JPH02191227A - Basal solution for hyperalimentation - Google Patents

Abstract

PURPOSE:To obtain a basal solution for hyperalimentation capable of suppressing digestive tract atrophy of patients under operation of total parenteral nutrition(TPN) by blending a human epidermal growth factor(hEGF) with glucose and various electrolytes. CONSTITUTION:A basal solution for hyperalimentation obtained by mixing and dissolving 1mug-10mg/l, preferably 10mug-5mg/l hEGF and 140-480g/l, preferably 150-440g/l glucose in a suitable diluent, such as distilled water for injection, adding various electrolytes thereto, regulating the concentrations of elements constituting the electrolytes in the aqueous solution within the ranges shown in the table and regulating the pH thereof within the range of 4.0-5.5, preferably 4.7-5.1. The above-mentioned basal solution is further blended with 200-1000ml amino acid pharmaceutical in about 7-12% concentration, further blending, as necessary, various vitaminic agents, fatty emulsions, etc., in use and employed as a solution for hyperalimentation used in TPN. The oral nutriment ingestion by patients under operation of TPN is facilitated by administering the aforementioned basal solution and the recovery period can be remarkably shortened.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to nutritional infusions, more particularly total parenteral nutrition (T
P N) This invention relates to a novel high-calorie infusion basic fluid that can significantly suppress atrophy of the gastrointestinal tract observed in patients at the time of treatment.

Conventional technology In general, peripheral veins are susceptible to phlebitis or thrombosis even with normal non-hypertonic infusions, and cannot withstand the administration of hypertonic, high-calorie nutrient infusions. It is commonly administered. Here, the TPN method is a method in which a catheter is inserted into a central vein such as the supraclavicular vein, and an energy source of about 500 to 2000 calories per day is administered and replenished as a nutritional infusion via the catheter. However, the above-mentioned TPN method is performed when gastrointestinal nutrition is impossible, such as when there is gastrointestinal malabsorption, after abdominal surgery trauma, or when there is a disturbance of consciousness, or when it is necessary to avoid gastrointestinal nutrition, such as when preparing for surgery. The treatment period usually ranges from a few hours to a few weeks, but can last up to several months in some patients.

However, according to the above-mentioned TPN method, in addition to side effects caused by large doses of acids, bases, carbohydrates, etc., such as hyperglycemia, increased urine sugar, acid-base balance disorders, and azotemia, the causes are still unknown. However, there have been various reports that it causes a disorder called gastrointestinal atrophy.

This atrophy of the gastrointestinal tract during TPN has disadvantages such as reducing the normal function of the gastrointestinal tract, making it difficult for patients to take oral nutrition after TPN, and significantly delaying the patient's recovery period. Although it is desired to develop an improvement means for suppressing the disease, no such improvement means are currently known, and no improvement drugs have been developed at all.

Problems to be Solved by the Invention An object of the present invention is to provide a new high-calorie infusion basic solution that can suppress the gastrointestinal atrophy observed in patients undergoing TPN.

In view of the above-mentioned current situation, the present inventors have conducted intensive research on gastrointestinal atrophy seen during TPN and measures to improve it.
mal Growth Factor, hereinafter referred to as rhE
When hEGF (referred to as GFJ) is administered to a patient in the form of a high-calorie nutritional infusion containing glucose and various electrolytes, hEGF's inherent biological activities, such as suppressing gastric acid secretion, gastric mucosal regeneration, and We have obtained the surprising finding that it exhibits a suppressive or improving effect on gastrointestinal atrophy, which is different from restorative effects and is completely unpredictable from such effects, and has now completed the present invention, which meets the above objectives. .

Means for solving the problem, that is, according to the present invention, contains glucose and at least the following electrolyte constituent elements, the concentration of these in an aqueous solution and the pH of the aqueous solution are within the following range, and human epidermal cells Growth factor (hEGF) from 1μg/l to 10mg/l! Provided is a high-calorie infusion base solution characterized by containing the following:

Glucose 140-480 g/ltNa
"49.0~89.0m net/lK"
28.0~64.0mmol/A! M
g" 3.0~7.5n+ mol//Ca
2+3.0~9. On mol/lCA'
49. 0-89. Ommol//P
8. Om23. 0m
mol/l pH 4.0-5.5゜ In the high-calorie infusion basic solution of the present invention, hEGF is used as a component that has the effect of suppressing gastrointestinal atrophy, and hEGF was first isolated from human urine by Gregory. (H, Gregot7. Nafute.

257, 324 (1975)). The latter (natural type) is a polypeptide with 53 amino acid residues and 3 disulfide bonds, and various recombinant hEGF and its derivatives are currently being produced using genetic recombination technology (J, Sm1th et if,, Nuc
leicAcids Rcsearch, 10.44
67 (1982); JP-A-58-21669; M, S, Urdex ef al, Pro
c.

Natl, ^cad, Sci,, U, S, ^1.80.
7461 (1983); JP-A-61-88881; JP-A-61-15691; JP-A-63-1
See Publication No. 2298, etc.]. hEGF has traditionally been used in the field of internal medicine to treat gastric acid secretion and other functions.
Although there have been attempts to use hEGF as an investigational drug for duodenal ulcers, it has been shown that hEGF has the effect of suppressing or improving gastrointestinal atrophy, and that a high-calorie nutritional infusion containing hEGF can effectively reduce gastrointestinal atrophy seen during TPN. This fact was discovered for the first time by the present inventors and was completely unknown in the past.

In the present invention, any of the previously known hEGFs mentioned above can be used. That is, the hEGF may be a natural type or a recombinant type obtained by genetic recombination technology;
As long as it has activity, even a fusion peptide type obtained according to genetic recombination techniques as shown in the above-mentioned documents can be obtained by modifying a part of the amino acid sequence of natural hEGF such as addition, deletion, or substitution. It may also be a derivative that can be used. Examples of such derivatives include those in which the 21st amino acid (methionine) of natural hEGF (consisting of 53 amino acids) is replaced with leucine or valine, and the 53rd amino acid (methionine) is replaced with leucine or valine.
Examples include those in which glutamine is substituted for (arginine), and combinations thereof.

These can be used in the present invention in commonly available purified forms. In addition, the second grade purified product may be further purified and used according to known methods, or it may be independently manufactured and purified according to various known methods and used.

The hEGF used in the present invention can be easily converted into a pharmaceutically acceptable acid addition salt by addition reaction with a suitable inorganic or organic acidic compound according to a conventional method, or can be easily converted into a pharmaceutically acceptable acid addition salt using a suitable alkali metal compound. It can be easily converted into a basic addition salt by addition reaction with a basic compound such as or amines.

These addition salts have pharmacological activity similar to the free form of hEGF and can be similarly utilized in the present invention.

The high-calorie infusion basic solution of the present invention contains each effective amount of hEGF (including its salt) and glucose, that is, glucose 140%
~480g//, preferably 150-440g/l and hEGF1μg/1-10mg//, preferably 1
Mix and dissolve 0 μg/l to 5 mg/l in a suitable diluent such as distilled water for injection, add various electrolytes to this solution, and adjust the concentration of the electrolyte constituent elements in the aqueous solution to the above-mentioned predetermined range and its pH to the same level. It is adjusted to the above-mentioned predetermined range, that is, 4.0 to 5.5, preferably 4.7 to 5.1. The concentration of each electrolyte constituent element in the aqueous solution is selected from the following ranges.

Composition range Preferred composition range Optimal composition range (m mol
/ /) (rrr mol/ l) (m mo
l/ /)N a 49.0-89.0 49.
O~67, 0 55.4~61°2 +28.0~64
．． 0 28.0~58.0 31.6~52.5Mg"
3.0~7.5 3.0~? ,0 3.9~61C
a”+3.0~9.0 3.0~9.0 3.9~7.
9CI 49.0~89.0 49.0~67.0
55.4~61.2P 8.0~23.0
8.0 to 23.8 9.5 to 21.0 Furthermore, the high calorie infusion basic solution of the present invention contains electrolyte constituent elements other than those mentioned above, such as sulfuric acid, acetic acid, zinc, etc. within the following ranges (tolerable and preferred ranges). ) can be contained at an appropriate concentration selected from.

Tolerable range suitable range SO+ 3.0~? , 5 3.0~7.0 (
m mol#)C)l+cOo 8.0-16.
0 8.0~16.0 (mmol/l)zn""
10.0-47.8 10.0-39.0 (μm
ol/V) Furthermore, if necessary, trace elements such as iron, copper, manganese, and iodine can be appropriately blended into the high-calorie infusion base solution of the present invention.

As the source of the electrolyte ions, compounds similar to those used in general electrolyte infusions and high-calorie infusion basic solutions can be used. Specific examples include sodium chloride, sodium acetate, sodium citrate, sodium phosphate, disodium phosphate, sodium sulfate, sodium lactate, etc. as Na+ sources, potassium chloride, potassium phosphate, etc. as K+ sources. Dipotassium phosphate, potassium acetate, potassium lactate, potassium sulfate, potassium citrate, etc., Ca2+ sources include calcium chloride, calcium gluconate, calcium pantothenate, calcium lactate, calcium acetate, etc., Mg2+ sources include magnesium sulfate, Magnesium chloride, magnesium acetate, etc., as a P source, orthophosphoric acid, sodium phosphate, disodium phosphate, sodium glycerophosphate, etc., C
Examples of I-sources include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc., which may be in the form of hydrates, and may be used in appropriate combinations so as to provide an electrolyte concentration composition within the above range. can be done.

In addition, the high calorie infusion basic solution of the present invention may include, if necessary,
Add appropriate amounts of pH adjusters such as hydrochloric acid, acetic acid, lactic acid, malic acid, citric acid, stabilizers such as sodium sulfite, sodium bisulfite, sodium pyrosulfate, sodium thiosulfate, and other additives such as various vitamins. It can also be blended.

The aqueous solution thus obtained can be sterilized by conventional heat sterilization, sterile filtration, etc. to prepare the high-calorie infusion base liquid product of the present invention.

The high calorie infusion base liquid product of the present invention prepared above is:
Its pH is 4.0-5.5, preferably 4.7-5.1
It is appropriate that it is prepared as follows.

The high-calorie infusion basic solution of the present invention, like general basic solutions of this type, is used at a dose of about 500 to 2000 yJ per adult per day, and the pathological condition, nutritional status, age, and weight of the patient to whom it is applied. The amount can be increased or decreased as appropriate depending on the situation. In addition, the above basic solution of the present invention generally has about 200% of the commercially available 7 to 12% amino acid preparations.
-100011 can be used as a high-calorie nutritional infusion for TPN by further adding various vitamins, fat emulsions, etc. as necessary.

Effects of the Invention The high-calorie infusion basic solution of the present invention has the effect of suppressing gastrointestinal atrophy in patients undergoing TPN, and its administration maintains a normal gastrointestinal tract even under TPN. The patient's oral nutritional intake after TPN can be maintained, and the patient's recovery period can be significantly shortened.

EXAMPLES Hereinafter, in order to explain the present invention in more detail, examples of manufacturing the high-calorie infusion basic solution of the present invention will be given as examples. In addition, as hEGF on each side, a product manufactured by Earth Pharmaceutical Co., Ltd. was used.

Example 1 Glucose 167 g Sodium chloride 2930 mg Dipotassium hydrogen phosphate 1740 mg Potassium acetate
1310mg calcium chloride dihydrate
610mg Magnesium sulfate heptahydrate 1030m
g Zinc sulfate heptahydrate 9. 6mghE
GF 300 μg After dissolving each of the above components in distilled water for injection, add citric acid 1180 mg and sodium citrate dihydrate 8 as a pH adjuster.
After adding 00 mH to adjust the pH to 5.0 and adding a small amount of sodium bisulfite as a stabilizer, the total amount was adjusted to 1.
! And so.

The obtained sugar-electrolyte aqueous solution was then sterile-filtered and filled into an infusion container to obtain a high-calorie infusion base solution of the present invention.

Example 2 Glucose 292 g Sodium chloride 2830 mg Dipotassium hydrogen phosphate 2610 mg Potassium acetate
1150mg calcium chloride dihydrate
730mg Magnesium sulfate heptahydrate 1230m
g Zinc sulfate heptahydrate 9. 6mghE
A high-calorie infusion base solution of the present invention was obtained in the same manner as in Example 1 using 450 μg of GF, 1520+ g of citric acid as a pH adjuster, and 970 mg of sodium citrate dihydrate.

Example 3 Glucose 417 g Sodium chloride 2540 mg Dipotassium hydrogen phosphate 3480 mg Potassium acetate
980mg calcium chloride dihydrate 1
100mg magnesium sulfate heptahydrate 1440m
g Zinc sulfate heptahydrate 9. 6+agh
A high-calorie infusion base solution of the present invention was obtained in the same manner as in Example 1 using 600 μg of EGF and each of the above components and 2110 mg of citric acid and 1460 mg of sodium citrate dihydrate as pH adjusters.

Example 4 Glucose 292 g Sodium chloride 2630 mg Dipotassium hydrogen phosphate 348011 g Calcium chloride dihydrate 590 mg Magnesium sulfate hexahydrate
810mghEGF 80
0μg Each of the above components and citric acid 11 as a pH adjuster
A high-calorie infusion base solution of the present invention was obtained in the same manner as in Example 1 using 80 mg of sodium citrate dihydrate and 880 mg of sodium citrate dihydrate.

Example 5 Glucose 375 g Dipotassium hydrogen phosphate 1450 mg Potassium chloride
1960mg sodium chloride
2310mg calcium gluconate 1
790mg Magnesium sulfate heptahydrate 1030m
g Zinc sulfate heptahydrate 4. 8mghE
A high-calorie infusion base solution of the present invention was obtained in the same manner as in Example 1 using 100 μg of GF and 820 mg of citric acid and 1,630 mg of sodium citrate dihydrate as pH adjusters.

Example 6 Glucose 292 g Sodium chloride 2830 mg Dipotassium hydrogen phosphate 2610 mg Potassium acetate
1150mg calcium chloride dihydrate
730mg Magnesium sulfate heptahydrate 1230
mg zinc sulfate heptahydrate 9.6BhEG
A high-calorie infusion base solution of the present invention was obtained in the same manner as in Example 1 using 800 μg of F and each of the above components, 1520 mg of citric acid as a pH adjuster, and 970+++ g of sodium citrate dihydrate.

Example 7 Glucose 417 g Sodium chloride 2540 mg Dipotassium hydrogen phosphate 3480 mg Potassium acetate
980mg calcium chloride dihydrate 1
100mg magnesium sulfate heptahydrate 1440m
g Zinc sulfate heptahydrate 9. 6mghE
A high-calorie infusion base solution of the present invention was obtained in the same manner as in Example 1 using 1000 μg of GF and 2110 mg of citric acid and 1460 mg of sodium citrate dihydrate as pH adjusters.

Example 8 Glucose 389g Sodium chloride 3770mg Dipotassium hydrogen phosphate 3480a+g Potassium acetate
1530mg calcium chloride dihydrate
980mg Magnesium sulfate heptahydrate 1640
+eg zinc sulfate heptahydrate 12.8+ag
A high-calorie infusion base solution of the present invention was obtained in the same manner as in Example 1 using 800 μg of hEGF and each of the above components and 2180 mg of citric acid and 1310 mg of sodium citrate dihydrate as p)I regulators.

(that's all)

Claims (2)

[Claims] (1) Contains glucose and at least the following electrolyte constituent elements, the concentration of these in the aqueous solution and the pH of the aqueous solution are within the following ranges, and human epidermal growth factor (hEGF)
) in a range of 1 μg/l to 10 mg/l. Glucose 140-480g/l Na^+49.0-89.0mmol/l K^+28.0-64.0mmol/l Mg^2^+3.0-7.5mmol/l Ca^2^+3.0-9 .0mmol/l Cl^-49.0~89.0mmol/l P8.0~23.0mmol/l pH4.0~5.5. (2) Contains glucose and at least the following electrolyte constituent elements, the concentration of these in the aqueous solution and the pH of the aqueous solution are within the following ranges, and human epidermal growth factor (hEGF).
) in a range of 1 μg/l to 10 mg/l. Glucose 140-480g/l Na^+49.0-67.0mmol/l K^+28.0-58.0mmol/l Mg^2^+3.0-7.0mmol/l Ca^2^+3.0-9 .0mmol/l Cl^-49.0-67.0mmol/l P8.0-23.0mmol/l pH4.0-5.5.