JPH0134972B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a bag containing a glucose electrolyte mixture for intravenous administration, which is stably sterilized and does not undergo thermal decomposition by sterilization using an autoclave or the like. Traditionally, oral nutrition,
If tube feeding is not possible or inadequate, or even if tube feeding is possible, the patient's digestive and absorptive functions are severely impaired, or food cannot pass through the gastrointestinal tract. It is well known and accepted that complete nutritional intravenous infusions are administered in cases of pathological conditions in which the primary disease is exacerbated. Complete nutrient infusion therapy, which aims to inject a large amount of nutrients through blood vessels that can replace oral administration, was extensively developed by Wretlind et al. Starting with the discovery that a fat emulsion made by emulsifying soybean oil with egg yolk lecithin could be safely injected intravenously, Dudrick et al.
It was developed based on the fact that a high-concentration glucose solution was used as the main nutritional source, amino acids were added to this solution, and a silicone rubber catheter was inserted into the superior vena cava from the subclavian vein to administer the drug, which achieved clinical effects. A complete nutritional infusion solution that can sustain life for a certain period of time by relying only on infusions must have all the nutrients necessary for life, including glucose, amino acids,
It is necessary to contain fats, vitamins and minerals. Currently, a single infusion solution containing all nutritional sources has not been manufactured due to the lack of stability among the combination drugs (particularly the stability of amino acids and fat emulsions). When performing complete nutritional infusion therapy, various complete nutritional infusions are prepared from existing infusions and hospital pharmacy preparations. In both formulations, glucose is the main nutrient source, and a highly concentrated glucose solution is used as the so-called base solution, which is supplemented with electrolytes and
Amino acids and rarely fat emulsions are added and used for infusion. Combinations of commercially available high-concentration glucose solutions and electrolyte preparations (infusions) do not provide the required combination of compound ratios, and magnesium, potassium, calcium, and phosphorus, which are said to be particularly necessary in complete nutritional infusion therapy, cannot be obtained. It was difficult to secure an appropriate amount of. Furthermore, when preparing complete nutritional infusions, there was a possibility of bacterial contamination when various electrolyte preparations were mixed at the time of use. Trace element deficiencies may appear when long-term, complete nutrient infusions containing high concentrations of glucose, electrolytes, and amino acids are administered. In order to solve the problems and shortcomings of the prior art, as a result of various researches, the present invention has developed a glucose containing the daily required amount of glucose for an adult and electrolytes containing the necessary elements for complete nutritional intravenous administration. A method for manufacturing bags containing electrolyte formulations has been achieved. The first aspect of the present invention is that the concentration range of glucose and the elements in the electrolyte in the aqueous solution is 100 to 300 g of glucose/20 to 60 mmol of potassium/5 to 10 mmol of calcium/2 to 8 mmol of magnesium/6 to 10 mmol of phosphorus. Add a pharmacologically acceptable organic acid to the aqueous solution to adjust the pH to a range of 3.5 to 5.0 to obtain a compounded drug, fill the compounded drug into a flexible plastic bag, and then heat sterilize it. It is an object of the present invention to provide a method for producing a bag containing a glucose electrolyte compound for intravenous administration, which is characterized by: The second aspect of the present invention is that the concentration range of glucose and the elements in the electrolyte in the aqueous solution is glucose 100 to 300 g/potassium 20 to 60 mmol/calcium 5 to 10 mmol/magnesium 2 to 8 mmol/phosphorus 6 to 10 mmol/ In a certain formulation, the concentration range of at least one element selected from the group consisting of zinc, iron, copper, iodine, and manganese in an aqueous solution is 15 to 45 micromoles of zinc/8 to 18 micromoles of iron/zinc, respectively. An electrolyte is added to the aqueous solution so that the content is 15-45 micromol/iron 8-18 micromol/copper 7-16 micromol/iodine 0.2-0.7 micromol/manganese 0.009-0.019 micromol/ Adjust the pH to 3.5 by adding a legally acceptable organic acid.
A method for manufacturing a bag containing a glucose electrolyte combination for intravenous administration, which comprises adjusting the concentration to a range of 5.0 to 5.0 to form a combination drug, filling the combination into a flexible plastic bag, and then sterilizing it by heat. It is about providing. In the present invention, commercially available JP glucose was used as glucose. In the electrolyte of the present invention, potassium is
Electrolytes with elemental potassium such as K ₂ HPO ₄ , KH ₂ PO ₄ , CH ₃ COOK, potassium lactate, and calcium are electrolytes with elemental calcium such as calcium gluconate, calcium pantothenate, calcium lactate, calcium acetate, etc. , magnesium is an electrolyte with elemental magnesium such as MgSO ₄ , and phosphorus is an electrolyte with elemental phosphorus such as K ₂ HPO ₄ , KH ₂ PO ₄ . Similarly, zinc in the electrolyte of the formulation filled in the second formulation bag of the present invention is
It is an electrolyte with elemental zinc such as _ZnSO4 , _ZnCl2 , iron is an electrolyte with elemental iron such as _Fe2 ( _SO4 ) ₃ , _FeSO4 , _FeCl2 , FeCl2 _, etc., and copper is an electrolyte with elemental iron such as _CuSO4 . It is an electrolyte with copper, iodine is an electrolyte with elemental iodine such as Kl, Nal, etc., and manganese is an electrolyte with elemental manganese such as manganese sulfate. Commercially available electrolytes can be used for all electrolytes used in the present invention. The formulations used in the first formulation bag of the present invention are formulated to provide the necessary amounts of nutrients and elements required by patients undergoing complete nutritional infusion therapy. That is, for the combination drug used in the first invention of the present application, the respective concentrations of glucose and elements are calculated with reference to the daily required amount of nutrients and elements for an adult and the required daily amount of water for an adult shown in Table 1. After researching the stability of the compounded drug, it was determined that the concentrations shown in Table 2 are appropriate.

【table】 I understand.

[Table] When amino acids and fats are made into an aqueous solution, even a simple aqueous solution does not have good stability, so it is preferable to mix them at the time of use. In addition, sodium is present in amino acid preparations as salts and
Since sodium hydroxide is present as a PH regulator by adding it, the required amount of sodium can be satisfied by adding the required amount of the amino acid preparation to the formulation of the present invention based on the above theory. The electrolyte in the combination drug used in the second combination drug bag of the present invention is used to prevent disorders caused by trace element deficiencies, which are not a particular problem in the short term when complete nutritional infusion is given for a long period of time. Trace elements are further added to the compounding agent used in the invention as necessary. For example, if a commonly used complete nutritional infusion consisting of a glucose electrolyte preparation and an amino acid preparation is given over a long period of time, copper deficiency may result, resulting in anemia within 2 to 7 months after starting the infusion. There have been cases where zinc deficiency has caused skin diseases between 9 and 13 days after the start of infusion, iron deficiency has caused anemia, iodine deficiency has caused thyroid adenoma, manganese deficiency has affected enzymes, etc. It is known to cause The second combination drug of the present invention is prepared by calculating the concentration of each trace element in accordance with the first combination drug, with reference to the trace elements and amounts required for adults per day shown in Table 3, and by calculating the concentration of each trace element in accordance with the first combination drug. Taking into consideration the stability of other ingredients, the concentrations shown in Table 4 were found to be appropriate.

【table】

[Table] If the concentration of these compounded drugs is below the concentration range shown in Tables 2 and 4, it will result in a deficiency of nutrients and elements.
Elements that exceed the concentration range may cause various disorders in patients, and conversely, elements that exceed the concentration range may cause toxic symptoms in some cases. The ingredients used in the first ingredient bag of the present invention include glucose, an electrolyte containing potassium,
It is obtained by weighing the magnesium-containing electrolyte and the phosphorus-containing electrolyte, respectively, and dissolving them in corresponding amounts of distilled water for injection. Conventionally, since calcium and phosphoric acid tend to form insoluble salts by mixing, it has been thought that precipitation is unavoidable during preparation and heat sterilization, and such a compound is not known. In the present invention,
For example, by adding a pharmacologically acceptable organic acid such as lactic acid to adjust the pH to a range of 3.5 to 5.0, it is possible to prevent the formation of insoluble salts of calcium and phosphoric acid. Regarding this point, regarding prescriptions 1 to 4 described below,
Prepare one without PH adjustment and one with PH adjusted with lactic acid, and autoclave (121℃ 20 minutes, 115℃ 30 minutes).
minutes), the appearance, pH, and transmittance were measured. Visible light with a wavelength of 420 nm was used to measure transmittance. (Hitachi Spectrophotometer Model 200-20) Prescription 1 Glucose 100g Calcium gluconate 2.24g (Ca: 5mM) Magnesium sulfate 0.49g (Mg: 2mM) Potassium dihydrogen phosphate 0.82g (P=K: 6mM) Potassium acetate 1.37g (K:14mM) Recipe 2 Glucose 300g per unit Calcium gluconate 4.48g (Ca:10mM) Magnesium sulfate 1.97g (Mg:8mM) Potassium dihydrogen phosphate 1.36g (P=K:10mM) Acetic acid Potassium 4.91g (K: 50mM) per Formulation 3 The following amount of zinc sulfate was added to Formulation 1. Zinc sulfate 4.3 mg (Zn: 15 μM) per formulation 4 The following amount of zinc sulfate was added to formulation 2. Zinc sulfate 12.9mg (Zn: 45μM) The measurement results are as follows. PH, appearance, transmittance T before autoclaving
(420nm) Prescription PH Appearance T (%) 1 Unadjusted 5.80 Colorless Clear 99.2 Adjusted 4.14 〃 99.5 2 Unadjusted 5.76 〃 99.5 Adjusted 4.24 〃 99.6 3 Unadjusted 5.81 〃 99.7 Adjusted 4.3 3 〃 99.6 4 Unadjusted 5.75 〃 99.7 Adjustment 4.28 〃 99.8 PH after autoclaving [121℃, 20 minutes], appearance,
Transmittance T (420nm) Prescription PH Appearance T (%) 1. Adjustment 5.12 Colorless, white precipitate *97.4 Adjustment 4.08 Colorless clear 98.6 2. Adjustment 5.19 Slight yellow, white precipitate *91.8 Adjustment 4.15 Slight yellow, clear 96.5 3 Final adjustment 5.07 Colorless, white precipitate *98.6 Adjustment 4.26 Colorless clear 98.3 4 Final adjustment 5.20 Slight yellow, white precipitate *90.2 Adjustment 4.19 Slight yellow, clear 96.4 PH, appearance after autoclaving [115℃, 30 minutes]
Transmittance T (420nm) Prescription PH Appearance T (%) 1 Final adjustment 5.10 Colorless, white precipitate *97.6 Adjustment 4.09 Colorless clear 98.3 2 Final adjustment 5.16 Slight yellow, white precipitate *95.5 Adjustment 4.16 Slight yellow, clear 97.6 3 Final adjustment 5.10 Colorless, white precipitate *99.0 Adjustment 4.25 Colorless clear 99.2 4 Final adjustment 5.19 Slight yellow, white precipitate *94.7 Adjustment 4.20 Slight yellow, clear 97.3 *...The transmittance of the supernatant liquid was measured. Furthermore, if the pH is below 3.5, no precipitation occurs, but the acidity is too strong, making it undesirable as a physiological infusion. Next, the compounding agent used in the present invention is bisque-fired to form fine particles, then filled into flexible plastic bags, and then sterilized by heat. The heat sterilization conditions are, for example, 115° for 30 minutes, 121° for 20 minutes, and 126° for 15 minutes as described in the Japanese Pharmacopoeia. In this case, the compounding agent used in the present invention is stable and does not yellow or precipitate due to thermal decomposition when sterilized by autoclave sterilization or the like. The second formulation of the present invention is produced by the same preparation method as the first formulation. In this case too, the formulation is stable. When used, the combination agent used in the first or second invention of the present application can be used as a base solution for an infusion for complete nutritional intravenous administration.
For example, 10% or 12 for 1000ml to 2000ml
By mixing 200 ml to 400 ml of the amino acid preparation at the time of use, the number of calories and elemental amounts required per day for an adult can be ensured. Furthermore, the formulation used in the present invention may include a fat emulsion instead of the amino acid formulation. In this case, since the present invention does not require the conventional operation of adding various electrolytes to a high concentration glucose solution, it is possible to prevent bacterial contamination when mixing electrolytes. The formulation used in the present invention is then heat sterilized while being filled in a flexible plastic bag. As described above, according to the present invention, the necessary daily calories and necessary elements are supplemented in just the right amount, so that it has the effect of eliminating disorders caused by accumulation of unnecessary components in the body or disorders caused by lack of necessary components. Further, the present invention reduces the chance of bacterial contamination that occurs when various electrolytes are mixed into a high concentration glucose solution, and is simplified and therefore easy to handle. Furthermore, in the present invention, since the combination drug is packed in a flexible plastic bag that complies with the provisions of the Infusion Plastic Container Test Method, an air needle is not used when it is mixed with an amino acid preparation packed in a similar plastic bag. Can be operated aseptically. The present invention will be explained below based on Examples. However, the present invention is not limited thereto. Example 1 Glucose: 140g, ZnSO ₄ 7H ₂ O: 3mg,
_MgSO4・_7H2O : 620mg, _KH2PO4 : _880mg ,
CH ₃ COOK: 28g, Calcium gluconate:
Dissolve 1.512g in distilled water for injection, add an appropriate amount of lactic acid to adjust the pH to 4.0, and add distilled water for injection to 700g.
ml, and place it in a flexible plastic bag (1) that complies with the Japanese Pharmacopoeia's Plastic Container Test Method for Infusions, and then sterilize it by heat sterilization according to the Japanese Pharmacopoeia's General Test Method for Sterilization. Example 2 Glucose: 120g, KH ₂ PO ₄ : 660mg,
CH ₃ COOK: Dissolve 2.47 g in distilled water for injection, add lactic acid to adjust the pH to 4.5, and add ZnSO ₄ 7H ₂ O 3
mg, MgSO ₄・7H ₂ O: 1.24g, calcium gluconate: 1.512g, and add distilled water for injection to 700
ml. The following steps are carried out in the same manner as in Example 1. Example 3 Glucose: 175g, KH ₂ PO ₄ : 880mg,
CH ₃ COOK: Dissolve 2.8 g in distilled water for injection, add lactic acid to adjust the pH to 4.5, and add ZnSO ₄ 7H ₂ O: 3
mg, MgSO ₄・7H ₂ O: 620 mg, calcium gluconate: 1.512 g, and add distilled water for injection to 700 mg.
ml. The following steps are carried out in the same manner as in Example 1. Example 4 Glucose: 175g, ZnSO ₄ 7H ₂ O: 3mg,
_MgSO4・_7H2O : 1.24g, _KH2PO4 : _660mg ,
CH ₃ COOK: 2.47g, Calcium gluconate:
Dissolve 1.512g in distilled water for injection, add lactic acid and adjust the pH.
Set it to 4.5. The following steps are carried out in the same manner as in Example 1. Example 5 Glucose: 175g, _K2HPO4 : _843mg ,
CH ₃ COOK: Dissolve 2.00g in distilled water for injection and add lactic acid to adjust the pH to 4.0. Add ZnSO ₄・7H ₂ O: 3
mg, MgSO ₄・7H ₂ O: 1.24 g, CuSO ₄・5H ₂ O:
2 mg of calcium gluconate and 1.512 g of calcium gluconate were added, and the same procedure as in Example 1 was carried out. Example 6 Glucose: 140g, ZnSO ₄ 7H ₂ O: 3mg,
_MgSO4・_7H2O : 620mg, _KH2PO4 : _880mg ,
CH ₃ COOK: 2.8g, Calcium gluconate:
Add 1.512g to distilled water for injection to make 700ml. The following steps are carried out in the same manner as in Example 1.

Claims (1)

[Claims] 1. The concentration range of glucose and elements in the electrolyte in the aqueous solution is set to 100 to 300 g of glucose/20 to 60 mmol of potassium/5 to 10 mmol of calcium/2 to 8 mmol of magnesium/6 to 10 mmol of phosphorus/ Add a pharmacologically acceptable organic acid to the aqueous solution to adjust the pH to a range of 3.5 to 5.0 to obtain a compounded drug, fill the compounded drug into a flexible plastic bag, and then heat sterilize it. A method for producing a bag containing a glucose electrolyte compound for intravenous administration, characterized by: 2 Zinc is added to a combination drug in which the concentration range of glucose and elements in the electrolyte in the aqueous solution is glucose 100 to 300 g/potassium 20 to 60 mmol/calcium 5 to 10 mmol/magnesium 2 to 8 mmol/phosphorus 6 to 10 mmol/ The concentration range of at least one element selected from the group consisting of iron, copper, iodine, and manganese in an aqueous solution is 15 to 45 micromol for zinc, 8 to 18 micromol for iron, 7 to 16 micromol for copper, and iodine. A pharmacologically acceptable organic acid is added to an aqueous solution containing an electrolyte so that the pH is 3.5 to 5.0.
A method for producing a bag containing a glucose-electrolyte combination for intravenous administration, which comprises adjusting the combination to a range of 1 to 1, preparing a combination, filling the combination into a flexible plastic bag, and then sterilizing it by heat.