JPH10226636A - Intravenous infusion for integrated nutrition contained in two-room vessel - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an intravenous integrated nutritious infusion put in a two room vessel which possesses excellent stability in the heat sterilization and the long term preservation, can be rapidly administrated at a required amount by convenient operation and further can be successively administrated because of no causing lactic acidosis. SOLUTION: This flexible vessel divided into two rooms by means of separation capable of mutually passing is composed of the first room filled with an infusion containing glucose and vitamin B1 and the second room filled with an infusion containing an amino acid, and an electrolyte is formulated with the infusion put in either the first or the second rooms or with the infusion put in the both rooms. The infusion in the first room contains 1.25-15.0mg/L of thiamin hydrochloride or thiamin nitrate as vitamin B1 and the infusion in the second room contains 0.05-0.2g/L of a sulfite as an stabilizer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a two-chamber intravenous comprehensive nutritional infusion preparation containing vitamin B1, and more particularly, to a first flexible container divided into two chambers by a communicating isolation means. The present invention relates to a total nutritional infusion preparation for intravenous use in a two-chamber container containing an infusion containing glucose and vitamin B1 in a chamber and an infusion containing amino acids in a second chamber.

[0002]

2. Description of the Related Art In recent years, parenteral nutrition therapy has made remarkable progress, such as nutritional management to make up for the lack of oral intake, less severe upper gastrointestinal surgery, radical surgery for malignant tumors, and severe infection. It has also been applied to severe cases such as cases and liver dysfunction. When intravenous nutrition therapy is applied to patients with such severe cases and a large amount of sugar is applied, glucose metabolism may be significantly abnormal and lactic acidosis may occur (Tadashi Okada, Annual Report 1991: High Administration of caloric infusion and acidosis, Chugai Medical, Tokyo,
991, P83). Lactic acidosis is suspected only after the appearance of symptoms of circulatory insufficiency such as respiratory failure and decreased blood pressure, and is diagnosed by measuring blood lactate concentration. However, clinically rapid measurement of blood lactate is often difficult.
In the treatment of lactic acidosis, circulatory dynamics and hypoxemia are required to be improved, and an alkalinizing agent such as a vasopressor or sodium bicarbonate is used depending on the case. However, these treatments are not fundamental treatments, and these treatments alone can cause severe lactic acidosis,
Symptoms often worsen (Naoshi Ishida et al., Infusion Guide: Infusion Therapy for Lactic Acidosis, Bunkodo, Tokyo, 19
92, p214). Therefore, it is very important to pay attention to the onset of lactic acidosis due to abnormal glucose metabolism during parenteral nutrition therapy.

On the other hand, lactic acidosis that developed during parenteral nutrition therapy was reduced by vitamin B1 (300 mg).
/ Day) showed a remarkable effect (S. Mattiol et al., JPEN: Wernicke's Encephalopa)
thy during total parenteralnutrition, 12, 626 (198
8)). However, although vitamin B1 has a deep relationship with glucose metabolism, and it has been known for a long time that vitamin B1 deficiency is caused by glucose load, there are those that are mainly characterized by nervous symptoms and those with a focus on cardiovascular disorders, Furthermore, they show various clinical features, from acute to chronic types (J. Zak et al.,
JPEN: Dry beriberi: unusual complication of prolong
ed parenteral nutrition, 15,200 (1991), etc.), it is often difficult to make a clinically accurate diagnosis. In addition, sufficient knowledge has not been obtained regarding the dose of vitamins for substantially preventing lactic acidosis that occurs during parenteral nutrition therapy. Furthermore, even if vitamins are added, it is necessary to open an ampoule of the vitamin injection solution for each infusion preparation and to co-inject into the infusion with a syringe, which not only complicates the procedure, but also poses risks such as incorrect medication, microbial contamination, and contamination of glass fragments. Inevitable (Hideo Takamatsu et al., Japanese clinical practice, parenteral enteral nutrition: vitamin preparations, 629, 1991 special issue, P13
0). Therefore, in clinical practice, rapid administration of vitamins that have a substantial preventive effect on lactic acidosis by simple operations is very important because it can eliminate a number of complex factors of lactic acidosis. It is. Due to these problems, the development of infusions premixed with vitamins has been promoted, but these vitamins are very unstable (Kazuyoshi Saito et al., Japanese clinical practice, parenteral nutrition: parenteral and parenteral nutrition). Enteral nutrition and essential vitamins, 629, 1991 special issue, P27) and many others). It is still difficult to prepare a heat-sterilized preparation of an intravenous total nutritional infusion having excellent storage stability.

[0004] Japanese Patent Application Laid-Open No. 8-182739 discloses an intravenous nutritional infusion preparation containing various vitamin preparations including vitamin B1 and the like in advance. However, in this infusion preparation, each preparation must be distributed and accommodated in three chambers, and it is necessary to develop a new infusion container having three chambers. Further, an infusion preparation characterized by containing vitamins in an infusion container comprising two chambers has also been disclosed (JP-A-Hei.
No. 8-191873), this infusion preparation uses fat as a calorie source, and can prevent the deficiency of essential fatty acids, but the administration of fat causes accumulation in organs and an increase in blood triglyceride concentration. There is a risk (Kiichi Isono et al., Infusion Guide: High Calorie Infusion Formulation, Bunkodo, Tokyo, 1992, p106). Furthermore, if the fat emulsion and the amino acid are stored in the same container, the fat particles become coarse and phase separation occurs. On the other hand, an in-use mixing type infusion containing water-soluble vitamin Bs has also been proposed (Japanese Patent Application Laid-Open No. Hei 8-134559). However, since it does not contain sulfite, it can be used as an amino acid infusion during sterilization or storage. Quality deterioration such as coloring is inevitable.

[0005] In addition, only vitamin B1 which is used in injections includes thiamine, fursultiamine, succitiamine, thiamine disulfide, bisbutitiamine, prosultiamine, thiamine diphosphate chloride and its hydrochloride. In addition, there may be mentioned many such as dicetiamine, octiamine, bisbutiamine, bisbenthamine and benfotiamine, including those used as oral preparations. Furthermore, the pharmaceutical stability of these vitamin B1s differs greatly when formulated in nutrient infusions, and even vitamin B1 developed to be used as a raw material for injections is stable in intravenous comprehensive nutritional infusions. You can't maintain sex.

[0006] Furthermore, when administering parenteral nutrition therapy, various amino acids need to be administered in order to normalize the metabolic mechanism of the living body, which is utilized for body protein synthesis and nitrogen balance. However, among the amino acids, it is clear that highly reactive amino acids, for example, L-cysteine have a strong reducing action on vitamin B1, but in order to enhance the overall nutritional effect, these amino acids are also required. Must be included. In addition, amino acid infusion containing L-cysteine,
Since not only L-cysteine itself is easily decomposed but also the infusion itself is likely to be colored yellow-brown, a stabilizer such as sulfite is conventionally added. Therefore, by opening the partition of the flexible container (double bag) during clinical use and mixing the amino acid infusion containing L-cysteine and the infusion containing vitamin B1, the stability of vitamin B1 can be sufficiently ensured. In addition, there was a problem that the required amount could not be administered.

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to excel in stability during heat sterilization and long-term storage, and in a clinical setting, a required amount can be rapidly administered by a simple operation, and lactic acidosis is caused. An object of the present invention is to provide a total intravenous nutritional infusion preparation in a two-chamber container which can be continuously administered without performing the treatment.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies on the above problems, and as a result, have used glucose as a sugar source for an intravenous comprehensive nutritional infusion preparation in a two-chamber container and optimally used only vitamin B1. It has been found that when added, the development of lactic acidosis due to parenteral nutrition therapy can be substantially prevented, and when thiamine hydrochloride or thiamine nitrate is used as vitamin B1, the stability can be maintained even after mixing. This led to the completion of an intravenous total nutritional infusion preparation in a chamber container.

That is, according to the present invention, an infusion solution containing glucose and vitamin B1 is contained in a first chamber of a flexible container partitioned into two chambers by communicable isolation means, and an amino acid is contained in a second chamber. In an infusion container containing an infusion solution and an electrolyte mixed in one or both of the infusion solutions contained in the first and second chambers, thiamine hydrochloride or thiamine nitrate as vitamin B1 is added to the infusion solution in the first chamber. 25
２15.0 mg / L, and 0.05 to 0.2 g / L of sulfite as a stabilizer in the infusion in the second chamber, wherein the two-room container contains an intravenous general nutritional infusion preparation. It is.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The ratio of the volumes of infusions contained in the first chamber and the second chamber of the total intravenous nutritional infusion preparation in a two-chamber container according to the present invention can be appropriately adjusted. The ratio of the capacity of the chamber to the capacity of the second chamber is preferably 4: 1 to 1: 1 (V / V). Further, the total volume when the infusions contained in the individual compartments are mixed is preferably in the range of 0.5 to 3.0 L.

Therefore, when the infusions contained in the individual compartments are mixed, they are preferably prepared in the following composition range. Glucose 25-350 g / L Amino acid total amount 10-45 g / L L-isoleucine 0.5-5.6 g / L L-leucine 0.9-7.4 g / L L-lysine 0.3-7. 1 g / L L-methionine 0.05 to 6.9 g / L L-phenylalanine 0.04 to 6.9 g / L L-threonine 0.2 to 3.3 g / L L-tryptophan 0.08 to 1.9 g / L L-valine 0.4 to 6.2 g / L L-arginine 0 to 9.2 g / L L-histidine 0 to 3.5 g / L aminoacetic acid 0 to 7.2 g / L LL-alanine 0-5.0 g / L L-cysteine 0.02-0.5 g / L L-aspartic acid 0-2.4 g / L L-glutamic acid 0-2.9 g / L L- Proline 0 to 4.6 g / L L-Serine 0 to 2.9 g / L -Tyrosine 0 to 0.4 g / L Sodium 20 to 150 mM Potassium 0 to 50 mM Calcium 0 to 20 mM Magnesium 0 to 20 mM Phosphorus 0 to 20 mM Chlorine 20 to 150 mM Zinc 0 to 100 μM Vitamin B1 0.8 ~ 12.0 mg / L sulfite 0.01 ~ 0.07 g / L

The infusion solution contained in the second chamber of the above-mentioned infusion solution contains a sulfite as a stabilizer, and its concentration can be appropriately adjusted, but is preferably 0.05 to 0.2 g / L.
Range. Further, the preferable concentration when the two chambers are opened and mixed is 0.01 to 0.07 g / L. Examples of the sulfite used include sodium hydrogen sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, and Rongalite.

The infusion solution contained in the first chamber may have a pH of 2.0 to 6.0, preferably acetic acid or maleic acid, by adding a pH adjuster such as hydrochloric acid, acetic acid, citric acid, maleic acid, sodium hydroxide and the like. The pH is adjusted to 3.0 to 5.0 using an acid.

The vitamin B1 used for the infusion stored in the first chamber is thiamine hydrochloride or thiamine nitrate, preferably thiamine hydrochloride. The preferred concentration is 1.25 to 15.0 mg / L, and the concentration when the two chambers are opened and mixed is 0.8 to 12.0 mg / L.

The amino acids used for the infusion stored in the second chamber include not only free amino acids but also pharmacological agents such as metal salts such as sodium salts, organic acid salts such as acetate salts, and mineral acid salts such as hydrochloride salts. Or a part of amino acids may be converted into a peptide.

As the electrolyte used in the present invention, any of the conventionally used electrolytes can be used. For example, sodium hydrogen carbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, lactic acid Sodium, sodium citrate, sodium chloride, sodium sulfate, potassium chloride, potassium iodide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium lactate, potassium citrate, potassium acetate, potassium lactate,
Calcium lactate, sodium glycerophosphate, potassium glycerophosphate, calcium glycerophosphate, calcium gluconate, calcium chloride, magnesium chloride, magnesium sulfate, magnesium acetate, zinc chloride, zinc sulfate, iron sulfate, ferrous chloride, ferric chloride, glucon Iron acid,
Examples thereof include copper sulfate and manganese sulfate.

Furthermore, the nutrients such as trace elements and other vitamins may be incorporated into the two-chamber container intravenous total nutritional infusion preparation of the present invention, if necessary, in consideration of the daily intake. Can be.

The infusion container used in the present invention is, for example, a flexible plastic container made of plastic, the central portion of which is welded by a thermal pseudo-welding method so as to be stripped in a strip shape, and is a strictly isolated private chamber. Can be used, each of which has an infusion inlet or an outlet. The infusion container can communicate the infusion quickly with a simple operation even in clinical practice by communicating between the isolated private rooms immediately before the infusion administration.

The total intravenous nutritional infusion preparation in a two-chamber container according to the present invention can be produced according to a known method using commonly used pharmaceutical additives.

[0020]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 The first chamber composition shown in Table 1 below was dissolved in distilled water to make 700 ml, the pH was adjusted to 4.5 with acetic acid, and the total amount was made 800 ml. This solution was filtered through a membrane filter and filled into the first chamber of a double bag defined by an easy-peal seal.
The space was replaced with nitrogen gas and sealed. Next, the second chamber composition shown in Table 2 below was dissolved in distilled water to give a total amount of 300.
ml. This solution was filtered through a membrane filter, filled in the second chamber of the double bag, and the space was replaced with nitrogen gas and sealed. The prepared double bag was subjected to high-pressure steam sterilization according to a conventional method. After cooling, an oxygen scavenger was enclosed, and outer packaging was performed with an EVAL film.

[0022]

[Table 1]

[0023]

[Table 2]

Example 2 The same procedure was followed as in Example 1 except that thiamine nitrate was used.

Example 3 The first chamber composition shown in Table 3 below was dissolved in distilled water to make 700 ml, the pH was adjusted to 4.5 with acetic acid, and the total amount was made 800 ml. This solution was filtered through a membrane filter and filled into the first chamber of a double bag defined by an easy-peal seal.
The space was replaced with nitrogen gas and sealed. Next, the second chamber composition shown in Table 4 below was dissolved in distilled water to make up to 350 ml, and the pH was adjusted to 7.0 with acetic acid.
l. This solution is filtered through a membrane filter,
The double bag was filled in the second chamber, and the space was replaced with nitrogen gas and sealed. The prepared double bag was subjected to high-pressure steam sterilization according to a conventional method. After cooling, an oxygen scavenger was enclosed, and outer packaging was performed with an EVAL film.

[0026]

[Table 3]

[0027]

[Table 4]

Example 4 The first chamber composition shown in Table 5 below was dissolved in distilled water to make 700 ml, the pH was adjusted to 4.5 with acetic acid, and the total amount was made 800 ml. This solution was filtered through a membrane filter and filled into the first chamber of a double bag defined by an easy-peal seal.
The space was replaced with nitrogen gas and sealed. Next, the second chamber composition shown in Table 6 below was dissolved in distilled water to make a total amount of 400.
ml. This solution was filtered through a membrane filter, filled in the second chamber of the double bag, and the space was replaced with nitrogen gas and sealed. The prepared double bag was subjected to high-pressure steam sterilization according to a conventional method. After cooling, an oxygen scavenger was enclosed, and outer packaging was performed with an EVAL film.

[0029]

[Table 5]

[0030]

[Table 6]

[Examples 5 to 7] Of the first chamber compositions shown in Table 5 above, the added amounts of thiamine hydrochloride were 2.5 mg (Example 5), 6.0 mg (Example 6), and 12. Except that the amount was 0 mg (Example 7), it was produced in the same manner as in Example 4.

Example 8 The first chamber composition shown in Table 7 below was dissolved in distilled water to make 700 ml, the pH was adjusted to 4.5 with acetic acid, and the total amount was made 800 ml. This solution was filtered through a membrane filter and filled into the first chamber of a double bag defined by an easy-peal seal.
The space was replaced with nitrogen gas and sealed. Next, the second chamber composition shown in Table 8 below was dissolved in distilled water to make 250 ml, and the pH was adjusted to 7.0 with acetic acid.
l. This solution is filtered through a membrane filter,
The double bag was filled in the second chamber, and the space was replaced with nitrogen gas and sealed. The prepared double bag was subjected to high-pressure steam sterilization according to a conventional method. After cooling, an oxygen scavenger was enclosed, and outer packaging was performed with an EVAL film.

[0033]

[Table 7]

[0034]

[Table 8]

Embodiments 9 and 10 The second embodiment shown in Table 8 above
In the chamber composition, the amount of sodium bisulfite added was set to 0.1.
Production was carried out in the same manner as in Example 8, except that the amounts were 03 g (Example 9) and 0.06 g (Example 10).

[Comparative Examples 1 to 4] The production of Control Examples 1 to 4 used in Test Example 1 was carried out by using fursultiamine hydrochloride (Control Example 1), thiamine disulfide (Control Example 2), and cicotiamine (Vitamin B1) as a source. Comparative Example 3) was performed in the same manner as in Example 1 except that thiamine diphosphate chloride (Control Example 4) was used.

[Comparative Example 5] The preparation of Comparative Example 5 used in Test Example 2 was the same as that of Example 3 except that thiamine hydrochloride was not added.
The same was done.

[Comparative Examples 6 and 7] The production of Control Examples 6 and 7 used in Test Example 3 was carried out except that the amount of thiamine hydrochloride added was 0 mg (Control Example 6) and 24.0 mg (Control Example 7). Performed in the same manner as in Example 4.

[Comparative Examples 8 to 10] In Comparative Examples 8 to 10 used in Test Example 4, the amount of sodium bisulfite added was 0 g (Control Example 8), 0.003 g (Control Example 9) and 0.15 g.
g (Comparative Example 10) was carried out in the same manner as in Example 8.

Test Example 1 Examples 1 and 2 and Comparative Examples 1 to
The storage stability of the first room of No. 4 was determined by the residual ratio and transmittance of vitamin B1 after storage at 40 ° C. (75% RH) for one month (430 n).
m) and properties (Table 9). As a result, in Control Examples 3 and 4 using sicotiamine and thiamine diphosphate chloride, it was clarified that although the transmittance and the properties were not changed, the stability of vitamin B1 after storage could not be maintained. Also, it was shown that thiamine hydrochloride (Example 1), thiamine nitrate (Example 2), fursultiamine hydrochloride (Control example 1) and thiamine disulfide (Control example 2) maintain a residual ratio of 90% or more. .
Therefore, the remaining ratio of vitamin B1 after mixing was measured by further connecting the first chamber and the second chamber of the double bag (Table 10). As a result, the residual rates of fursultiamine hydrochloride (Comparative Example 1) and thiamine disulfide (Comparative Example 2) sharply decreased immediately after mixing, and became 50% or less.
However, in Examples 1 and 2, it became clear that the residual ratio was maintained at 90% or more. As mentioned above, vitamin B
It was clarified that the infusion using thiamine hydrochloride or thiamine nitrate as 1 has excellent storage stability and can maintain the stability even after the double bag is opened.

[0041]

[Table 9]

[0042]

[Table 10]

Test Example 2 Male 7-week-old Crj: CD male rats (7 rats per group) were fasted overnight and then catheterized through the right external jugular vein under ether anesthesia. Then, the test liquid of Example 3 and Control Example 5 was added to 1.0 ml on the first day.
Infusion was continued for 14 days at a dose rate of 2.0 ml / hr on the second day and 2.0 ml / hr on the third and subsequent days (the infusion was changed daily) for 14 days. In the administration group of Control Example 5, one animal died of lactic acidosis on Day 10 and one animal on Day 12. When the blood pH after the infusion administration was measured, the blood pH was 7.154 ± 0.1 in the control group of Control Example 5.
04 (mean value of 5 cases) and 7.401 ± 0.0 of the administration group of Example 3
Compared to 17, she showed acidosis symptoms. The blood lactic acid value was 71.3 ± 5.12 mg / dl, which was 22.1 in Example 3.
The value was clearly higher than ± 4.35 mg / dl. From the above results, it was clarified that if an infusion solution containing only thiamine hydrochloride as vitamin B1 was used, lactic acidosis during parenteral nutrition therapy could be prevented, and thus continuous administration was possible. In addition, there was no danger of erroneous administration, microbial contamination, contamination of glass fragments and the like during use, and administration was possible by a simple operation.

[Test Example 3] Five-week-old Crj: CD male rats were used (six rats per group), and vitamin B1 deficient feed and water were added to 12 rats.
Intake of vitamin B1 deficient rats (7
Weeks of age). Vitamin B1 deficient rats fasted overnight underwent catheterization from the right external jugular vein under ether anesthesia. Next, each test solution was added at 1.0 ml / h on the first day.
r, continuous infusion at a dose rate of 2.0 ml / hr on the second day and 2.5 ml / hr on the third and subsequent days for 7 days. Comparative Example 6
The administration group was dissected after the administration was stopped because four out of six animals died of lactic acidosis on the fourth day. Table 11 summarizes the blood vitamin B1 concentration after the infusion administration and the measurement result of the vitamin B1 balance on the last day. In addition, the value of the free-feeding group of the same age was measured and set as a normal value. As a result, in the administration group of the control example 6, 4 cases dropped out, and the blood vitamin B1 concentration and the vitamin B1 balance of the remaining 2 cases were also 17 ng / ml.
(Day 4) and −0.3 μg / day (3 to 4 days), 272.2 ng / ml (Day 7) and 68.4 μg / day (6 to
7), a clear lower value was shown. Comparative Example 7
333.2 ng / ml (day 7) and 96.3 μg / day
(6-7 days), significantly higher than the free-feeding group. On the other hand, in the administration groups of Examples 4 to 7, 252.5 to 271.3 ng /
ml (day 7) and 67.7-70.3 μg / day (6-7 days), which were equivalent to those in the free-feeding group. As described above, there is an optimum range of the amount of vitamin B1 to be added, and it can be continuously and safely administered without causing lactic acidosis at the time of parenteral nutrition therapy when the optimum amount is added. Became clear.

[0045]

[Table 11]

Test Example 4 Examples 8 to 10 and Control Example 8
By communicating the first chamber and the second chamber of No. 10 to No. 10, the residual ratio of vitamin B1 after mixing was measured (Table 12). As a result, in Control Example 10, it became clear that stability after mixing could not be maintained for 2 days. On the other hand, it became clear that Examples 8 to 10 and Control Examples 8 and 9 maintain a residual ratio of 90% or more. Then, Examples 8 to 1
0 and the storage stability of the second chambers of Control Examples 8 and 9 were measured at 40 ° C. (7
(5% RH) The transmittance and the properties at 430 nm after storage for one month were evaluated by measuring the residual ratio of L-cysteine (Table 1).
3). As a result, in Control Examples 8 and 9, significant changes were observed in the transmittance and properties, and the L-cysteine content could not be sufficiently maintained. Was stable in each case. From the above, there is an optimal range for the amount of vitamin B1 added in the first compartment and the amount of sodium bisulfite added in the second compartment, while maintaining the stability of amino acids and maintaining the stability of amino acids after opening the double bag. It is noteworthy that a stable addition amount which can be administered stably was found.

[0047]

[Table 12]

[0048]

[Table 13]

[0049]

As described above, the total intravenous nutritional infusion preparation in a two-chamber container according to the present invention takes into account the amount of vitamin B1 and the amount of the sulfite as a stabilizer. Outstanding stability in storage, and in clinical practice, the required amount can be rapidly and stably administered by a simple operation, and can be administered continuously since it does not cause lactic acidosis.

Claims (1)

[Claims] An infusion solution containing glucose and vitamin B1 is accommodated in a first chamber of a flexible container divided into two chambers by a communicating isolation means, and an infusion solution containing an amino acid is accommodated in a second chamber. In an infusion container containing an electrolyte in one or both of the infusions accommodated in the first and second chambers, 1.25 to 15 thiamin hydrochloride or thiamine nitrate as vitamin B1 is added to the infusion in the first chamber. 0 mg / L, and 0.1% of sulfite as a stabilizer in the infusion in the second chamber.
An intravenous general nutritional infusion preparation containing a two-chamber container, containing 0.5 to 0.2 g / L.