JP6174309B2 - Test liquid product - Google Patents

Description

  The present invention relates to a test liquid product in which a test liquid used in a dissolution test or a disintegration test for solid preparations such as tablets, capsules and granules is filled in a container.

In solid preparations such as tablets, capsules, granules and the like, even when the same amount of active ingredient is contained, the effect may be different if the dissolution rate of the active ingredient after taking is different. For this reason, there is a dissolution test as one of the important quality control items in the manufacture of pharmaceuticals, and dissolution tests are prescribed by the Japanese Pharmacopoeia, the US Pharmacopoeia and the European Pharmacopoeia. For example, the 16th revision of the Japanese Pharmacopoeia stated that the purpose of the dissolution test method is to “determine whether or not the oral drug product conforms to the dissolution test standards. It is intended to prevent. "And the equipment to be used, operation, judgment method, etc. are prescribed in detail. For example, in the rotating basket method and paddle method, the amount of the test solution is within ± 1% of the specified volume, the temperature of the test solution is kept within 37 ± 0.5 ° C, and a buffer solution is used as the test solution Is defined to keep the pH of the test solution within the prescribed pH ± 0.05.
As the test solution for the dissolution test, there are various buffers and water from strong acidity to weak alkalinity (pH 1.2 to 8.0). For each formulation, the dissolution test conditions including the type of test solution and the amount of the test solution and the conformance conditions are defined, and it is determined whether the manufactured formulation conforms to the dissolution test standards. At this time, the same test is performed on at least six samples, and the determination is performed based on the elution rate of the active ingredient from each sample.

Although the test solution for the dissolution test was prepared by the tester, this was a heavy burden on the tester. For example, when a dissolution test is performed by the rotating basket method or the paddle method, the tester weighs and mixes the reagent and water, dissolves and mixes before starting the test, and adjusts the pH to obtain the required test solution (at least six samples). In order to carry out the above test, prepare a test solution volume of at least 6 times the specified one), and measure the specified test solution volume accurately (within ± 1%), The test can be started only after it is put in a container and heated to the specified temperature. Therefore, it takes a lot of time and labor to start the test. Further, among the prepared test solutions, those which are not used immediately must be stored in a sealed container so that moisture evaporation, pH change, and microbial growth do not occur.
In the development and production of solid preparations, a disintegration test is performed to confirm whether the preparation disintegrates within a specified time in the test solution, but the same problem exists with the test solution used in this disintegration test. is there.

  Recently, products in which containers are filled with test solutions used in dissolution tests or disintegration tests and concentrated liquids thereof have become commercially available. As the shape of the container, a bottle shape or a plastic tank shape is used, and as the material of the container, glass, polyethylene, polypropylene, fluorine resin or the like is used. As the size of the container, 3L to 18L in the case where the content liquid is a test liquid, and 250 mL to 1L in the case where the content liquid is a concentrated liquid are in circulation (for example, Non-Patent Documents 1 to 3). 2).

“Reagent for formulation stability test”, [online], Kanto Chemical Co., Ltd. [searched on May 7, 2012], Internet <URL: http://www.kanto.co.jp/siyaku/pdf/iyakuhin_03 .pdf> “Accessories for dissolution test, concentrated test solution for dissolution test”, [online], Ivic Research, Inc. [searched May 7, 2012], Internet (http://www.ivicres.com/cgi-bin /ivic_research/siteup.cgi?category=1&page=5)

When using a product filled with a test liquid or its concentrated liquid as described above, the content liquid can be used as it is or as a test liquid by diluting with water. The burden of is reduced.
However, the effect is not sufficient. For example, many products that are filled with the test solution as it is have a large container size. However, the work of transporting such a product or accurately subdividing a specified amount of test solution (for example, 900 mL) from the product is not possible. It is hard work, especially for women.
In the case of a product filled with a concentrate, the load of transportation is less than that of a product filled with the same amount of the test solution prepared from the concentrate, but the concentrate is diluted accurately. It takes time and effort. Further, in the case of a test solution having a low pH such as pH 1.2, the concentrated solution is very acidic and requires care in handling.

  This invention is made | formed in view of the said situation, Comprising: It aims at providing the test liquid product which can reduce the work burden of the tester in a dissolution test or a disintegration test, and can improve work efficiency.

The present invention has the following aspects.
[1] In a test liquid product for transferring the test liquid to a test container used for the dissolution test or disintegration test, wherein the test liquid used for the dissolution test or disintegration test of the solid preparation is filled in the container .
A test liquid product in which a filling amount of the test liquid is within a range of a capacity ± 1% defined as a test liquid amount used when the dissolution test or the disintegration test is performed once.
[2] The test liquid product according to [1], wherein an amount of the test liquid used when the disintegration test is performed once is 900 mL.
[ 3 ] The container includes a bag-shaped container body made of a film that contains the test solution,
The test liquid product according to [1] or [2] , wherein the container body is capable of self-supporting.

  ADVANTAGE OF THE INVENTION According to this invention, the test liquid product which can reduce the work burden of the tester in a dissolution test or a disintegration test, and can improve work efficiency can be provided.

It is a schematic perspective view which shows one Embodiment of the test liquid product of this invention.

  The test liquid product of the present invention is used when a test liquid used in a dissolution test or disintegration test of a solid preparation is filled in a container, and the filling amount of the test liquid is used when the dissolution test or disintegration test is performed once. The volume is within the range of ± 1% defined as the amount of the test solution.

By using the test liquid product of the present invention, the work burden on the tester in the dissolution test or the disintegration test is reduced, and the work efficiency is improved.
For example, in the test liquid product of the present invention, since the test liquid of the kind and amount necessary for one dissolution test or disintegration test is accurately filled in the container, the tester opens the container, The dissolution test or disintegration test can be started simply by transferring the content liquid to the test container.
For this reason, in the prior work required by the test operator, for example, when measuring the reagent and water necessary for preparing the test solution, stirring and dissolving, and preparing a strongly acidic test solution, Work in a fume hood required to use a strong acid such as hydrochloric acid, pH measurement / adjustment work, and work to accurately dispense a specified amount of test liquid (eg 900 mL) from a large amount of test liquid Become. Moreover, the amount of the transferred test solution can be accurately obtained only by measuring the weight of the test solution in the container before and after the transfer.
The prepared test solution is filtered and sterilized as necessary, and then filled into a container. A large amount (for example, 20 L) of the test solution is filled into the container, and a part of the test solution is collected therefrom. In such a case, the remaining test solution may be contaminated with microorganisms or propagate over time due to repeated opening and closing of the container. In the present invention, since the container is filled and sealed with an amount of the test solution that can be used at a time, contamination and propagation of microorganisms are unlikely to occur.
In addition, since the dissolution test and the disintegration test are performed at 37 ° C., generally, a prescribed amount of the test solution is placed in a test container and then heated to 37 ° C. On the other hand, if the test liquid product of the present invention is preliminarily heated to 37 ° C. in a thermostatic bath or the like together with the container, the test can be started immediately after the content liquid is transferred to the test container. Therefore, the time until the start of the test can be saved and the efficiency of the test can be increased.
Thus, the test liquid product of the present invention has epoch-making convenience.

In the test liquid product of the present invention, it is preferable that the container includes a bag-shaped container main body made of a film that contains the test liquid. When the container body containing the test liquid is in the shape of a bottle or a plastic tank, the volume of the container body does not change before and after taking out the test liquid, but in the case of a bag shape composed of a film, the film has flexibility. After removing the test solution, the volume of the container body is greatly reduced. For this reason, waste (empty container after use) is reduced both in mass and volume.
The bag-like container body is preferably a self-supporting one (for example, a standing pouch). As a result, compared to the case of using a bag-like container that does not have self-supporting property, a storage place and a place for carrying out the test are not taken. Since no place is used, the work space for the tester is widened and the workability is improved.

The test liquid product of the present invention may be a dissolution test liquid product filled with a test liquid used for a dissolution test (hereinafter also referred to as a dissolution test liquid), or a test liquid used for a disintegration test (hereinafter referred to as a disintegration test liquid). It may be a dissolution test solution product filled with a. There are many types of dissolution test solutions compared to disintegration test solutions, and the amount of solution used in one test is strictly defined. Therefore, the test liquid product of the present invention is preferably a test liquid product for dissolution test filled with a dissolution test liquid in that the effect of reducing the burden on the tester according to the present invention is large.
Hereinafter, the test liquid product of the present invention will be described by showing an embodiment.

[First embodiment]
In FIG. 1, the schematic perspective view of the test liquid product 1 of this embodiment is shown.
The test liquid product 1 is obtained by filling a bag (container body) 3 with a test liquid 2 (shaded portion in the figure) used in a dissolution test or disintegration test for a solid preparation.
The bag 3 is a standing pouch having a body 3a made of a pair of films and a bottom 3b made of a film.

Test solution 2 may be a dissolution test solution or a disintegration test solution. As the dissolution test solution and the disintegration test solution, those described in Japanese Pharmacopoeia, US Pharmacopoeia, European Pharmacopoeia and the like can be used without any particular limitation.
As the dissolution test solution and the disintegration test solution, those described in Japanese Pharmacopoeia, US Pharmacopoeia, European Pharmacopoeia and the like can be used without any particular limitation.
Examples of the dissolution test solution include buffers and water having various pH values of 1.2 to 8.0. Examples of the buffer solution include a dissolution test first solution (pH 1) described in the 16th revised Japanese Pharmacopoeia. .2), acetic acid / sodium acetate buffer solution (pH 4.0), dissolution test second solution (pH 6.8), phosphate buffer solution (pH 6.8), phosphate buffer solution (pH 8.0) and the like. Can be mentioned.
As the disintegration test solution, for example, in the disintegration test method described in the 16th revision Japanese Pharmacopoeia, three types of disintegration test first solution (pH 1.2), disintegration test second solution (pH 6.8), and water are used. It is done.
The same disintegration test first liquid and dissolution test first liquid are used. Therefore, the test liquid product filled with water or the first dissolution test liquid as the dissolution test liquid can be used as the test liquid product for the disintegration test.

The filling amount of the test solution 2 is within the range of ± 1% of the volume defined as the amount of the test solution used when the dissolution test or the disintegration test is performed once.
The amount of the test solution used when performing the dissolution test once is specified for each preparation by the Japanese Pharmacopoeia and the like, but is usually 900 mL. Therefore, when the test solution 2 is a dissolution test solution, the filling amount of the test solution 2 is preferably in the range of 900 mL ± 1% from the viewpoint of versatility.
However, the amount of the test solution may not be 900 mL (for example, 500 mL), and is not limited to the above range. It can be set as the filling amount according to the various test liquid amount prescribed | regulated.
Regarding the amount of the test solution used when the disintegration test is carried out once, for example, in the disintegration test method described in the 16th revision Japanese Pharmacopoeia, “When the tester is the highest, The mesh surface of the tester should be at least 15 mm below the liquid level and when the tester is at its lowest position, the mesh surface should be 25 mm or more from the bottom of the beaker and the tester must not sink completely. ”And there is no clear regulation of liquid volume. Therefore, the amount of the test solution used when the disintegration test is carried out once is defined by the test operator so as to satisfy the above-mentioned provision according to the apparatus used for the disintegration test. Generally, it is about 900 mL. Therefore, when the test solution 2 is a disintegration test solution, the filling amount of the test solution 2 is preferably in the range of 900 mL ± 1% from the viewpoint of versatility.

As described above, the bag 3 is a standing pouch having a body 3a made of a pair of films and a bottom 3b made of a film.
In the bag 3, a pair of films constituting the body portion 3 a are welded at the side edge portion and the upper edge portion to form side edge seal portions 4 a and 4 b and an upper edge seal portion 4 c. The film constituting the bottom 3b is arranged in a half-folded state so that the half-folded fold line is between the pair of films constituting the body 3a, and the film constituting the bottom 3b is folded. One surface and the other surface with the line as a boundary are welded to the lower edge portions of the opposing films of the pair of films constituting the body portion 3a, and lower edge seal portions 4d and 4e are formed. In the region where the side edge seal portions 4a, 4b and the lower edge seal portions 4d, 4e overlap, the pair of films constituting the body portion 3a are partially welded.
The side edge seal portions 4a and 4b are provided with notches 5a and 5b slightly below the lower end of the upper edge seal portion 4c in order to facilitate the opening of the bag 3.

  As a pair of films constituting the body part 3a of the bag 3 and a film constituting the bottom part 3b, conventionally known films can be used without particular limitation as a film forming the bag. For example, one side of the base film And a laminate film in which a sealant film is laminated. The laminate film can be easily processed into a standing pouch shape by heat sealing.

The substrate film in the laminate film is preferably a single layer or multilayer film including at least a highly moisture-proof film. The highly moisture-proof film has low moisture permeability, and by using this as a base film, it is possible to suppress the evaporation of moisture in the test solution during storage of the test solution product. Can be suppressed.
Specific examples of the highly moisture-proof film include, for example, polyester resins such as polyethylene terephthalate (PET) and polyethylene-2,6-naphthalate (PEN), polyamide resins such as nylon 6, nylon 66, nylon 12, and copolymer nylon. A metal foil laminated film obtained by laminating an unstretched or stretched resin film made of the above resin and a metal foil such as an aluminum foil; a metal vapor deposited film obtained by depositing a metal such as aluminum on one or both surfaces of the resin film; Coating an organic and / or inorganic barrier coating agent (for example, polyvinylidene chloride, ethylene-vinyl alcohol copolymer, crosslinked product of modified or non-modified polyvinyl alcohol and unsaturated carboxylate, etc.) on the resin film Coated film; and the like. As a metal foil laminated film, what laminated | stacked metal foil on the single side | surface or both surfaces of a resin film, and what sandwiched metal foil between the two resin films, etc. are mentioned. When the highly moisture-proof film includes a plurality of resin films, the material of each resin film may be the same or different.
Among the above, the highly moisture-proof film is preferably an aluminum foil laminated film.
However, the present invention is not limited to this, and a film having low moisture resistance, for example, an unstretched or stretched resin film made of a resin such as the polyester resin or the polyamide resin as a raw material or a laminate is a base film. It may be used as In the case of a laminate, the materials of the plurality of resin films constituting the laminate may be the same or different.
When the storage period of the test liquid product is short, a decrease in the amount of the test liquid, a change in pH, and the like can be sufficiently suppressed even when such a resin film with low moisture resistance is used. In addition, such a resin film is less expensive than a highly moisture-proof film, and has an advantage that it is easier to discard than a metal foil laminated film. Therefore, the bag using this as a base film is useful as a disposable container.
The thickness of the base film is preferably in the range of 5 to 500 μm, more preferably in the range of 7 to 200 μm, from the viewpoint of mechanical strength, flexibility, and the like.

The sealant film is a layer that imparts heat sealability to the laminate film. When the laminate film is made into a bag shape by heat sealing, it is melted by heating, and the laminate film and another film in contact with the sealant film are bonded. To do.
The sealant film is not particularly limited as long as it is a film having heat sealability, but as the sealant film disposed in the innermost layer (layer which becomes the inner surface of the bag 3) of the laminate film, the test liquid 2 is hardly adsorbed. A polyolefin resin film is preferred from the standpoint that elution from the bag 3 to the test solution 2 hardly occurs. Examples of the polyolefin resin include polyethylene such as high density polyethylene (HDPE), low density polyethylene (LDPE), and linear low density polyethylene (LLDPE), polypropylene, and polybutene.
Although the thickness of a sealant film is not specifically limited, Usually, it is about 20 micrometers-300 micrometers.
The method for laminating the sealant film and the base film is not particularly limited, and a known method such as a dry laminating method using an adhesive or an extrusion laminating method using a heat-adhesive resin can be used.

  When the laminate film is used as a pair of films forming the body portion 3a and a film constituting the bottom portion 3b, the layer configuration of the laminate film used for each film may be the same or different. In view of facilitating heat-sealing between films, a laminate film including a sealant film made of the same kind of resin is preferred.

The capacity of the bag 3 is not particularly limited as long as it is within a range in which a predetermined amount of the test solution 2 can be accommodated, but is within the range of (fill amount of the test solution 2 + 30 mL) to (fill amount of the test solution 2 + 300 mL). It is preferable that it is in the range of (filling amount of test solution 2 + 50 mL) to (filling amount of test solution 2 + 150 mL). For example, when filling 900 mL of test liquid, it is preferable that it is 930-1200 mL, and it is more preferable that it is 950-1050 mL.
When the capacity of the bag 3 is the filling amount of the test solution 2 + 30 mL or more, the test solution 2 hardly leaks when the bag 3 is opened, and when the filling amount of the test solution 2 + 300 mL or less, a predetermined amount of test is performed. When the liquid 2 is filled, the container does not become excessively large and the amount of waste after use is small.

The test liquid product 1 is, for example, prepared from the opening of the upper edge portion of the bag 3 to the bag 3 in a state in which a part or all of the upper edge portion of the body portion 3b is not welded. After the test solution 2 is filled and degassed as necessary, the opening is heat-sealed and sealed.
The test liquid 2 can be prepared according to the regulations of the Japanese Pharmacopoeia according to the type of the test liquid 2 to be filled.
As the bag 3 filled with the test liquid 2, a commercially available product may be used, or a bag produced using the laminate film as described above may be used. The manufacturing method of the bag 3 is not particularly limited, and can be carried out by a known method as a manufacturing method of the bag 3 shaped standing pouch.
The obtained test solution product 1 may be sterilized. The sterilization treatment can be performed, for example, under conditions of wet heat sterilization at 120 ° C for 30 to 60 minutes.

As mentioned above, although the test liquid product of this invention was demonstrated showing 1st embodiment, the test liquid product of this invention is not limited to the said embodiment.
For example, the shape of the bag-shaped container main body configured of a film that contains the test solution is not limited to the shape of the bag 3 described above. For example, a standing pouch having a shape different from that of the bag 3 may be used, or a bag other than the standing pouch may be used. Examples of bags other than the standing pouch include flat bags such as gusset bags, three-side seal bags, and four-side seal bags. From the viewpoint of improving work efficiency, the container body is preferably capable of being self-supporting, and is particularly preferably a standing pouch or a gusset bag.

The container filled with the test solution may be composed only of a bag-like container body made of a film, such as the bag 3, or may be provided with a member other than the container body. As an example of the latter, a container provided with this container main body and the spout which pours out the contents (test solution) from this container main body is mentioned, for example.
As the spout, a spout with a plug having a plug at the spout is preferable. When a spout with a spout is provided, it is easy to open and seal, and it becomes easy to put a test solution into a glass vessel for dissolution test and the test preparation time is shortened.
Furthermore, it is preferable to employ a plug structure with a tamper evidence in which the opened evidence remains once the bottle is opened. In the test liquid product once opened, the pH of the stored test liquid tends to change. The quality can be guaranteed by adopting a plug structure with tamper evidence.
The container filled with the test solution may have a container body for storing the test solution in a shape other than the bag shape. The shape other than the bag shape is preferably a structure that can be immediately sealed after filling with the test solution, and examples thereof include a bottle shape and a polytank shape. However, from the viewpoint of reducing waste, it is preferable that the container body has a bag shape.
When the shape of the container main body is a bottle shape or a polytank shape, the material is preferably a material that can be easily discarded for waste disposal, and examples thereof include PET, polyethylene (PE), and polypropylene (PP).
The container filled with the test solution includes a bag-like container body composed of a film and the contents from the container body in terms of easiness of taking out the test solution and little waste after taking out the test solution. A container having a spout for pouring out is preferable, and the container body is particularly preferably a standing pouch or a gusset bag.

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto.
<Example 1>
Accurately measure 70 mL of concentrated hydrochloric acid (special grade reagent manufactured by Kanto Chemical) and 20.0 g of sodium chloride (special grade reagent manufactured by Wako Pure Chemical Industries) and dissolve in JP purified water (manufactured by Kyoei Pharmaceutical Co., Ltd.) to make the total amount accurately 10 L. .
900 mL of the resulting solution was accurately dispensed into a 900 mL volumetric flask and filled from the upper opening of the laminate bag 1 described below. Thereafter, the upper opening of the laminated bag 1 was heat sealed and sealed to obtain a test liquid product.
Laminate bag 1: A laminate bag made of a laminate film in which a nylon film and a low density polyethylene film are laminated (Kitami Co., Ltd., MBA type stand bag, capacity of about 1000 mL). It has the same shape as the bag 3 shown in FIG. 1 (state in which the upper edge portion of the body portion 3b is not welded), and the vertical and horizontal size before filling is approximately 235 mm × 120 mm.
The same operation (sorting, filling into the laminating bag 1 and sealing) was performed for the remaining solutions to obtain 11 test liquid products in which 900 mL of the first dissolution test liquid was accurately packaged.

<Example 2>
Accurately measure 17.0 g of monopotassium dihydrogen phosphate (Kanto Chemical Reagent Special Grade) and 17.75 g of disodium monohydrogen phosphate (Kanto Chemical Reagent Special Grade) and dissolve in JP purified water (Kyoei Pharmaceutical). The total amount was exactly 10 L.
900 mL of the obtained solution was accurately dispensed into a 900 mL volumetric flask and filled from the upper opening of the laminate bag 2 described below. Thereafter, the upper opening of the laminate bag 2 was heat sealed and sealed to obtain a test liquid product.
Laminate bag 2: A laminate bag made of a laminate film in which a polyethylene terephthalate film, an aluminum foil, a nylon film and a polypropylene film are laminated in this order (Kitami Co., Ltd., HRS type stand bag, capacity of about 1000 mL). It has the same shape as the bag 3 shown in FIG. 1 (state in which the upper edge portion of the body portion 3b is not welded), and the vertical and horizontal size before filling is approximately 235 mm × 120 mm.
For the remaining solution, the same operation (sorting, filling into the laminating bag 2, sealing) was performed, and the dissolution test second solution (diluted phosphate buffer having a pH of 6.8) was accurately packaged. Eleven liquid products were obtained.

<Example 3>
71.0 g of anhydrous disodium hydrogen phosphate (manufactured by Wako Pure Chemicals, reagent grade) was dissolved in JP purified water (manufactured by Kyoei Pharmaceutical) to make 10 L. To this solution, 53 g of citric acid monohydrate (manufactured by Junyaku, special grade reagent) was dissolved in JP purified water (manufactured by Kyoei Pharmaceutical Co., Ltd.) to make 10 L, and the pH was adjusted to 8.0.
900 mL of the resulting solution was accurately dispensed into a 900 mL volumetric flask and filled from the upper opening of the laminate bag 3 described below. Thereafter, the upper opening of the laminate bag 3 was heat sealed and sealed to obtain a test liquid product.
Laminate bag 3: A laminate bag made of a laminate film in which a polyethylene terephthalate film, an aluminum foil, a nylon film and a polypropylene film are laminated in this order (Kitami Co., Ltd., HRS type stand bag, capacity of about 1000 mL). It has the same shape as the bag 3 shown in FIG. 1 (state in which the upper edge portion of the body portion 3b is not welded), and the vertical and horizontal size before filling is approximately 235 mm × 120 mm.
The remaining solution was subjected to the same operation (sorting, filling into the laminating bag 3, sealing), and the test solution 12 in a container in which 900 mL of pH 8.0 dihydrogen phosphate / citrate buffer was accurately packaged. I got a piece.

1 Test liquid product 2 Test liquid 3 Bag (container body)

Claims (2)

In a test liquid product for transferring the test liquid to the test container used for the dissolution test or disintegration test, in which the test liquid used for the dissolution test or disintegration test of the solid preparation is filled in a container,
The filling amount of test liquid, Ri volume of ± 1% range der defined as a test solution amount used in the practice once the dissolution test or disintegration test,
It said container, for accommodating the test solution, provided with a bag-shaped container body formed of a film, said container body, der Ru test liquid product self-sustainable ones.   The test liquid product according to claim 1, wherein an amount of the test liquid used when the disintegration test is performed once is 900 mL.

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