JP2885261B2 - Infusion preparation comprising 3-hydroxybutyric acid oligomer and salt thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention aims to provide an effective alternative to carbohydrates and suppress protein catabolism especially for patients who have difficulty in replenishing energy with normal carbohydrates due to abnormal glucose metabolism. The formulation relates to The subjects were (1) patients with invasion such as severe infections after trauma, burns, and surgical operations, (2) patients with reduced liver function and reduced liver ketone body synthesis function, and (3) nutrition Effective for patients with disabilities.

[0002]

2. Description of the Related Art The unit monomers 3-hydroxybutyric acid, acetoacetic acid and acetone which constitute the oligomer which is the subject of the infusion composition of the present invention are collectively derived from lipids called ketone bodies. Energy substrate. Of these, 3-hydroxybutyric acid and acetoacetic acid are physiologically important. Ketone bodies were initially found in the urine of diabetic patients and were considered to be useless metabolites found in vivo in pathological conditions. In addition, attention has been paid to long-chain fatty acids as an energy substrate derived from fats, and attention has not been paid to the physiological significance of ketone bodies for a long time.

[0003] Since the 1970s, its physiological importance has been recognized. It is a substance that is responsible for the maintenance of caloric homeostasis (caloric homeostasis) as a complementary substrate in place of glucose and as a substitute for glucose. In a sense, a remarkable significance has been elucidated (HA Krebs et al., Adv. Enzyme Regul. 9:38).
7-392, 65, 1971, AM Robinson et al., Physiologi
cal Reviews, 60 (1), 143-187, 1980). Further, ketone bodies are fat-derived energy substances and hydrophilic substances with extremely good tissue transfer properties. Ketone bodies administered intravenously during dieting in obese patients inhibit protein catabolism (GLS Pawan et al., Lancet, i, 15
-17, 1983), that 3-hydroxybutyric acid has a protective effect on myocardial metabolism (Japanese Patent Laid-Open No. 58-201746).
-Hydroxybutyric acid can be given to patients with difficulties in supplementing energy with normal carbohydrates due to abnormal glucose metabolism, patients with increased in vivo protein catabolism, patients with reduced liver function, or patients with nutritional disorders. It is known to be effective (Japanese Patent Laid-Open No. 2-191212).

[0004] In a patient who has undergone a surgical insult such as trauma, burns, or after a surgical operation, energy consumption increases, catabolism increases, and body protein is destroyed. However, in these patients, the metabolism of glucose, the most dominant energy substrate during normal times, changes, and glucose tolerance is impaired. For this reason, nutritional administration is not usually performed, and only infusion of an electrolyte such as Ringer's lactate is performed in the acute phase. It is known that the use of 3-hydroxybutyric acid as an energy supplement at this time suppresses the catabolism of body protein (Hirade Atsushi et al., Journal of the Japanese Surgical Society, 89 (5), 786,
1988). However, 3-hydroxybutyric acid is an acid, and when this load attempts to load a considerable amount of energy, there arises a drawback that a large amount of a hypertonic solution is loaded and a sharp fluctuation occurs in an acid-base equilibrium. Thus, when administered in the form of a sodium salt, fluctuations in the acid-base equilibrium are slightly alleviated, but this time, the load of sodium ions cannot be ignored and has a significant effect on electrolyte metabolism. The basic amino acid salt form also affects the amino fraction and seriously impairs the patient's amino acid metabolism. Therefore, there is a need for a preparation of 3-hydroxybutyric acid that does not have a high osmotic pressure and does not cause a rapid change in acid-base equilibrium.

[0005]

Means for Solving the Problems and Actions In view of the circumstances described above, the present inventors have found that the osmotic pressure of an infusion preparation is not high, does not cause a sudden change in acid-base equilibrium, and the load of electrolytes and amino acids is excessive. As a result of diligent research on an infusion of 3-hydroxybutyric acid, the present inventors have found an infusion preparation containing at least one oligomer of 3-hydroxybutyric acid or a salt thereof, thereby completing the present invention.

[0006] The polymers of 3-hydroxybutyric acid are generally poorly soluble in water, whereas our oligomers are soluble in water and can be used as nutritional infusions. That is, a first aspect of the present invention is to provide a patient having at least one oligomer of 3-hydroxybutyric acid or a salt thereof and having difficulty in supplementing energy with ordinary saccharides due to abnormal glucose metabolism. The present invention relates to an infusion preparation for the purpose of providing effective energy supplementation and suppressing protein catabolism. In addition, the subjects were (1) patients who were invasive to severe infectious diseases, etc. after trauma, burns, and surgical operations, (2) patients whose liver function was reduced and the ketone body synthesis function of the liver was reduced, (3) The present invention relates to an infusion preparation which is effective for patients with nutritional disorders, can vary the content of electrolyte to a low concentration, and has a continuous energy supply.

A second aspect of the present invention is that, in the oligomer contained in the infusion preparation, the configuration of 3-hydroxybutyric acid, which is a monomer constituting the oligomer, is (R)
Type, (S) type or any mixture thereof. A third aspect of the present invention relates to the oligomer contained in the infusion preparation, wherein the number of 3-hydroxybutyric acid is from dimer to decamer. Fourth Embodiment of the Present Invention
Relates to the fact that the oligomer salt contained in the infusion preparation is a potassium salt, sodium salt, L-lysine salt, L-histidine salt or L-arginine salt. A fifth aspect of the present invention relates to the infusion preparation containing an amino acid.

The oligomer of 3-hydroxybutyric acid used in the present invention can be produced as a pure product or as a mixture by a known method. For example, Kato et al. Have found that certain bacteria that produce poly (3-hydroxybutyric acid) release trimers predominantly into their cultures (N. Kato et al., J. Ferment. Bioeng., 73 (3), 246
-247, 1992). On the other hand, Tanaka et al. Have reported the formation of oligomers from dimers to pentamers by the condensation of 3-hydroxybutyric acid monomer catalyzed by ethanesulfonic acid (Y. Tanaka et al., Eur. J. Biochem. ., 118, 177
-182, 1981). In addition, it has been reported that an oligomer or its methyl ester can be obtained by treating poly (3-hydroxybutyric acid) with ethanesulfonic acid / water or boron trifluoride / methanol (Noel Van Trout et al. No. 57-45131, EP 0,043,620, B. Hauttecoeur et al., CR
Hebd. Seances Acad. Sci. Ser. D. Nat., 280, 2899-
2902, 1975). Furthermore, the production of oligomers by a stepwise organic synthesis method using monomers is also known (I. Olsen et al., Biochemistry., 3, 453-456, 196).
5, T. Tanio et al., Eur. J. Biochem., 124, 71-77, 1
982, and D. Seebach et al., Helv. Chim. Acta, 71,
155-167, 1988).

Among the above oligomers, those derived from microorganisms have the asymmetric carbon configuration of (R), and in synthetic products, are arbitrarily defined by the configuration of the starting monomer used. For example, in the dimer, all possible diastereomers, RR-forms, RS-forms, SR-forms and SS-forms are synthesized by making full use of the synthesis method. Naturally, by using a racemic monomer as a raw material, a diastereomer mixture 2
Can be synthesized. As an oligomer of 3-hydroxybutyric acid, use of only a blood purification drug has been found (Japanese Patent Application Laid-Open No. 1-160917).

As the oligomer of 3-hydroxybutyric acid of the present invention, a dimer to a 10-mer can be used, and a pure product thereof or a mixture thereof can be used. For example, intravenous injection requires a water-soluble oligomer, and it is preferable to use a dimer to a tetramer. As the enteral nutritional supplement, it is preferable to use a trimer to a 10-mer, because of its absorption from the intestinal tract and the effect of osmotic pressure on the intestinal tract.

The oligomeric salt of 3-hydroxybutyric acid according to the present invention may be an inorganic salt such as sodium salt or potassium salt, or a basic amino acid salt such as L-lysine salt, L-histidine salt or L-adenine salt. Can be used. In particular, the latter amino acid salt is useful when energy supplementation is performed in combination with other nutrients such as an amino acid-containing infusion preparation.

The concentration of an oligomer of 3-hydroxybutyric acid or a salt thereof in an infusion preparation varies greatly depending on the monomer used or the mixing ratio thereof, but it is 0.2 to 3 mol / L in terms of monomer concentration. It can be used by dissolving it in distilled water so as to obtain a concentration. The lower limit is from the viewpoint of controlling the effective blood concentration and osmotic pressure ratio when administered as an energy source, and the upper limit is the osmotic pressure ratio, pH, and nutrition. It is determined as appropriate from the viewpoint of balance and solubility.

[0013]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. Example 1 Blood of (R) -3-hydroxybutyric acid oligomer
9-week-old decomposed wister rats by Qingqi pentobarbital (50 mg / k
After anesthesia by gip), laparotomy was performed and blood was collected from the aorta. This serum was reacted with (R) -3-hydroxybutyric acid oligomer (average 2.3-mer composed of 2 to tetramer containing no monomer) at a concentration of 0.125 to 4 μmol / ml, and acetoacetic acid and The concentration of the 3-hydroxybutyric acid monomer was measured (the concentration of the ketone body was measured using Ketone Test Sanwa [Sanwa Chemical Laboratory]). The results are shown in FIG. 1 and showed that the oligomer was converted by the serum to a physiologically active monomer. In the figure, 3-HB means 3-hydroxybutyric acid, and Ac-Ac means acetoacetic acid.
The meaning of this abbreviation is the same in FIGS.

Example 2 (R) -3-hydroxybutyric acid
Decomposition of Rigomer by Rat Liver Homogenate (R) -3-Hydroxybutyric acid oligomer (average 2.3-mer composed of 2 to tetramer containing no monomer) was added to rat liver at a concentration of 0.125 to 4 μmol / ml. After reacting with homogenate, the concentrations of acetoacetic acid and 3-hydroxybutyric acid monomer were measured (the concentration of ketone bodies was measured using a ketone test Sanwa [Sanwa Chemical Laboratory]). The results are shown in FIG. 2 and showed that the oligomer was converted to a physiologically active monomer by the liver homogenate.
It suggests that oligomers can be converted to monomers via the liver and replenished energy even when administered intra-enterally.

Example 3 (R) -3-H on rats
Intravenous administration test of droxybutyric acid oligomer A 9-week-old (300 g) Wistar rat was cannulated into the right external jugular vein and the left common carotid artery under pentobarbital (50 mg / kg ip) anesthesia. 10 μmol / kg / min (monomer equivalent) of a sample of (R) -3-hydroxybutyric acid oligomer (having an average of 2.3 trimers consisting of 2 to 4 trimers containing no monomer) dissolved in distilled water from the external jugular vein route For 1 hour at a rate of 25 μmol / kg / min). 180 before administration and every 15 to 30 minutes after administration
Until a minute later, the concentrations of acetoacetic acid and 3-hydroxybutyric acid monomer were measured (the concentration of ketone bodies was measured using Ketone Test Sanwa [Sanwa Chemical Laboratory]). The results are shown in FIG. It is known that in the case of administration of the monomer, the normal blood concentration (0.1 to 0.2 mmol / L) decreases promptly after the administration is stopped. 0.5 over 3 hours
A monomer concentration of about mmol was maintained.

Infusion Formulation Example 1 (R) -3-Hydroxybutyric acid oligomer (dimer) 4
7.5 g (0.25 mol) was suspended in 800 ml of distilled water for injection, and this was suspended in aqueous sodium hydroxide solution to adjust the pH.
After neutralizing and dissolving to 7.0, distilled water was further added to make 1 L. After filling this into a 1 L plastic container, the filling port was sealed and sterilized by heating at 110 ° C. for 2 hours with steam to prepare an infusion solution.

Infusion Formulation Example 2 (R) -3-hydroxybutyric acid oligomer (2
A transfusion having an extracellular fluid replenisher composition containing a sodium salt and an inorganic electrolyte was prepared. (R) -3-Hydroxybutyric acid oligomer (dimer) sodium salt 7.4 g Sodium chloride 4.1 g Potassium chloride 3.0 g Calcium chloride 2.0 g The above components were diluted and dissolved in distilled water for injection to make a total volume of 1 L. . The pH of the resulting composition was 7.1. The electrolyte composition was as follows. Na + 105 meq / L K + 4 meq / L Ca ++ 3 meq / L Cl- 77 meq / L [Oligomer] + 35 meq / L After filling the above composition into a 1 L plastic container. The filling port was sealed and sterilized by the same operation as in Preparation Example 1.

Infusion Formulation Example 3 (R) -3-hydroxybutyric acid oligomer (2
A maintenance infusion containing sodium, glucose and an inorganic electrolyte was prepared. Glucose 43 g (R) -3-hydroxybutyric acid oligomer (dimer) sodium salt 6.3 g Sodium chloride 0.9 g Potassium chloride 1.5 g The above components were diluted and dissolved in distilled water for injection to make a total volume of 1 L. The pH of the resulting composition was 7.1. The electrolyte composition was as follows. Na + 45 meq / L K + 20 meq / L Cl- 35 meq / L [oligomer] + 30 meq / L After filling the above composition into a 1 L plastic container, sealing the filling port, Sterilization was carried out in the same manner as in Example 1.

Infusion Formulation Example 4 (R) -3-hydroxybutyric acid oligomer (2
) And an extracellular fluid replenisher composition containing an inorganic electrolyte was prepared. (R) -3-Hydroxybutyric acid oligomer (dimer) 5.7 g Sodium chloride 6.0 g Potassium chloride 3.0 g Calcium chloride 2.0 g Sodium hydroxide Adjusted to pH 7.0 The above components were diluted and dissolved in distilled water for injection. The total volume was 1 L. The electrolyte composition was as follows. Na + 130 meq / L K + 4 meq / L Ca ++ 3 meq / L Cl- 77 meq / L [Oligomer] + 30 meq / L After filling the above composition into a 1 L plastic container. The filling port was sealed and sterilized by the same operation as in Preparation Example 1.

[0020]

The infusion preparation of the present invention uses an oligomer of 3-hydroxybutyric acid as a main component, and is converted into a monomer in a living body to supply energy. It is a new infusion formulation that has a feature that the concentration of electrolytes can be varied over a wide range and that energy supplementation can be maintained after administration is stopped, compared to the case where monomers are used directly.

[0021]

[Brief description of the drawings]

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagram showing a process in which oligomers of 3-hydroxybutyric acid are converted into physiologically active ketone bodies (3-hydroxybutyric acid and acetoacetic acid) by serum.

FIG. 2. Oligomers of 3-hydroxybutyric acid are physiologically active ketone bodies (3-
The figure which shows the process which is converted into (hydroxybutyric acid and acetoacetic acid).

FIG. 3 is a diagram showing the course of conversion of a 3-hydroxybutyric acid oligomer to a ketone body by intravenous administration to Wistar rats.

[Explanation of symbols]

 3-HB: 3-hydroxybutyric acid Ac-Ac: acetoacetic acid

────────────────────────────────────────────────── ─── Continuing on the front page Examiner Takanobu Morii (58) Fields investigated (Int.Cl. ⁶ , DB name) A61K 31/19 A61K 9/08 A61K 9/107 A61K 31/195 CA (STN) MEDLINE (STN )

Claims (6)

(57) [Claims] An infusion preparation containing at least one oligomer of 3-hydroxybutyric acid or a salt thereof. 2. The configuration of 3-hydroxybutyric acid, which is a monomer constituting an oligomer, is (R) type,
The infusion preparation according to claim 1, which is (S) type or an arbitrary mixture thereof. 3. The infusion preparation according to claim 1, wherein the oligomer of 3-hydroxybutyric acid is a dimer to a 10-mer. 4. The infusion preparation according to claim 1, wherein the salt of the 3-hydroxybutyric acid oligomer is a potassium salt, a sodium salt, an L-lysine salt, an L-histidine salt or an L-arginine salt. 5. The infusion preparation according to claim 1, comprising an amino acid. 6. The method can be given to a patient who is in a state where it is difficult to supply energy with normal carbohydrates due to abnormal glucose metabolism, a patient who is in a state of enhanced protein catabolism in a living body, a patient with reduced liver function, or a patient with a nutritional disorder. 2. The infusion preparation according to 1.