JP2000034223A - Preparation of medicinal liquid and medicinal liquid container receiving the medicinal liquid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for preparing a medicinal liquid capable of being safely received for a long period in a resin container comprising a resin wall which is partially or wholly transparent and flexible, and to provide a medicinal liquid container in which the medicinal liquid is received. SOLUTION: This method for preparing a medicinal liquid comprises receiving the liquid in a resin container, preparing the liquid in a pH range of 2.37-5.5 and adding a sulfurous acid component as a stabilizer. Therein, an acid having an electric dissociation constant K in a range of from 0.72×10-3 to 1.55×10-6 is added as a pH-maintaining agent to the medicinal liquid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for preparing a medicinal solution such as an injectable solution or a dialysis solution, and a medicinal solution container containing a medicinal solution according to the method. The present invention relates to a method for preparing a drug solution that can stably store an injection solution or a dialysate to which a sulfurous acid component is added as a stabilizer for stable storage in a gas-permeable resin container or the like for a long period of time. The present invention also relates to a liquid medicine container in which the liquid medicine prepared by the above preparation is stored in a transparent and flexible resin container, for example, a molded product such as a resin ampule, an infusion bag, a dialysate bag, or a prefield syringe.

[0002]

2. Description of the Related Art Medical fluids such as lidocaine hydrochloride solution, procainamide hydrochloride solution, epinephrine hydrochloride solution, ephedrine hydrochloride solution, procaine hydrochloride solution, dopamine hydrochloride solution, dobutamine hydrochloride solution, reducing sugar solution, etc. A sulfite such as sodium sulfite or sodium hydrogen sulfite is added as a stabilizer, and is contained in a glass ampule or a glass container. In addition, since the above-mentioned chemicals and the like are disliked to be stored in an alkaline solution, they are usually prepared in an acidic state, for example, in the range of PH2 to 5.5, and stored in a container. By preparing sulfurous acid, the main agent such as lidocaine hydrochloride does not undergo discoloration or deterioration due to oxidation. In particular, discoloration and deterioration can be prevented even when heat is applied as in high-pressure steam sterilization. Such a drug solution container is used as an ampoule, used as an infusion container for infusion or the like, or used as a container for a dialysis solution. It is used as a syringe containing a drug solution.

[0003]

Recently, resin-made ampules, infusion containers, syringes, and the like are frequently used. This is because there is less risk of breakage as compared with a glass container, and the disposal can be made easier as compared with a glass container or the like. In the case of an infusion container, a peritoneal dialysis solution container, or the like, the container wall is partially or wholly transparent and flexible, so that an air bleeding needle or the like is not required, and it is convenient to carry. However, when the injection solution, the infusion solution, and the dialysate are stored in such a resin container, the pH of the stored solution may be extremely increased. This is a phenomenon that has not occurred in a glass container or the like. Since the infusion or dialysate is acidic, sulfurous acid as a stabilizer in the solution is easily generated as sulfur dioxide, and it is assumed that such gas easily passes through the resin container wall. If the sulfite ion in the infusion or dialysate is significantly reduced, it is expected that the number of negative ions will decrease and the PH will increase. It is clear that an increase in the pH of the solution during storage is not preferable for a medical container. Accordingly, the present invention provides a method for preparing a chemical solution that can be safely contained in a transparent and flexible resin container for a long period of time, and a chemical solution container containing the chemical solution.

[0004]

SUMMARY OF THE INVENTION The present invention relates to a method for preparing a chemical solution which is housed in a resin container, has a pH of 2.37 to 5.5, and is added with a sulfite component as a stabilizer. The above solution has an ionization constant K (temperature of 25 ° C.) of 9.72 ×
An object of the present invention is to provide a method for preparing a drug solution contained in a resin container, wherein an acid in the range of 10 ^{−3 to} 1.55 × 10 ⁻⁶ is added as a pH maintaining agent.

[0005] The present invention is a drug solution prepared with a pH value in the range of 2.37 to 5.5. Such chemicals include medical chemicals such as epinephrine hydrochloride, ephedrine hydrochloride, procainamide hydrochloride, dopamine hydrochloride, dobutamine hydrochloride, and reducing sugar. Such drug solutions are injection solutions, dialysates,
Examples include organ preservation solutions, nutrients, and in some cases, solutions of reducing sugars and the like. The drug solution is used for infusion for infusion, dialysate, etc. in addition to injection. Incidentally, an electrolyte or the like may be usually added to the chemical solution in addition to the diluting solution. The PH value of the above chemical solution is in the range of 2.37 to 5.5, particularly 2.5 to 5.0.
Is desirably within the range. The pH of the chemical is 2.3
If it is less than 7, the sulfite concentration [H ₂ SO ₃ ] in the total added concentration [C] of the sulfite component is large in the chemical solution from the first ionization constant of the sulfite, and the bisulfite ion concentration [HSO ₃ ⁻ ] is increased. Less than 80%. As the sulfurous acid concentration [H ₂ SO ₃ ] increases in the chemical, the generation of sulfur dioxide in the chemical increases accordingly. When a chemical solution is stored in a glass container or the like, there is no problem because the generated sulfurous acid gas does not pass through the container wall. However, in the case of a resin container that partially transmits a gas having a transparent wall that is not laminated with aluminum foil or the like, the generated sulfurous acid gas passes through the resin wall. For this reason,
When the generation of sulfurous acid gas is intense, the sulfurous acid component in the resin container is lost, and the total concentration [C] and the concentration of ionized bisulfite ion [HSO ₃ ⁻ ] also decrease. For this reason, the P
Making H less than or equal to the above range is an unfavorable preparation method when accommodating in a resin container. In addition, the P
When H exceeds the above range of 5.5, it becomes difficult to stably store the main ingredients such as lidocaine, procainamide, epinephrine, dopamine and the like.

[0006] A sulfite component is added to the above chemical solution. The sulfurous acid component is widely used as a stabilizer and prevents oxidation of the above-mentioned chemical solution in the main component. The chemical is added as a sulfite such as sodium bisulfite, sodium sulfite, potassium bisulfite, and potassium sulfite. The total added concentration [C] of the sulfurous acid component is 0.1 to 0.1.
It is desirable to add to the chemical solution in the range of 15 mEq / L. If the total concentration [C] of the sulfite component in the chemical solution is less than the above range, the stabilizing effect on the main ingredient is deteriorated, and the sulfite is lost as sulfurous acid gas for a long period of time, so that the main ingredient cannot be stably maintained. . If the total amount of added sulfurous acid [C] in the chemical solution exceeds the above range, the adverse effect of sulfurous acid on the body due to medical use increases.

In the method for preparing a chemical solution according to the present invention, the chemical solution has an ionization constant K (at a temperature of 25 ° C.) of 9.72 × 10 ⁻³ or less.
An acid in the range of 1.55 × 10 ⁻⁶ is added as a pH maintainer. Essentially, a maintenance agent for the pH of the chemical solution is not required. In the case of a glass container, the sulfurous acid gas does not permeate the glass wall even when the sulfurous acid gas is generated from the chemical solution during the high-pressure steam sterilization or during the storage as described above. There is no possibility that the sulfurous acid component in the chemical solution is lost as sulfurous acid gas during the storage period. However, when a chemical solution is accommodated in a resin container, particularly a container having a transparent and even flexible container wall, a problem occurs in the conventional preparation method. That is, the container wall allows the sulfur dioxide gas to permeate. The sulfurous acid component in the chemical permeates through the resin container wall as sulfurous acid gas, and the sulfurous acid gas is remarkably lost particularly in a heated state such as high-pressure steam sterilization. The loss of sulphite component from such chemical solution bisulfite ion concentration in the chemical ^- leading to loss of bisulfite ion concentration ^{_{[HSO 3] [HSO 3 -}} ] decreased appears as a rise in the PH of the liquid medicine. That is, conventionally, the pH of a chemical solution is determined by a strong acid, a strong alkali, and a bisulfite ion concentration [HSO ₃ ⁻ ].
For this reason, when bisulfite ion (HSO ₃ ⁻ ) is lost as sulfurous acid gas, the pH of the chemical solution is changed to bisulfite ion (HSO ₃ ⁻ ).
₃ ^-) is determined by the strong acid and strong alkali or the like after the loss of. The amount of bisulfite ion (HSO ₃ ⁻ ) lost is affected by the initial sulfurous acid concentration, the gas permeability of the resin container, and the like. For example, if the pH of the chemical rises from 3.0 to 4.0, it is reduced to 10%. It may be considered that ^-3 mol / L-10 ^-4 mol / L (about 1 mmol / L) of bisulfite ion has been lost.

An acid having an ionization constant K (at a temperature of 25 ° C.) in the range of 9.72 × 10 ^{−3 to} 1.55 × 10 ⁻⁶ is added as a pH maintaining agent. Even if the bisulfite ion concentration [HSO ₃ ⁻ ] in the chemical solution decreases, the maintenance agent can suppress the fluctuation of the PH of the chemical solution. Due to a slight increase in the pH of the chemical, the ionizing rate of the acid in the maintenance agent changes, and the maintenance agent tries to maintain the pH of the chemical.

For example, the ionization constant K of lactic acid is 1.39 × 1
It is 0 ^-4 . Case of adding lactic acid to the chemical PH3, lactate ^- ionization rate of the ^{[Lc] [Lc -] /} ([HLc] +
[Lc ⁻ ]) can be obtained from the equation [H ⁺ ] = K · [HLc] / [Lc ⁻ ]. [H +] = 10 ^-3 and K =
Substituting 1.39 × 10 ^-4 gives a lactate ionization rate of 12
%. When the pH of the chemical solution is 3.0, the concentration of bisulfite ion [HSO ₃ ⁻ ] from the chemical solution is lost as sulfurous acid gas to 1
When it is reduced by about mmol / L, it is conventionally about PH 4.0. However, if the above lactic acid is present at 5 mmol / L as a maintenance agent, the chemical will theoretically have the following PH.
The lactate ionization rate at PH3 can be changed from 12% (lactate ion amount: 0.12 × 5 mmol / L) to 32% (increase in lactate ion concentration: (0.32-0.12) × 5 mmol / L). For example, it can be theoretically understood that the reduced ion amount of 1 mmol / L of the sulfite component is offset by this. The PH at which the lactate ion rate is 32% is 3.52, and the chemical solution is suppressed to PH 3.52 instead of PH4.

The above-mentioned maintenance agent has an ionization constant K (temperature 25
° C) is in the range of 9.72 ^{10-3 to} 1.55 ^10-6 . If the ionization constant K of the above-mentioned maintenance agent exceeds the above-mentioned range, the above-mentioned maintenance agent will have an ionization ratio of more than 70% in the chemical solution within the above-mentioned range of PH, and will not be able to sufficiently exhibit the above-mentioned action. Further, if the ionization constant K of the above-mentioned maintenance agent is below the above-mentioned range, the above-mentioned maintenance agent has an ionization ratio of less than 30% in the chemical solution within the above-mentioned range of the above-mentioned pH. Can not. Such a maintaining agent may be an inorganic acid or an organic acid, and particularly preferably an acid used in the body. Such acids are lactic acid,
Organic acids such as acetic acid, formic acid, citric acid, succinic acid, cinnamic acid, salicylic acid, tartaric acid and chloroacetic acid, and inorganic acids such as phosphoric acid can be mentioned. In the method for preparing a drug solution according to the present invention prepared as described above, when such a drug solution is housed in a gas-permeable container, PH can be stably maintained, and the drug solution is kept stable for a long period of time. It can be.

The preparation method according to claim 2 of the present invention is characterized in that
The method according to claim 1, wherein the acid concentration of the maintenance agent is added in the range of 0.1 to 15 mEq / L. The sulfurous acid component is expected to decrease by a maximum of about 1.5 mmol / L during a storage period of about 3 years. On the other hand, the allowable range of the increase of the PH of the chemical is less than 1, and the ideal increase limit is about 0.6. Assuming such an ideal increase in PH, the difference in ionization rate is 1
Expected to be around 0%. Therefore, the acid concentration of the above-mentioned maintainer that can be covered by such an ionization rate is at least 15 mE.
q / L. On the other hand, when the acid concentration of the above-mentioned maintenance agent is 0.1 mE
If it is less than q / L, the pH of the chemical cannot be suppressed for a long time.

[0012] The preparation method according to claim 3 of the present invention comprises:
3. The preparation method according to claim 2, wherein the ionization index pK of the maintenance agent is (PH of the chemical solution) with respect to PH of the chemical solution.
0.5 ≦ pK ≦ (pH of chemical solution) +2.0. The ionization index pK of the above maintenance agent is P
If H is within the above range, the difference in ionization rate is 10% as described above with respect to the allowable increase in PH of the chemical solution.
I can no longer expect it. Therefore, the P
Outside the above range in relation to H, the maintenance agent cannot sufficiently suppress the increase in PH of the drug solution. That is, Table 1 described below shows the ionization index pK (a value obtained by taking the negative logarithm of the ionization constant K) of each of the maintenance agents, and the ionization rate [A ⁻ ] /
[C] is shown. Such ionization rate ^[A -] /
The relationship of [C] is obtained from the following equation: K = [H ⁺ ] · [A ⁻ ] / [A] and [C] = [A] + [A ⁻ ] [A ⁻ ] / [C] =
A relationship of K / ([H ⁺ ] + K) × 100% can be obtained. From Table 1, it is desirable that the pK of the maintenance agent is within the above range with respect to the pH of the chemical solution. Within such a range, the ionization rate of the maintenance agent sufficiently increases with an increase in PH,
An increase in PH due to the disappearance of the sulfite component can be prevented. If the ionization index pK of the maintenance agent is less than 0.5 with respect to the pH of the chemical, the maintenance agent does not exhibit the above-mentioned effect because the ionization rate has already been increased. Further, when the ionization index pK of the maintenance agent exceeds 2.0 with respect to the pH of the chemical, there is a problem that the chemical needs to be increased by PH 1.0 or more until the effect of the ionization rate appears.

[0013]

[Table 1]

According to a fourth aspect of the present invention, there is provided a chemical solution container, comprising:
A chemical solution obtained by the preparation method according to any one of claims 1 to 3 is housed in a transparent resin container. The resin container may be a hard container such as an ampule or a syringe, or may be a soft container such as an infusion bag, a blood bag, or a dialysate bag. The resin container may be formed by processing a film or the like, or may be formed by injection molding.
Blow molding may be used. The resin container is a container having a transparent wall partially or entirely. This is so that the drug solution in the container can be checked before use. Therefore, the above-mentioned resin container does not include a container in which aluminum foil or the like is completely laminated on a container wall or the like and gas transmission is completely blocked.
The resin container according to the present invention is a container whose container wall has poor gas permeability or gas permeability.

The resin material for the resin container is a general-purpose resin such as polyolefin resin, vinyl chloride, vinylidene chloride resin, polyester resin, polyvinyl alcohol resin, polyacrylonitrile resin, polyacrylic resin, polyamide resin and the like. Resin. Further, the resin container may be formed in a single layer or a multilayer. The innermost layer that comes into contact with the drug in the container is preferably a resin layer that does not affect the drug and does not generate elutes. As such a resin, a polyolefin resin is desirable, for example,
Examples include low-, middle-, and high-density lower-olefin resins such as polyethylene and polypropylene, cyclic polyolefins, and copolymers of two or more of these.

According to a fifth aspect of the present invention, there is provided a drug solution container comprising:
5. The chemical liquid container according to claim 4, wherein the inner wall of the container is made of a polyolefin resin. Examples of the polyolefin resin include high-pressure low-density polyethylene, high-density polyethylene, linear low-density polyethylene, medium-density polyethylene, ultra-low-density polyethylene, polyethylene such as ultra-high-molecular-weight polyethylene, isotactic polypropylene, syndiotactic Polypropylene, polypropylene such as atactic polypropylene, polybutene-1, poly-4-methylpentene-1,
And amorphous polyolefins. These are acid-resistant and do not adversely affect the contents of the chemical solution. The container may be packed in a gas-impermeable or non-gas-permeable package, and an oxygen absorber may be stored in the package to prevent the chemical solution from being altered by oxygen.

[0017]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Preferred embodiments of a method for preparing a drug solution and a drug container containing the drug solution according to the present invention will be described in detail below with reference to the accompanying drawings. FIG. 1 is a plan view of a method for preparing a chemical solution according to the first embodiment and a resin ampule containing the chemical solution. FIG. 2 is a plan view in which the resin ampule according to the first embodiment is individually wrapped.

In the method for preparing a chemical according to the first embodiment, a chemical 6 is contained in a resin container 1 and has a pH in the range of 2.37 to 5.5, and a sulfurous acid component is added as a stabilizer. Is the way. The chemical solution 6 has an ionization constant K (temperature of 25 ° C.)
There 9.72 × 10 ^- is added to the acid in the range of ^{3 ~1.55} × 10 ^-6 as maintaining agent of PH. The acid concentration of the above-mentioned maintenance agent is added in the range of 0.1 to 15 mEq / L.
The ionization index pK of the maintenance agent with respect to the pH of the chemical solution 1
Is (PH of chemical solution) −0.5 ≦ pK ≦ (PH of chemical solution) +
2.0. Further, the chemical solution 6 obtained by the preparation method according to the first embodiment is housed in a resin ampule 1 which is a transparent resin container. The inner wall of the container 1 is made of a sheet 2 of low density polyethylene which is a polyolefin resin.

The method for preparing a drug and the resin ampoule 1 according to the first embodiment will be described in more detail. First, 5000 mg of procainamide hydrochloride and 0.1 mg of sterile distilled water are added to sterile distilled water.
The mmol of sodium sulfite is dissolved to make a 40 ml preparation. Next, butyric acid (with an ionization constant of 1.
The ionization index pK is 4.82 at 51 × 10 ⁻⁵ and is 0.15 m.
Add mol weight. Next, the above solution was adjusted to pH 3 with hydrochloric acid.
7 and sterile distilled water is further added to adjust the volume to 50 ml to prepare a drug solution 6. Therefore, the pH of the chemical solution 6 is 3.7.
Thus, the concentration of sodium sulfite is 2 mmol / L, and the concentration of butyric acid is 3 mmol / L.

As shown in FIG. 1, a plurality of resin ampules 1
Is formed from two resin sheets 2. The resin sheet 2 is made of a 0.5 mm thick polypropylene sheet. A predetermined portion of the stacked resin sheets 2 is heat-sealed and sealed, and a plurality of ampule-shaped space portions 3 are formed. A notch 4A for opening and a notch 4B for separating are formed at predetermined positions of the resin sheet 2. The chemical solution 6 is passed through a sterilizing filter, and the ampule-shaped space portions 3 of the resin sheet 2 are removed.
Each of them is filled with 5 ml, and the filling port 5 is heat-welded. As shown in FIG. 2, the resin sheet 2 is cut along the cuts 4 </ b> B for sealing, and each resin ampule 1 is subdivided.
The resin ampoule 1 is hermetically packaged in a package 7, and the package 7
Consists of a gas-impermeable packaging sheet having an aluminum foil layer. The package 7 contains an oxygen absorber 7A.

The resin ampoule 1 was stored in an oven at a temperature of 40 ° C., and after 7 days, 14 days, 1 month, 3 months, and 6 months, the ampule 1 was opened and the pH of the drug solution was examined. . The results are shown in Table 2. In addition, as a comparative example, a solution in which butyric acid was not added at all in the above-mentioned method for preparing a chemical solution was prepared, and this was accommodated in a resin ampule made of the resin sheet 2 to obtain a first comparative example. This comparative ampule was stored in an oven at a temperature of 40 ° C. in the same manner as the resin ampule 1 and the change with time was examined. The results are shown in Table 2.

[0022]

[Table 2]

From the results shown in Table 2, it can be seen that the pH of the chemical solution 6 according to the method of preparing a chemical solution according to the present embodiment can be increased by about 0.6 even under severe conditions for 6 months. On the other hand, it turns out that the chemical liquid of the comparative example cannot withstand the severe condition for three months. In addition, oxidation of procainamide hydrochloride, which is the main agent of the chemical solution 6 according to this example, is not observed.
Therefore, in the method for preparing a drug solution according to the present embodiment, PH is sufficiently maintained.

FIG. 3 is a plan view of an infusion bag according to the second embodiment. As shown in FIG. 3, a drug solution 11 containing dobutamine hydrochloride is accommodated in a transfusion bag 8 together with the bag 8 after being subjected to high-pressure steam sterilization at 110 ° C. As a method for preparing the drug solution 11, 300 mg of dobutamine hydrochloride was used for 200 ml.
And the pH is adjusted to 3.2. Then, 3 mM sodium bisulfite is contained in the chemical solution 11.
l, and 5 mmol of lactic acid (ionization constant K = 1.39 × 10 ⁻⁴ ) is added. The infusion bag 8 is made of a low-density polyethylene sheet, and the polyethylene sheet is formed by folding back, sealing the periphery, and attaching a drip hole. Further, the infusion bag 8 is packaged in a poorly permeable package 10 having a polyvinylidene chloride layer after high-pressure steam sterilization, and a deoxidizer 9 is contained in the package 10 to prevent the chemical solution 11 from being oxidized. After placing the infusion bag 8 in an oven at a temperature of 40 ° C. for 6 months, the P
H was 3.56. As a comparative example, an infusion bag to which lactic acid was not added was manufactured and used as a comparative example.
The pH of the drug solution after 5. months was 5.48. Therefore, it can be seen that when the ionization index pK of lactic acid is 3.86 and the pH of the chemical solution 11 is 3.2, lactic acid exerts a sufficient effect as a PH maintainer.

[0025]

As described above, in the method for preparing a chemical solution according to the present invention, the pH of the chemical solution is set to 2.37 to
A method for preparing a chemical solution prepared in the range of 5.5 and to which a sulfite component is added as a stabilizer, wherein the chemical solution has an ionization constant K (temperature of 25 ° C.) of 9.72 × 10 ^{−3 to} 1.55 × 10 ^-6
Is added as a pH maintainer,
The chemical solution can be safely stored for a long time in a resin container having a transparent and flexible resin wall in part or all.

[Brief description of the drawings]

FIG. 1 is a plan view of a method for preparing a chemical solution according to a first embodiment and a resin ampule containing the chemical solution.

FIG. 2 is a plan view in which the resin ampule according to the first embodiment is individually wrapped.

FIG. 3 is a plan view of an infusion bag according to a second embodiment.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Resin ampoule 2 Resin sheet 3 Space part 5 Welding part of filling port 6 Chemical solution 7 Package 7A Deoxidizer

Claims (5)

[Claims] (1) The resin is contained in a resin container and has a pH of 2.37 to 5.
5. A method for preparing a chemical solution prepared in the range of 5 and to which a sulfite component is added as a stabilizer, wherein the chemical solution has an ionization constant K
A method for preparing a drug solution contained in a resin container, wherein an acid having a temperature (25 ° C.) in the range of 9.72 × 10 ^{−3 to} 1.55 × 10 ⁻⁶ is added as a pH maintaining agent. 2. The method according to claim 1, wherein said maintaining agent has an acid concentration of 0.1 to 15 mEq.
The method according to claim 1, wherein the compound is added in the range of / L. 3. The method according to claim 2, wherein the ionizing index pK of the maintenance agent is in the range of (pH of the chemical solution) −0.5 ≦ pK ≦ (PH of the chemical solution) +2.0 with respect to the pH of the chemical solution. The preparation method according to claim 2, wherein 4. A chemical container obtained by accommodating a chemical obtained by the preparation method according to claim 1 in a transparent resin container. 5. The chemical container according to claim 4, wherein the inner wall of the container is made of a polyolefin resin.