JP2010088502A - Water-soluble oral liquid medicine container, and method of filling the container with water-soluble oral liquid medicine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a water-soluble oral liquid medicine container capable of preserving for a long period a water-soluble oral liquid medicine with famotidine having stability and excellent taste as an effective component, and a method of filling the container with the water-soluble oral liquid medicine. <P>SOLUTION: The container 10 is constituted of: a medical liquid storage part 11 for containing the medical liquid; a mouth 12 for easily taking the medical liquid contained in the medical liquid storage part 11; a cap 13 for closing an outlet of the mouth 12; and a tab 14 joined to the cap 13. The container 10 is filled with the water-soluble oral liquid medicine under the substitution of nitrogen gas. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a container for containing a water-soluble internal solution and a method for filling a container for containing a water-soluble internal solution, and in particular, a container that has realized storage stability that can withstand the market distribution of water-soluble internal solutions containing famotidine as an active ingredient The present invention relates to a container and a method for filling a water-soluble internal solution into the container.

  Although tablets and powders containing famotidine as an active ingredient are distributed in the market as excellent ulcer and gastritis treatment drugs, they have not been developed or sold as internal liquids. The reason for this is that famotidine is a basic compound and is unique in that it is soluble in the acidic region but has low stability and the solubility is extremely reduced in the stable neutral region.

  Of course, an injection solution, which is one of the solutions, has been developed. However, in the case of an internal solution, it is necessary to consider stability and taste that can withstand market distribution, unlike an injection solution. Therefore, Patent Document 1 proposes a water-soluble internal liquid solution that solves the problems of stability and taste.

The water-soluble internal solution of Patent Document 1 is obtained by adding edetic acid or a salt thereof to famotidine. According to this water-soluble internal solution, it is possible to provide a low-concentration famotidine internal solution in which the residual ratio of famotidine is 97% or more even after storage at room temperature in December. In other words, famotidine is contained at a low concentration, and various additives can be added like a normal oral solution, so that the taste can be cleared and the water-soluble internal product can withstand market distribution. A liquid agent can be provided.
International Publication No. WO02 / 41892

However, according to Patent Document 1, although stability and taste characteristics that can withstand market distribution are improved, there are the following unsolved problems in terms of storage stability.
(1) In commercializing this water-soluble internal solution, the accommodation form of the water-soluble internal solution that can be stored for a long period of time while maintaining stability has not yet been clarified.
(2) Although a brown glass container is generally distributed as a container for storing an internal liquid, there is a risk that air will be mixed and the internal liquid will deteriorate when the glass liquid is filled into the glass container during the manufacturing process. Therefore, it is common to produce products by adding preservatives, but inventing the problem that adding preservatives to water-soluble oral solutions containing famotidine as an active ingredient reduces stability. Found them.

  Accordingly, an object of the present invention is to provide a water-soluble internal liquid container capable of storing for a long time a water-soluble internal liquid solution having a stable and excellent palatability as an active ingredient, and to the storage container. The object is to provide a method for filling a water-soluble internal solution.

  In order to achieve the above-mentioned object, the present invention provides a medical solution storage part that stores a water-soluble internal liquid solution, a mouth part that is connected to the upper part of the chemical liquid storage part and serves as a mouth of the water-soluble internal liquid solution, A water-soluble type comprising a cap part that closes the drinking part and a knob part joined to the cap part through a thin area part, and the drinking part is opened by threading the knob part. It is a container for internal liquids, and the water-soluble internal liquid is filled in the medicinal solution storage part under replacement of nitrogen gas.

  In the above configuration, it is desirable that the water-soluble internal preparation is obtained by adding edetic acid or a salt thereof to famotidine.

  Moreover, it is desirable that the container is sealed in a packaging bag together with an oxygen scavenger.

  The packaging bag is preferably formed of an oxygen barrier resin film.

  In order to achieve the above object, the present invention provides a pair of left and right body molds for molding a container body part and a pair of left and right upper molds provided on the upper part of the body mold to mold the container upper part. A cylindrical resin molded body is suspended while being separated, the resin molded body is sandwiched between the main body molds, and compressed nitrogen gas is blown into the resin molded body to mold the container main body portion. Filling the container body portion with a water-soluble internal liquid, sandwiching the resin molded body with the upper mold, and forming the vacuum inside of the upper mold to mold and seal the upper part of the container. A method for filling a water-soluble internal liquid medicine into a storage container is provided.

  It is desirable that the water-soluble internal solution is obtained by adding edetic acid or a salt thereof to famotidine.

  According to the present invention, since the internal container is filled with a water-soluble internal liquid solution in which edetic acid or a salt thereof is added to famotidine under nitrogen gas replacement, the chemical liquid is not brought into contact with air. For this reason, preservatives are not required, long-term storage is possible while ensuring the stability of famotidine, and the storage stability of the aqueous solution solution itself can be enhanced.

  Moreover, long-term storage becomes possible by enclosing the storage container in which the water-soluble internal solution is stored in a packaging bag formed of an oxygen-barrier resin film together with an oxygen scavenger.

Next, the water-soluble internal liquid container and the method for filling the internal liquid solution into the storage container according to the present embodiment will be described with reference to the drawings.
<Container configuration>
1A and 1B are diagrams showing a configuration of a storage container for storing a water-soluble internal solution, wherein FIG. 1A is a perspective view and FIG. 1B is a front view.
As shown in FIGS. 1 (a) and (b), the storage container 10 has a chemical solution storage part 11 for storing a chemical solution and a chemical solution stored in the chemical solution storage part 11 so that it can be easily taken. It comprises a drinking part 12, a cap part 13 that closes the outlet of the drinking part 12, and a knob part 14 joined to the cap part 13.

  In the above configuration, the container 10 has a twist-off configuration in which the knob portion 14 is threaded and opened. For this purpose, an opening 11a is formed at one end facing the bottom 16 in the longitudinal direction along the central axis 15 of the drug solution storage part 11, and a drinking mouth part 12 is connected to the opening 11a. The cap portion 13 is continuously provided, and the cap portion 13 and the knob portion 14 are joined by the thin region portion 14a. And the opening of the drinking mouth part 12 appears by screwing the knob part 14 by twist-off opening.

  The container 10 itself is formed by blow fill seal (BFS) molding and is made of synthetic resin. BFS molding is a molding method in which a resin container is molded with a molding machine, and a chemical solution is immediately filled and sealed, and the molding, filling and sealing can be performed in a series of operations. For this reason, for example, it becomes possible to fill and seal the chemical solution in an aseptic environment. In addition, as a material of the container 10 used in the BFS molding, for example, polyolefin such as polyethylene and polypropylene, polyvinyl chloride, ethylene / vinyl acetate copolymer, and the like can be given.

2 is a cross-sectional view taken along the line AA in FIG. 1A, and FIG. 3 is a cross-sectional view taken along the line BB in FIG.
As shown in FIG. 2, the knob part 14 is joined to the cap part 13 via the thin area part 14a. Further, as shown in FIG. 3, a slight gap is interposed between the drinking mouth portion 12 and the thin region 14 a of the knob portion 14. Since this slight gap exists, the chemical solution storage portion 11 and the knob portion 14 are twisted off by grasping the chemical solution storage portion 11 and the knob portion 14 and twisting in the opposite directions.

FIG. 4 is a view showing a state in which the knob portion 14 is separated from the chemical solution storage portion 11.
As shown in the figure, when the drug solution storage portion 11 and the knob portion 14 are gripped and twisted in opposite directions, the cap portion 13 is integrated with the knob portion 14 and separated from the drinking mouth portion 12. When the cap part 13 is separated from the drinking part 12, the upper part of the drinking part 12 is opened, and the drug solution is discharged from the opening and taken.

FIG. 5 is a diagram showing a configuration in which a plurality of water-soluble internal liquid containers are connected according to the present embodiment.
As shown in the figure, it is possible to mold the container 10 in a state where two storage containers 10 are connected. In this case, the side surface of the chemical solution storage portion 11 and the side surface of the knob portion 14 are molded in a state where the side surface of the chemical solution storage portion 11 and the side surface of the knob portion 14 of another adjacent container 10 are partially connected, Are formed so that they can be separated by twisting in the opposite direction. In addition, although the figure showed the state which two storage containers connected, it is not restricted to this, It can shape | mold in the state which connected two or more storage containers. By doing so, a large amount of containers can be manufactured in a short time.

<Manufacturing method of container and filling / sealing method of chemical solution>
Next, the manufacturing method of said storage container 10 and the filling / sealing method of a chemical | medical solution are demonstrated with reference to FIGS.
First, as shown in FIG. 6, the chemical solution is adjusted by the adjustment tank 20 by a predetermined adjustment method and sent to the storage tank 30. At this time, the chemical solution is sent from the adjustment tank 20 to the storage tank 30 via the sterilization filter 21.

  Next, the chemical solution stored in the storage tank 30 is sent to the filling tank 40 that stores the chemical solution in order to fill the container 10. Also at this time, the chemical solution is sent to the filling tank 40 through the sterilizing filters 31 and 32 twice. Thereby, it is possible to perform sufficient sterilization from the adjustment of the chemical solution to the filling and improve the quality maintenance. And the chemical | medical solution filling from the filling tank 40 to the storage container 10 is performed under substitution of nitrogen gas.

Since the filling of the chemical solution and the production of the storage container 10 are performed substantially simultaneously, the manufacturing method of the storage container and the filling / sealing method of the chemical solution will be described in the order of steps.
(1) Extrusion of Cylindrical Synthetic Resin Molded Body 100 First, before blow molding, the synthetic resin molded body 100 with the lower end closed is extruded and suspended between the molds 300 separated by the extruder 200 ( FIG. 7 (a)).
The mold 300 used when blow-molding the cylindrical synthetic resin molded body 100 is composed of a pair of left and right main body molds 301 and a pair of left and right upper molds 302. The main body mold 301 is formed with a concave portion 301 a having the shape of the chemical solution storage portion 11 of the storage container 10, and the upper mold 302 includes the drinking mouth portion 12, the cap portion 13, and the knob portion 14 of the storage container 10. A concave portion 302a having a shape is formed.

(2) Molding of chemical solution container 11 and filling of chemical solution Next, the body mold 301 in a separated state is clamped to fix the synthetic resin molded body 100 in the mold 300, and the position above the mold 300 Cut with a knife or the like (not shown) heated at (Fig. 7 (b)). Then, compressed air (nitrogen gas) is blown by the air nozzle 400 from the opening end formed by cutting (FIG. 8A), the synthetic resin molded body 100 is expanded inside the main body mold 301, and the chemical solution storage portion 11. The shape is formed (FIG. 8B). Next, the chemical solution injection nozzle 500 is lowered to the vicinity of the bottom of the formed chemical solution storage part 11 and the chemical solution is injected from the chemical solution injection nozzle 500 (FIG. 9A).

(3) Molding of drinking mouth part 12 Next, the chemical injection nozzle 500 is taken out from the mold 300, and the upper mold 302 in a separated state is clamped. A suction port 302b is provided in the inner wall of the upper mold 302, and when the upper mold 302 is clamped, the inside of the upper mold 302 is evacuated. As a result, the synthetic resin formed body 100 is vacuum-formed along the shape of the recess 302a in which the upper mold 302 is formed, and at the same time is sealed, and the drinking mouth portion 12 and the knob portion 14 are formed (FIG. 9). (B)). Then, the main body mold 300 is separated again, and the molded container 10 is taken out (FIG. 10).

  The container 10 filled with the chemical solution thus manufactured is further sealed in a packaging bag (not shown) formed of an oxygen-impermeable multilayer film, so that the filled chemical solution can be stored for a long time. It becomes possible. Further, it is better to enclose an oxygen scavenger (not shown) together with the container 10 or to enclose the container 10 and the oxygen scavenger in a packaging bag substituted with nitrogen gas.

The packaging bag shown here is not particularly limited as long as it is a resin film having an oxygen gas barrier property, and is generally an aluminum laminate film, a silicon oxide vapor deposition film, and an alumina vapor deposition film formed into a bag shape by heat sealing.
The oxygen scavenger is not particularly limited as long as it adsorbs ambient oxygen, and for example, a known oxygen scavenger (trade name “AGELESS”) is suitable.
Furthermore, the packaging bag substituted with nitrogen gas is a packaging technology that is held in nitrogen gas and prevents changes due to oxygen in the air, and a known packaging technology is adopted.

<About chemicals to be filled>
The chemical | medical solution accommodated in the above-mentioned storage container 10 is demonstrated.
In addition, although an Example, a test example, and a comparative example are demonstrated to this invention, this invention is not limited by the Example, test example, and comparative example which are shown below.
An example of a chemical solution stored in the storage container 10 is a water-soluble internal solution containing famotidine as an active ingredient, and is a stable internal solution of famotidine having a residual ratio of famotidine of 97% or more even after storage at room temperature for 12 months. .
The internal liquid preparation is a water-soluble internal liquid preparation containing famotidine and edetic acid or a salt thereof. In Examples 1 to 10 below, examples of producing a water-soluble internal liquid preparation are shown.

Example 1
900 ml of purified water was heated to 40 ° C., 1 g of disodium edetate and 1 g of famotidine were dissolved, 2.5 g of mannitol was added, and after cooling, purified water was added to make 1000 ml. The pH of this water-soluble internal liquid preparation was 6.7, and the residual ratio of famotidine was 97.4% when stored under conditions of 40 ° C. for 2 months.

(Example 2)
900 ml of purified water was heated to 40 ° C. to dissolve 1 g of disodium edetate and 1 g of famotidine. After cooling, purified water was added to make 1000 ml. The pH of this water-soluble internal liquid preparation was 6.7, and the residual rate of famotidine was 97.5% when stored at 40 ° C. for 2 months.

(Example 3)
90 ml of purified water is heated to 40 ° C., 100 mg of sodium disodium edetate and 100 mg of famotidine are dissolved, and after cooling, an appropriate amount of 1% citric acid solution and purified water are added, and the pH is 6.0. 100 ml was made. The residual ratio of famotidine was 98.0% when stored for 12 months under room temperature conditions.

Example 4
90 ml of purified water is heated to 40 ° C., 100 mg of sodium disodium edetate and 100 mg of famotidine are dissolved, and after cooling, an appropriate amount of 1% citric acid solution and purified water are added, and the pH is 6.25. 100 ml was made. The residual rate of famotidine was 97.7% when stored at room temperature for 12 months.

(Example 5)
90 ml of purified water is heated to 40 ° C., 100 mg of sodium disodium edetate and 100 mg of famotidine are dissolved, and after cooling, an appropriate amount of 1% citric acid solution and purified water are added, and the pH is 6.5. 100 ml was made. The residual rate of famotidine when stored for 12 months under the room temperature condition of this preparation was 98.7%.

(Example 6)
90 ml of purified water was heated to 40 ° C., 44 mg of methylparaben, 6 mg of propylparaben, 100 mg of sodium disodium edetate and 100 mg of famotidine were dissolved, and after cooling, an appropriate amount of 1% citric acid solution and purified water were added to adjust the pH to 5. 100 ml of 75 water-soluble internal preparations were prepared. The residual rate of famotidine was 98.1% when stored for 12 months under room temperature conditions.

(Example 7)
90 ml of purified water is heated to 40 ° C., 44 mg of methylparaben, 6 mg of propylparaben, 100 mg of sodium disodium edetate and 100 mg of famotidine are dissolved, and after cooling, an appropriate amount of 1% citric acid solution and purified water are added to adjust the pH to 6. 100 ml of 25 water-soluble internal preparations were prepared. The residual ratio of famotidine was 98.0% when stored for 12 months under room temperature conditions.

(Example 8)
90 ml of purified water is heated to 40 ° C., 44 mg of methylparaben, 6 mg of propylparaben, 100 mg of sodium edetate and 100 mg of famotidine are dissolved, and after cooling, an appropriate amount of 1% citric acid solution and purified water are added to adjust the pH to 7 0.0 water-soluble internal preparation was prepared. The residual rate of famotidine was 97.6% when the preparation was stored for 12 months at room temperature.

Example 9
90 ml of purified water is heated to 40 ° C., 44 mg of methylparaben, 6 mg of propylparaben, 10 mg of sodium edetate and 10 g of famotidine are dissolved, 15 mg of sucralose is added, and after cooling, an appropriate amount of 1% lactic acid solution and purified water are added. Thus, 100 ml of a water-soluble internal liquid preparation having a pH of 6.5 was produced. When this preparation was stored for 12 months at room temperature, the residual ratio of famotidine was 99.0%.

(Example 10)
90 m of purified water is heated to 40 ° C., 44 mg of methylparaben, 6 mg of propylparaben, 10 mg of sodium edetate and 50 mg of famotidine are dissolved, 15 mg of sucralose is added, and after cooling, an appropriate amount of 1% lactic acid solution and purified water are added. Thus, 100 ml of a water-soluble internal liquid preparation having a pH of 6.5 was produced. When this preparation was stored for 12 months under room temperature, the residual ratio of famotidine was 98.8%.

  According to the above Examples 1 to 10, it is possible to ensure that the residual rate of famotidine is sufficiently stable to withstand market distribution, that is, the residual rate after 12 months at room temperature is 97% or more. it can.

  Next, the storage stability of a water-soluble internal solution containing famotidine stored in the storage container 10 will be described.

The components of the famotidine oral solution used in the test are shown below.
The manufacturing method manufactured the liquid according to the item of a Japanese Pharmacopoeia general rule "liquid agent".

(In 10 ml)
Famotidine 10mg
Sodium disodium edetate Appropriate amount Sucralose Appropriate amount Fragrance Trace amount Lactic acid Appropriate amount Purified water balance

(Test Example 1)
The famotidine oral solution obtained as described above was molded by the above-described production method, filled and sealed with 10 ml under nitrogen gas replacement, and sealed with an oxygen scavenger in a bag made of alumina-deposited polyester film.

(Comparative Example 1)
10 ml of the famotidine solution obtained as described above was filled and sealed in a brown glass bottle.

(Accelerated aging test)
The preparations of Test Example 1 and Comparative Example 1 were stored for 6 months under conditions of a temperature of 40 ° C. and a relative humidity of 75%. The residual rate of famotidine at 1, 3 and 6 months is shown in Table 1. The data at 6 months of this accelerated aging test corresponds to storage for 3 years under normal conditions.

  As shown in Table 1, it was revealed that the case where the famotidine solution was filled and sealed in a plastic bottle had better storage stability than the case where the famotidine solution was filled and sealed in a brown glass bottle.

In addition, as a reproducibility test example, 10 ml of famotidine solution is filled and sealed in a plastic bottle manufactured by the above-described manufacturing method, and then sealed and sealed together with an oxygen scavenger in a bag made of alumina-deposited polyester film. An accelerated aging test was conducted under the following conditions.
The test results are shown in Table 2.

  As shown in Table 2, also in the reproducibility test example, it was shown that the storage stability of the famotidine solution filled and sealed in the plastic bottle was high.

  As is clear from the above description, since the water-soluble internal solution is filled in the storage container under nitrogen gas replacement by BFS molding, the water-soluble internal solution does not come into contact with air. Therefore, even when no preservative is added, long-term storage and storage stability of famotidine are possible.

  In addition, the storage container containing the water-soluble internal solution can be sealed and sealed together with the oxygen scavenger in a packaging bag formed of an oxygen gas barrier resin film under nitrogen gas replacement. It becomes possible.

Fig.1 (a) is the perspective view which showed the structure of the storage container which accommodates a water-soluble internal solution, FIG.1 (b) is the front view which showed the structure of the storage container which stores a water-soluble internal solution. is there. It is the sectional view on the AA line of Fig.1 (a). It is the BB sectional drawing of FIG.1 (b). It is a figure which shows the state which the knob part isolate | separated from the chemical | medical solution storage part. It is a figure which shows the structure which connected two or more storage containers of the water-soluble internal use liquid medicine concerning this Embodiment. It is the figure which showed the manufacturing method of chemical | medical solution, and the process of filling. It is a figure which shows the manufacturing method of a storage container, (a) is the figure which showed the resin molded object hanging state between the spaced apart metal mold | die, (b) is the main body metal mold | die pinched | interposed the resin molded object It is the figure which showed the state. It is a figure which shows the manufacturing method of a storage container, (a) is the figure which showed the state which injected nitrogen gas inside the resin molding, (b) is a chemical | medical solution storage part shape | molded in the recessed part of a main body metal mold | die. It is the figure which showed the state made. It is a figure which shows the method of filling and inject | pouring a chemical | medical solution to a storage container, (a) is the figure which showed the state by which the chemical | medical solution was inject | poured into the chemical | medical solution storage part, (b) is an upper metal mold | die resin molding It is the figure which showed the state which shape | molded the chemical | medical solution discharge part and the knob part by inserting | pinching. It is the figure which showed the state which was shape | molded and the storage container with which the chemical | medical solution was filled and inject | poured is taken out.

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 Storage container 11 Chemical solution storage part 12 Drinking part 13 Cap part 14 Knob part 14a Thin area part 15 Center axis 16 Bottom part 20 Adjustment tank 21, 31, 32 Sterilization filter 30 Storage tank 40 Filling tank 100 Resin molding 200 Extruder 300 Mold 301 Main body mold 301a, 302a Recess 302 Upper mold 400 Air nozzle 500 Chemical solution injection nozzle

Claims (6)

A liquid medicine container for containing a water-soluble internal liquid solution; a mouth part that is connected to the upper part of the liquid medicine container part and serves as a mouth for the water-soluble internal liquid medicine; a cap part that closes the mouth part; and the cap A water-soluble internal liquid container containing the knob part joined to the part through a thin region part, and opening the drinking mouth part by threading the knob part,
The water-soluble internal liquid preparation container is filled with the chemical liquid storage section under replacement of nitrogen gas.   The water-soluble internal liquid preparation container according to claim 1, wherein the water-soluble internal liquid preparation is obtained by adding edetic acid or a salt thereof to famotidine.   The said container is sealed in a packaging bag with an oxygen scavenger, The container for the water-soluble internal use liquid agent of Claim 1 or 2 characterized by the above-mentioned.   The said packaging bag is shape | molded with the resin film of oxygen barrier property, The storage container of the water-soluble internal use liquid agent of Claim 3 characterized by the above-mentioned. A cylindrical resin molded body is suspended while a pair of left and right main body molds for molding the container main body part and a pair of left and right upper molds for molding the upper part of the container provided on the upper part of the main body mold are separated from each other,
The resin molded body is sandwiched by the main body mold,
At the same time as forming the container body portion by blowing compressed nitrogen gas into the resin molded body, the molded container body portion is filled with a water-soluble oral solution,
The resin molded body is sandwiched between the upper molds, the inside of the upper mold is evacuated and the upper part of the container is molded and sealed,
A method for filling a water-soluble internal solution into a container.   The method for filling a water-soluble internal liquid preparation into a storage container according to claim 6, wherein the water-soluble internal liquid preparation is one obtained by adding edetic acid or a salt thereof to famotidine.

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