The solution on p. 1, characterized in that it contains no sulfites.

9. The solution on p. 1, wherein the following set of amino acids, the number, g/l, which is specified in terms of 100 g/l of amino acids:

Isoleucine 4,7-5,3

Leucine Is 8.5-9.5

Lysine 6,5-7,5

Methionine 4,0-5,0

Phenylalanine 4,5-5,5

Threonine 4,0-5,0

Tryptophan 1,5-1,7

Valine 6,0-7,0

Arginine 11,0-12,0

Histidine 2,5-3,5

Alanine 10,0-11,0

Aminouksusnoy acid (glycine) 11,0-12,0

Asparagine 0-0,5

Aspartic acid 5,5-6,0

Acetylcysteine 0,2-1,0

Glutamic acid 6,0-8,0

Ornithine 0-0,5

Proline 5,0-6,0

Serine 2,0-3,0

Tyrosine* 0,1-0,5

*as acetyltyrosine 0-2,0

Taurine 0-2,5

10. Races Who 30,0

Magnesium 20,0-30,0

Calcium 0-4,0

Zinc 0-0,04

Phosphate 5,0-15,0

Chloride* 25,0-75,0

Acetate* 25,0-75,0

Citric acid 1,0-3,0

Malate 0-40,0

Lactate 0-5,0

Glycyrrhizinate 5-30,0

and/or

Gluconate 25-120,0



 

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