TW202102263A - Infusion for subcutaneous administration - Google Patents

Abstract

An objective of the present invention is to provide an infusion of improved subcutaneous diffusivity. Bicarbonate ions are included in the infusion for subcutaneous administration to improve the subcutaneous diffusivity of the infusion for subcutaneous administration. The infusion for subcutaneous administration is preferably in the form of Ringer's solution having a bicarbonate ion concentration of 10-50 mEq/L, a pH of 6.0-8.5, an osmolality ratio of 0.8-1.3 with respect to the osmolality of normal saline, and a dosage of 20-1500 ml/day, and can further contain sodium ions, potassium ions, calcium ions, magnesium ions, and citrate ions.

Description

Infusion for subcutaneous administration

Invention field

The invention relates to an infusion solution for subcutaneous administration. More specifically, the present invention relates to an infusion solution for subcutaneous administration with enhanced subcutaneous diffusivity.

Background of the invention

The subcutaneous infusion method refers to the infusion method in which the infusion is injected under the skin due to applicable reasons such as the inability to insert an injection needle or catheter into the vein, and medical system reasons such as home medical treatment or terminal medical treatment, etc. Until the 1950s before the current infusion and nutrition management were not established, the subcutaneous infusion method was used as a general administration method together with subcutaneous injection for supplementary infusion. Since then, after the development and popularization of intravenous nutrition, it has been replaced by intravenous injection (hereinafter also referred to as intravenous injection) and the subcutaneous infusion method has declined. Recently, however, subcutaneous infusion has received renewed attention as an administration route for dehydration treatment in home medical treatment and supplementary infusion at the end of the period.

It is known that the subcutaneous infusion method squeezes and injects the liquid into the subcutaneous tissue, so similar to the subcutaneous injection, it is accompanied by swelling and the resulting pain. The relationship between the pain of subcutaneous injection and the amount of injection is also known. For example, in Non-Patent Document 1, the pain when subcutaneously injected solutions of different volumes are compared, and it has been concluded that a significant difference in pain related to the injection volume has been observed. In addition, in Non-Patent Document 2, the pain associated with subcutaneous injection is evaluated based on various combinations of injection speed and volume, and it is concluded that the injection speed does not affect the injection pain, but the more the injection volume, the more the pain increases. In addition, in Japan, among the infusions, in terms of subcutaneous injection (subcutaneous administration), basically only physiological saline is in compliance with the law concerning the assurance of the quality, effectiveness, and safety of medicines and medical equipment (Pharmaceutical Affairs Law). of Japan).

On the other hand, the lactic acid/acetate Ringer's solution made by adding an alkalizing agent such as lactate or acetate to Ringer's solution is used for the purpose of correcting blood acidosis. Non-Patent Document 3 discloses that lactic acid or Ringer's acetate are commonly used as supplementary infusions. However, if the lactic acid and Ringer's acetate are used for subcutaneous infusion, the blood bicarbonate ions will be released to the subcutaneously. The possibility of making acidosis more serious requires special attention. Advanced technical literature Non-patent literature

[Non-Patent Document 1] The Annals of Pharmacotherapy 1996 July/August, Volume 30, 729-732 [Non-Patent Document 2] Diabetes, Obesity and Metabolism 16: 971-976, 2014. [Non-Patent Document 3] Guidelines for Infusion Therapy for Patients with Terminal Cancer (2013 Edition), edited by the Committee for the Preparation of Palliative Medical Guidelines of the Japanese Society of Palliative Medicine, a specific non-profit organization, Chapter 2 "Background Knowledge", "7 Subcutaneous Infusion Method" , Page 43

Summary of the invention The problem to be solved by the invention

As disclosed in Non-Patent Documents 1 and 2, the pain associated with subcutaneous injection is related to the amount of injection. That is, the more the injection volume, the liquid is squeezed into the narrow area under the skin, and the squeezed-in liquid compresses the surrounding tissues, thus producing stronger pain. On the other hand, compared with subcutaneous injection, the subcutaneous infusion method will squeeze a larger amount of liquid into the skin. Therefore, the subcutaneous infusion method is more harmful than subcutaneous injection, the liquid is squeezed into the skin. In fact, it is known that in the subcutaneous infusion method, the swelling of the piercing part caused by the liquid being squeezed into the skin is a representative side effect. At this time, the infusion that is squeezed into a specific area under the skin will spread over time to a wider area under the skin (subcutaneous diffusion). It is conceivable that if the infusion squeezed into the subcutaneous area can be accelerated to spread under the skin, the amount of infusion remaining in a specific area under the skin will be reduced more quickly, and the side effects will be alleviated.

Therefore, the purpose of the present invention is to provide an infusion solution with improved subcutaneous diffusion. Means to solve the problem

The inventors deliberately focused on Ringer's solution, which is specially formulated for intravenous injection, and has no proven performance in subcutaneous infusion. As a result, surprisingly, it was found that Ringer's liquid containing bicarbonate ions has improved subcutaneous diffusivity compared to normal saline or lactated Ringer's liquid. Secondly, it was found that the increase in subcutaneous diffusibility was caused by the presence of bicarbonate ions. The present invention is completed in view of these knowledge and further repeated research.

That is, the present invention provides inventions in the aspects described below. Item 1. An infusion solution for subcutaneous administration, characterized in that it contains bicarbonate ions. Item 2. The infusion solution for subcutaneous administration as in Item 1, wherein the concentration of the aforementioned bicarbonate ion is 10-50 mEq/L. Item 3. The infusion solution for subcutaneous administration as in Item 1 or 2 has a pH of 6.0 to 8.5. Item 4. The infusion solution for subcutaneous administration in any one of items 1 to 3 has an osmotic pressure ratio of 0.8 to 1.3 relative to the osmotic pressure of physiological saline. Item 5. The infusion solution for subcutaneous administration according to any one of items 1 to 4, which further contains sodium ions. Item 6. The infusion solution for subcutaneous administration according to Item 5, wherein the ion source of the bicarbonate ion and the sodium ion is sodium bicarbonate. Item 7. The infusion solution for subcutaneous administration according to any one of items 1 to 6, which further contains potassium ions and calcium ions. Item 8. The infusion for subcutaneous administration of any one of items 1 to 7, which is in the form of Ringer's solution. Item 9. The infusion solution for subcutaneous administration according to any one of items 1 to 8, which further contains magnesium ions. Item 10. The infusion solution for subcutaneous administration according to any one of items 1 to 9, which further contains citrate ions and chloride ions. Item 11. The infusion solution for subcutaneous administration according to Item 10, wherein the concentration of the aforementioned sodium ions is 50~154mEq/L, the concentration of the aforementioned potassium ions is 2~30mEq/L, and the concentration of the aforementioned calcium ions is 2~6mEq/L, The concentration of the aforementioned magnesium ion is 1~3mEq/L, the concentration of the aforementioned citrate ion is 2~7mEq/L, and the concentration of chloride ion is 90~170mEq/L. Item 12. For the infusion for subcutaneous administration in any of items 1 to 11, the dosage is 20 to 1500 ml/day. Item 13. A method for improving the subcutaneous diffusivity of an infusion solution for subcutaneous administration, characterized in that bicarbonate ions are added to the infusion solution for subcutaneous administration. Item 14. A use of bicarbonate ions for the manufacture of infusion solutions for subcutaneous administration. Item 15. A subcutaneous infusion method comprising the step of administering to a patient an infusion solution for subcutaneous administration containing bicarbonate ions. Invention effect

According to the present invention, an infusion solution with improved subcutaneous diffusion can be provided.

The form used to implement the invention

1. subcutaneously infusion subcutaneously administered with the present invention characterized in that the infusion comprises bicarbonate ion (HCO ₃ ^-), and the administration is carried out subcutaneously infusion method. It is known that bicarbonate ions can be used to correct blood acidosis. The bicarbonate ion in the present invention can improve the subcutaneous diffusibility of the infusion solution for subcutaneous administration.

The bicarbonate as the ion source of bicarbonate ions can be exemplified by the formula: M ¹ HCO ₃ (where M ¹ represents a monovalent metal ion or ammonium ion) or the formula: M ² (HCO ₃ ) ₂ (formula Among them, M ² represents a compound represented by a divalent metal ion) and is pharmacologically acceptable. As specific examples thereof, sodium hydrogen carbonate, ammonium hydrogen carbonate, potassium hydrogen carbonate, calcium hydrogen carbonate, magnesium hydrogen carbonate, and the like can be given. Among these bicarbonates, sodium bicarbonate is particularly preferred.

In the infusion solution for subcutaneous administration of the present invention, the content of bicarbonate ions is not particularly limited, and can be determined based on the subcutaneous diffusibility that should be imparted, or the acidosis correction ability that should be further imparted, and/or the overall osmotic pressure ratio of the infusion. Properly set, for example, 10-50 mEq/L, preferably 15-45 mEq/L, more preferably 20-40 mEq/L, more preferably 25-35 mEq/L, and even more preferably 25-30 mEq/L.

The infusion solution for subcutaneous administration of the present invention may further include body fluid electrolytes contained in body fluids (for example, blood, interstitial fluid, intracellular fluid).

For example, the infusion solution for subcutaneous administration of the present invention may further contain sodium ions. The salt as an ion source of sodium ions is not particularly limited, and examples thereof include sodium bicarbonate, sodium chloride, sodium lactate, sodium acetate, sodium sulfate, sodium glycerophosphate, and sodium citrate. The ion sources of the sodium ions can also be in the form of hydrates. Furthermore, among the ion sources of sodium ions, preferable ones include sodium bicarbonate, sodium chloride, and sodium citrate.

The content of sodium ions in the infusion solution for subcutaneous administration of the present invention is not particularly limited. It can be appropriately set according to the osmotic pressure ratio of the infusion solution, the amount of extracellular fluid that should be given, and the maintenance of circulatory dynamics, etc., for example, 50~180mEq /L, preferably 100~175mEq/L, more preferably 110~150mEq/L, more preferably 120~140mEq/L, and even more preferably 125~135mEq/L.

In addition, the infusion solution for subcutaneous administration of the present invention may further include potassium ions and/or calcium ions, preferably potassium ions and calcium ions.

The salt as an ion source of potassium ion is not particularly limited, and examples thereof include potassium chloride, potassium acetate, potassium citrate, potassium glycerophosphate, potassium sulfate, and potassium lactate. The ion source of the potassium ions can also be in the form of hydrate. Among the ion sources of potassium ions, potassium chloride is preferred.

The potassium ion content in the infusion solution for subcutaneous administration of the present invention is not particularly limited. It can be appropriately set according to the osmotic pressure ratio of the infusion solution, the excitement and contraction effects of nerve and muscle cells to be imparted, for example, 2~30mEq/ L is preferably 2 to 5 mEq/L, more preferably 3 to 5 mEq/L.

The salt as an ion source of calcium ions is not particularly limited, and examples thereof include calcium gluconate, calcium chloride, calcium glycerophosphate, calcium lactate, calcium pantothenate, and calcium acetate. The ion source of the calcium ions can also be in the form of hydrates. Among the ion sources of calcium ions, calcium chloride is preferred, and calcium chloride hydrate is more preferred.

The calcium ion content in the infusion solution for subcutaneous administration of the present invention is not particularly limited. It can be appropriately set according to the osmotic pressure ratio of the infusion solution, the excitement and contraction effects of nerve and muscle cells to be imparted, for example, 2~6mEq/ L, preferably 3~5mEq/L.

In addition, the infusion solution for subcutaneous administration of the present invention may further contain magnesium ions. The salt as an ion source of magnesium ions is not particularly limited, and examples thereof include magnesium chloride and magnesium acetate. The ion source of the magnesium ions can also be in the form of hydrates. Among the ion sources of magnesium ions, the preferred one may be magnesium chloride.

The content of magnesium ions in the infusion solution for subcutaneous administration of the present invention is not particularly limited. It can be appropriately set according to the osmotic pressure ratio of the infusion solution, the activation of the enzyme to be given, etc., for example, 1~3mEq/L, preferably It is 1~2.5mEq/L.

In addition, the infusion solution for subcutaneous administration of the present invention may further contain citrate ions. The salt as an ion source of citrate ions is not particularly limited, and examples thereof include sodium citrate and potassium citrate. The ion source of the citrate ions may also be in a hydrate state. Among the ion sources of citric acid ions, the preferred one may be sodium citrate, and sodium citrate hydrate is more preferred.

The content of citrate ion in the infusion solution for subcutaneous administration of the present invention is not particularly limited, and can be appropriately set according to the osmotic pressure ratio of the infusion solution, the pH to be adjusted, the amount of bicarbonate ions that should be generated due to metabolism, etc. For example, 2~7mEq/L, preferably 3~6mEq/L, more preferably 4~5mEq/L.

In addition, the infusion solution for subcutaneous administration of the present invention may further contain chloride ions. The salt as an ion source of chloride ions is not particularly limited, and examples thereof include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride.

The chloride ion content in the infusion solution for subcutaneous administration of the present invention is not particularly limited, and can be appropriately set according to the osmotic pressure ratio of the infusion solution, for example, 90~170mEq/L, preferably 100~150mEq/L, more Preferably it is 100~120mEq/L.

The pH of the infusion solution for subcutaneous administration of the present invention can be appropriately set so that the stimulation to the tissue is suppressed, for example, 6.0 to 8.5, preferably 6.5 to 8.0.

In addition to the above-mentioned components, the infusion solution for subcutaneous administration of the present invention may further contain a pH adjusting agent. The pH adjuster is not particularly limited, and examples thereof include inorganic acids such as hydrochloric acid and carbon dioxide (carbonic acid); organic acids and their salts; alkaline substances such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. Examples of organic acids include citric acid, acetic acid, lactic acid, malic acid, and succinic acid, and salts of organic acids include sodium, potassium, and calcium salts. The salts of these organic acids may also be in the form of hydrates.

From the viewpoint of further enhancing the subcutaneous diffusibility, in the transfusion solution for subcutaneous administration of the present invention, among the above-mentioned electrolytes, it is preferable that the salt does not contain the salt as the ion source of lactic acid ion and the salt as the ion source of acetate ion.

Since the osmotic pressure of the infusion solution for subcutaneous administration of the present invention is used for subcutaneous administration, it is better to adjust the osmotic pressure closer to that of physiological saline, specifically, the osmotic pressure relative to the osmotic pressure of physiological saline The ratio (that is, the relative ratio when the osmotic pressure of physiological saline is taken as 1) is 0.8 to 1.3, preferably 0.85 to 1.25.

The solvent of the infusion solution for subcutaneous administration of the present invention is water, and distilled water for injection is usually used.

In addition to bicarbonate, the liquid preparation may also contain other agents. Examples of other drugs contained in the liquid preparation include sugars such as glucose, vitamins (C, B1, B2, B6, B12, K, folic acid, nicotinic acid, etc.), antibiotics (β-lactam series, monocyclic Endolamine, clindamycin, aminoglycoside, etc.), antipsychotics (haloperidol, etc.), benzodiazepines (midazolam, etc.), anesthetics (morphine, pentazol, etc.) Xin, etc.), anticholinergics (toxin, etc.), metopramide, antihistamines (clofenac, diphenylamine, etc.), local anesthetics (picolin, mepivacaine, etc.) Etc.), Steroids, Insulin, Heparin, Tranexamic Acid, Lidocaine, Serum, etc. Among these other drugs, preferred ones include glucose, beta lactam antibiotics, vitamins, morphine, pentazocine, metopramide, clophenamine, insulin, and heparin.

The infusion solution for subcutaneous administration of the present invention can also be provided in the form of Ringer's solution. Ringer's solution is an infusion for the purpose of correcting the amount of circulating plasma reduced by bleeding from surgery or trauma, and/or correcting metabolic acidosis in which the blood tends to be acidic. In this case, as acidosis correcting agents, bicarbonate ions, lactic acid ions, and acetate ions can be cited. From the viewpoint of further improving subcutaneous diffusion, the acidosis corrector is preferably composed of bicarbonate ions only.

The infusion solution for subcutaneous administration of the present invention can be manufactured according to a well-known method. For example, the following materials are mixed and stirred to manufacture: electrolyte as an ion source of bicarbonate ions; other electrolytes and pH adjusters added as needed; other agents added as needed; and solvents.

The use of the infusion solution for subcutaneous administration of the present invention is not particularly limited as long as it is an infusion solution for subcutaneous administration. For example, it can be used for dehydration treatment, fluid rehydration, and other treatment purposes in the field of in-home medical treatment and terminal medical treatment. Specifically, it can be used for cases where it is difficult to secure peripheral blood vessels and cases where self-extubation is frequent; more specifically, it can be used for patients such as the elderly, terminal patients, infants, etc. The infusion solution for subcutaneous administration of the present invention improves subcutaneous diffusion, and is also effective for patients of the age (for example, under 40) with the original side effects of edema and the tightness of the skin.

The dosage and speed of the infusion solution for subcutaneous administration of the present invention can be appropriately set according to the symptoms and age of the person to be administered, considering that it is used for subcutaneous administration. As a specific dosage, for an adult, the puncture site is, for example, 20~1500mL/day, preferably 50~1000mL/day, preferably 100~1000mL/day, more preferably 300~1000mL /Day, more preferably 500~1000mL/day. The number of puncture points per day can be, for example, 1 to 2 points. In addition, as a specific dosage rate, for example, 20 to 500 mL/hour, preferably 40 to 300 mL/hour, and more preferably 60 to 200 mL/hour.

2. Methods to improve subcutaneous diffusion As mentioned above, bicarbonate ions can enhance the subcutaneous diffusivity of the infusion. Therefore, the present invention also provides a method for improving the subcutaneous diffusivity of an infusion solution for subcutaneous administration, which is characterized by adding bicarbonate ions to an infusion solution for subcutaneous administration. That is, in the method for enhancing subcutaneous diffusivity of the present invention, bicarbonate ions are used as a subcutaneous diffusivity enhancing agent for infusion.

In addition, the so-called subcutaneous diffusivity refers to the characteristics of the infusion that is squeezed into a specific area under the skin through subcutaneous administration and spreads to a wider area under the skin over time; the so-called enhancement of subcutaneous diffusivity refers to the fact that it does not contain heavy In the case of carbonate ions, the infusion that is squeezed into a specific area under the skin through subcutaneous administration spreads faster to a wider area under the skin.

In the method for enhancing subcutaneous diffusibility of the present invention, the types and amounts of ingredients used are as described in the column of "1. Infusion for subcutaneous administration". Example

Hereinafter, embodiments and comparative examples will be disclosed and the present invention will be further described, but the present invention is not limited by these.

Test example 1 Prepare the infusion with the composition shown in Table 1. As the infusion solution (Bic) of Example 1, prepare bicarbonate Ringer's solution "BICANATE infusion"; as the infusion solution (Sal) of Comparative Example 1, prepare physiological saline solution "Otsuka Shengshizu"; as the infusion solution of Comparative Example 2 (Lac ), prepare lactated Ringer's solution "Lactec Note"; as the infusion solution (KN3) of Comparative Example 3, prepare a comprehensive electrolyte infusion (maintenance solution) "KN3 infusion solution" (all of the above are manufactured by Otsuka Pharmaceutical Factory). For each infusion, the subcutaneous diffusibility was evaluated according to the following steps. In addition, the bicarbonate Ringer's solution "BICANATE infusion" contains sodium bicarbonate as its component.

[Table 1] Example 1 (Bic) Comparative Example 1 (Sal) Comparative Example 2 (Lac) Comparative example 3 (KN3) Na ⁺ (mEq/L) 130 154 130 50 K ⁺ (mEq/L) 4 - 4 20 Ca ²⁺ (mEq/L) 3 - 3 - Mg ²⁺ (mEq/L) 2 - - - Cl ^- (mEq / L) 109 154 109 50 Lactic acid ion (mEq/L) - - 28 20 HCO ₃ ^- (mEq / L) 28 - - - Citrate ion (mEq/L) 4 - - - Sugar (%) - - - 2.7 Energy (kcal/L) - - - 108 pH 6.8~7.8 4.5~8.0 6.0~8.5 4.0~7.5 Osmotic pressure ratio (calculated value) About 0.9 1 About 0.9 About 1 Cast amount 30mL 30mL 30mL 30mL

(Making of subcutaneous cast model) To 12-year-old male SD rats, three mixed anesthesia (medetomidine, midazolam, and metofinol) were administered intraperitoneally at a dose of 5 mL/kg body weight, and the back ( Shave from the scapula to the tail) with an electric clipper. After puncturing the center of the scapula from the head to the tail, and confirming that the needle tip can move freely under the skin, each infusion solution was administered subcutaneously in a dose of 30 mL. After subcutaneous administration, the rat's maxillary incisors were hung on sutures and hung with the head facing upward, and the forelimbs were fixed to the vertical wall with tape to fix the rat in a vertical position. Mark the upper, lower, left, and right ends of the swelling part (edema) caused by the dosing solution with oily strokes. Take this as a record of the swelling (edema) at the moment (0 minutes) after the administration (Figure 1).

(Observation and marking) Observe the movement of the infusion under the skin by recording the movement of the lower end of the swelling part (edema) of the back. Specifically, from the moment after the administration (0 minutes) to the elapse of 30 minutes, the elapse of 60 minutes (FIG. 2), and the elapse of 90 minutes, the lower end of the swelling part (edema) of the back was marked with an oily stroke. In addition, because the observation is performed under anesthesia, it is also monitored whether the anesthesia state continues to be maintained during the observation. If there is awakeness during the observation, add 0.2 times the dose of the above three mixed anesthesia.

(Measurement of the moving distance of the dosing liquid) After the marking of 90 minutes has passed, the skin on the back is removed in a way that includes all the markings. In order to prevent the skin from stretching, spread the skin and place it on a metal tray containing physiological salt solution. Use a ruler with a scale of 1 mm to measure the upper and lower width (vertical width) and left and right width (horizontal width) of the swelling part (edema) immediately after administration; The mark interval between the instant (0 minutes) and 30 minutes after the administration (0'-30'); the mark interval between 30 minutes and 60 minutes; the mark interval between 60 minutes and 90 minutes; and the mark interval between 0 minutes and 90 minutes (0 '-90').

(result) Regarding the vertical and horizontal widths of the swelling part (edema) immediately after the administration, the infusions in any of Example 1 and Comparative Examples 1 to 3 were of the same degree. For the infusions of Example 1 and Comparative Examples 1 to 3, among the above-mentioned measured symbol spacing (movement distance), 0'-30' and 0'-90' are shown in FIG. 3. In Figure 3, the individual moving distances represent the average value of N=11. Also, 95% confidence in the difference between the average moving distance (N=11) between Sal (Comparative Example 1), Lac (Comparative Example 2), or KN3 (Comparative Example 3) and Bic (Example 1) The interval is shown in Table 2.

[Table 2] 95% confidence interval of the difference between the average moving distance (N=11) Sal vs. Bic (Comparative Example 1 vs. Example 1) Lac vs. Bic (Comparative Example 2 vs. Example 1) KN3 vs. Bic (Comparative Example 3 vs. Example 1) 0'-30' -0.4815~-0.0639 -0.4305~-0.0241 -0.6583~-0.2690 0'-90' -0.7913~-0.2633 -0.5834~-0.0348 -1.0994~-0.5551

From the comparison between Sal (Comparative Example 1), Lac (Comparative Example 2) and KN3 (Comparative Example 3) and Bic (Example 1) shown in Figure 3, and the Sal (Comparative Example 1) and Lac shown in Table 2 (Comparative Example 2) or KN3 (Comparative Example 3) and Bic (Example 1) are compared between the two individual groups. It can be seen that the infusion phase of Example 1 with bicarbonate ions is better than the comparative example without bicarbonate ions. 1~3 Infusion, the movement of the subcutaneous swelling part (edema) caused by the infusion is significantly faster, so it is known that the subcutaneous diffusion is improved. In addition, this subcutaneous diffusivity enhancement effect is manifested from the initial stage (within 30 minutes) immediately after the administration, and therefore, it is excellent from the viewpoint that it is expected to alleviate the pain from the initial stage when the pain is the strongest.

Test example 2 In Test Example 1, the infusion solution of Example 1 in which the subcutaneous diffusibility enhancement effect has been confirmed is compared with the infusion solution of Comparative Examples 1 to 3. The addition of bicarbonate ions is an obvious feature in composition. However, in addition to bicarbonate ions, it has Magnesium ion and citrate ion are also different in this point. Therefore, in this test example, in order to show that the subcutaneous diffusibility enhancement effect is related to bicarbonate ions, the test was conducted with an infusion solution of the composition shown in Table 3. The infusion solution (Bic) used in Example 2 is the same as the infusion solution (Bic) used in Example 1 of Test Example 1. The infusion solution (R+Mey) used in Example 3 is as shown in Table 3. Compared with Example 2, it has almost the same composition except that it does not contain magnesium ions and citrate ions. Specifically, the infusion of Example 3 was to extract 16.8 mL from 500 mL of Ringer’s solution "OTSUKA" (manufactured by Otsuka Pharmaceutical Factory), and then add 16.8 mL of sodium bicarbonate injection "Meylon intravenous injection 7% "((Co., Ltd.) Otsuka Pharmaceutical Factory) and stir and mix to prepare. The concentration of sodium bicarbonate in the infusions of Example 2 and Example 3 were both 2.35 g/L. In addition, pH is measured at 25°C using a pH measuring device (F-54S: Horiba Manufacturing Co., Ltd.).

[table 3] Example 2 (Bic) Example 3 (R+Mey) Na ⁺ (mEq/L) 130 172 K ⁺ (mEq/L) 4 3.9 Ca ²⁺ (mEq/L) 3 4.4 Mg ²⁺ (mEq/L) 2 - Cl ^- (mEq / L) 109 150 HCO ₃ ^- (mEq / L) 28 28 Citrate ion (mEq/L) 4 - pH (measured value) 7.4 8.0 Osmotic pressure ratio (calculated value) About 0.9 About 1.2 Cast amount 75mL/kg 75mL/kg

Except that the infusion of the above table was used and the dosage was 75 mL/kg, in the same manner as in Test Example 1, the preparation of the subcutaneous injection model, observation and marking, and the measurement of the movement distance of the injection were performed. As a result, the vertical and horizontal widths of the swelling part (edema) immediately after the administration were the same in the infusion of Example 2 and Example 3. For the infusion of Example 2 and Example 3, the above-mentioned measured symbol spacing (movement distance) is shown in FIG. 4. In Figure 4, the individual moving distances represent the average value of N=5. From the results, it can be seen that the moving distance at any stage is the same between Example 2 containing bicarbonate ion, magnesium ion and citrate ion and Example 3 containing bicarbonate ion but not magnesium ion and citrate ion. degree. That is, it was revealed that the subcutaneous diffusibility enhancement effect shown in Test Example 1 is strongly related to bicarbonate ions.

Complementary test example When the infusion is administered subcutaneously, within the swelling, the accumulation of the infusion will be absorbed into the subcutaneous connective tissue and swell, resulting in a jelly. If this is the case, the movement distance measured in the above test example may be the distance caused by the weight of the jelly produced by the increase in the subcutaneous connective tissue ingested by the infusion. That is, as a hypothesis, different infusion solutions will produce different amounts of jelly based on the differences in the composition. It is conceivable that those that produce more (that is, heavier) jelly may be more With heavier weight, the moving (descending) distance will become larger. Here, in order to show that the test system of Test Examples 1 and 2 excludes the above hypothesis and appropriately evaluates the subcutaneous diffusibility, a supplementary test was performed. Specifically, the dosage of the infusion solution (Bic) used in Example 1 of Test Example 1 was set to 15 mL (30 mL in Example 1), which resulted in the formation of a different amount of jelly under the skin, and Test Example 1 was tested in the same way (N=11). Next, the results are compared with Example 1.

(result) The vertical and horizontal widths of the swelling part (edema) immediately after the administration are shown in Fig. 5, and the measurement result of the movement distance of the administration solution is shown in Fig. 6. In addition, the 95% confidence interval of the difference between the average moving distance (N=11) between the two groups of the dose of 15 mL and the dose of 30 mL is shown in Table 4.

[Table 4] The 95% confidence interval of the difference between the average moving distance (N=11) is 15mL vs. 30mL 0'-30' -0.0677~0.2859 30'-60' -0.1953~0.0499 60'-90' -0.1585~0.0131 0'-90' -0.2673~0.1946

As shown in Fig. 5, regarding the vertical and horizontal widths of the swelling part (edema) immediately after the administration, it was confirmed that the dosage of 30 mL was larger than that of the dosage of 15 mL. On the other hand, as shown in FIG. 6, the movement distance of the infusion caused by the subcutaneous diffusion of the dose of 15 mL and the dose of 30 mL is the same degree. As shown in Table 4, there is no significant difference in these moving distances. Therefore, the test systems of Test Examples 1 and 2 were not affected by the weight of the jelly produced under the skin, indicating that the subcutaneous diffusibility of the injection solution was appropriately evaluated.

[Figure 1] In Test Example 1, a photograph of the swelling part (edema) taken immediately after the infusion was administered to the back of the rat. [Figure 2] In Test Example 1, a photograph of the swelling part (edema) taken 60 minutes after the infusion was administered to the back of the rat. [Fig. 3] A graph showing the movement distance of the lower end of the swelling part (edema) obtained in Test Example 1. [Fig. 4] A graph showing the movement distance of the lower end of the swelling part (edema) obtained in Test Example 2. [Fig. 5] A graph showing the size of the swelling part (swelling) at the moment of the completion of the injection obtained from the replenishment test example. [Fig. 6] A graph showing the movement distance of the lower end of the swelling part (edema) obtained from the complementary test example.

(no)

Claims (13)

An infusion solution for subcutaneous administration is characterized in that it contains bicarbonate ions. Such as the infusion solution for subcutaneous administration of claim 1, wherein the concentration of the aforementioned bicarbonate ion is 10-50mEq/L. Such as the infusion solution for subcutaneous administration of claim 1 or 2, its pH is 6.0~8.5. For the infusion solution for subcutaneous administration in any one of Claims 1 to 3, the osmotic pressure ratio relative to the osmotic pressure of physiological saline is 0.8 to 1.3. Such as the infusion solution for subcutaneous administration in any one of claims 1 to 4, which further contains sodium ions. Such as the infusion solution for subcutaneous administration of claim 5, wherein the ion source of the aforementioned bicarbonate ion and the aforementioned sodium ion is sodium bicarbonate. Such as the infusion solution for subcutaneous administration in any one of claims 1 to 6, which further contains potassium ions and calcium ions. For example, the infusion solution for subcutaneous administration in any one of claims 1 to 7 is in the form of Ringer's solution. Such as the infusion solution for subcutaneous administration in any one of claims 1 to 8, which further contains magnesium ions. Such as the infusion solution for subcutaneous administration in any one of claims 1 to 9, which further contains citrate ions and chloride ions. Such as the infusion solution for subcutaneous administration of claim 10, wherein the concentration of the aforementioned sodium ion is 50~154mEq/L, the concentration of the aforementioned potassium ion is 2~30mEq/L, the concentration of the aforementioned calcium ion is 2~6mEq/L, and the aforementioned magnesium The ion concentration is 1~3mEq/L, the aforementioned citrate ion concentration is 2~7mEq/L, and the chloride ion concentration is 90~170mEq/L. Such as the infusion solution for subcutaneous administration in any one of Claims 1 to 11, the dosage is 20~1500ml/day. A method for improving the subcutaneous diffusivity of an infusion solution for subcutaneous administration, which is characterized in that bicarbonate ions are added to the infusion solution for subcutaneous administration.

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