TWI539944B - Pharmaceutical packaging - Google Patents

Description

Pharmaceutical packaging

The present invention relates to a pharmaceutical package, and more particularly to a pharmaceutical package in which a particulate composition containing a penicillin antibiotic as an active ingredient is enclosed in a bag-shaped package.

The particulate composition containing the penem antibiotic is easy to absorb moisture, and if it absorbs moisture, it will cause abnormal odor, agglomeration, color tone change, and decrease in the strength, and the quality of the granular composition is lowered, so the package needs to be kept inside. The composition in the dry state. Therefore, the prior art has produced a package by using a packaging material including a barrier material such as aluminum foil, and a desiccant such as silicone rubber is sealed in the package body in the form of another individual.

On the other hand, since the particulate composition containing the penicillin antibiotic has a certain degree of humidity (over-drying), the moisture of the particulate composition is reduced, and causes disintegration or performance degradation (purity, price) The nature of the decline is therefore required for a package containing a particulate composition of penicillin antibiotics to maintain a moderate degree of humidity.

Patent Document 1 discloses a container containing a humidity control composition in which a specific magnesium sulfate is blended in a thermoplastic resin. However, an evaluation test was conducted on the same configuration as that of Patent Document 1, and as a result, it was found that the use of magnesium sulfate as a desiccant was insufficient in hygroscopic performance, particularly purity, as a package containing a particulate component of a penemidine antibiotic. Falling and becoming un Meet the specification value.

Further, in Patent Document 2, as a package for foods such as moisture-free foods, there is disclosed a moisture-regulating laminated bag having a moisture-absorbing layer containing a blend of a polyolefin and a moisture absorbent by a heat-sealable film layer. A sandwiched inner surface layer. However, in the examples, only the moisture absorbing layer obtained by disposing 1% by weight of zeolite having a particle diameter of 10 μm or 50 μm in LDPE (low density polyethylene), and the heat of the innermost layer is described. The thickness of the sealing film layer is only 10 μm. Therefore, the constitution required for maintaining a moderate humidity is not considered in the case of packaging a particulate composition containing a penem antibiotic.

[Previous Technical Literature] [Patent Literature]

Patent Document 1: Japanese Patent Laid-Open No. Hei 5-39379

Patent Document 2: Japanese Patent Laid-Open No. Hei 8-26348

Accordingly, it is an object of the present invention to provide a granular composition containing a penemidine antibiotic by controlling the humidity in the package to a moderate degree to prevent moisture absorption or excessive drying of the particulate composition containing the penemidine antibiotic. The preserved pharmaceutical package.

That is, the present invention relates to the following: (1) A pharmaceutical package in which a bag-like package is filled with a particulate composition containing a penicillin antibiotic as an active ingredient, and the package includes the sequential a laminate film comprising a base material layer of one or more layers of a thermoplastic resin, an aluminum foil, and an adsorption layer, wherein the adsorption layer is disposed on the side of the particulate material and sequentially lays the outer layer and the middle from the side of the aluminum foil. a layer comprising an LDPE resin and containing 0.2 to 0.4 mg/cm ² of a zeolite having a pore diameter of 1 nm or more, wherein the inner surface layer comprises a linear low density polyethlene (LLDPE) resin and The layer thickness is 20 to 30 μm; (2) The pharmaceutical package according to (1), wherein the penem antibiotic is faropenem or a pharmaceutically acceptable salt or hydrate thereof; (3) the pharmaceutical product as (1) The package wherein the penicillin antibiotic is faropenem sodium hydrate; (4) the pharmaceutical package according to (1), (2) or (3), wherein the granular composition is a granule, a fine granule, a powder Or dry syrup.

According to the present invention, the package body can be maintained at a moderate humidity without being excessively dried, so that it can be protected without deteriorating the performance of the particulate component containing the penicillin-containing antibiotic contained therein.

In the pharmaceutical package of the present invention, a granular composition containing a penicillin antibiotic as an active ingredient is enclosed in a bag-shaped package. Here, the so-called The penem antibiotic is an antibiotic having a mixed skeleton of penicillin and cephalosporin, and is classified as a β-endoxime antibiotic, and examples thereof include faropenem or a pharmaceutically acceptable salt or hydrate thereof. As a currently available penem antibiotic, (+)-(5R,6S)-6-[(R)-1-hydroxyethyl]-7-oxa-3-[(R)-2 is known. - tetrahydrofuranyl]-4-thia-1-azabicyclo[3.2.0]hept-2-en-2-carboxylate 2.5 hydrate (faropenem sodium hydrate). In addition, the particulate composition refers to a composition obtained by granulating an active ingredient and an additive by mixing, granulation, or the like, and is sold in the form of granules, fine granules, powders, dry syrups, and the like. .

The package for use in the pharmaceutical package of the present invention comprises a package film in which one or more base layers including a thermoplastic resin, an aluminum foil, and an adsorption layer are sequentially laminated.

The base material layer contains a thermoplastic resin such as PET (polyethylene terephthalate), and may be a single layer or a plurality of layers. The thickness of the base material layer is not particularly limited, and is preferably from 6 to 25 μm, more preferably from 10 to 25 μm, from the viewpoints of the strength of the package, the printability to the surface of the package, and the release property.

The aluminum foil may be pure aluminum or alloy aluminum, and the thickness thereof is not particularly limited as long as it functions as a barrier layer for oxygen or moisture (water vapor), and is preferably 6 to 12 μm, more preferably 9 to 12 μm. .

The adsorption layer is formed by sequentially laminating the outer surface layer, the intermediate layer and the inner surface layer from the side of the aluminum foil, and adsorbing moisture (water vapor) or the like.

The intermediate layer contains LDPE (low density polyethylene) resin and contains 0.2 to 0.4 mg/cm ² of a zeolite having a pore diameter of 1 nm or more. Here, the content of the zeolite is the weight of the zeolite contained in the entire thickness direction of the intermediate layer per unit area on the surface orthogonal to the thickness direction of the intermediate layer.

Examples of the zeolite include commercially available molecular sieves and the like. Molecular sieve system is a porous plasmid-like substance used for separating substances by the difference in molecular size, and has a structure with uniform pores, and absorbs small molecules that enter the pores of the pores to perform a representative synthesis of a sieve. Zeolite. The adsorption property of the zeolite is related to the pore diameter. When the pore diameter is less than 1 nm, the moisture adsorption property is very strong, and the package body becomes an excessively dry state. The pore diameter can be confirmed by an X-ray diffraction method, an X-ray small angle scattering method, a structural analysis by a gas adsorption method, or the like. In addition, when the content of the zeolite is less than 0.2 mg/cm ² , the moisture adsorption property is insufficient, and if it exceeds 0.4 mg/cm ² , it becomes an excessively dry state. The thickness of the intermediate layer is not particularly limited, and is preferably 20 to 40 μm from the viewpoints of the strength of the package, the release property, and the like.

The inner surface layer contains LLDPE (linear low density polyethylene) resin in order to infiltrate the moisture in the package to be easily adsorbed by the zeolite of the intermediate layer. The layer thickness of the inner surface layer is 20 to 30 μm from the viewpoints of moisture permeability, strength of the package, and release property. When the layer thickness of the inner surface layer is less than 20 μm, the moisture in the package is excessively permeated, so that it is excessively dried, and if it exceeds 30 μm, the hand release property is deteriorated.

The outer layer contains a thermoplastic resin such as LLDPE, and the thickness thereof is not particularly limited. In order to make the adsorption layer less likely to warp or shrink, it is preferable to set the thickness of the outer layer to the same level as the inner surface layer.

The adsorption layer can be obtained by co-extruding a resin for an outer layer, a LDPE resin in which a zeolite for an intermediate layer is blended, and an LLDPE resin for an inner surface layer by an expansion method, a T-die method, or the like.

The laminate of the substrate and the aluminum foil, the aluminum foil, and the adsorption layer can be carried out by dry lamination, interlayer lamination using PE (polyethylene), or the like.

The package-like package of the packaging system of the present invention can be obtained by disposing the package film so that the adsorption layer is inside (the side where the particulate composition is accommodated), and heat-sealing.

<Example> <Examples 1 to 3>

Using an ester-based adhesive (main agent: Takelac A525, hardener: Takenate A50, manufactured by Mitsui Chemicals Co., Ltd.), dry-laid aluminum foil ("BESPA" light aluminum foil (manufactured)) manufactured by a thickness of 9 μm (adhesive thickness) 3 μm) A PET film (base material, manufactured by "ESTER FILM E5100" Toyobo Co., Ltd.) having a thickness of 12 μm was obtained to obtain a substrate film.

On the other hand, LDPE ("Petrothene 202" manufactured by Tosoh Corporation) manufactured by using a 10% by weight zeolite ("Molecular Sieve 13X" UNION SHOWA (manufactured by UNION SHOWA Co., Ltd.)) as a resin for the intermediate layer was used. The outer layer and the inner surface layer were coextruded with a resin LLDPE ("Evolue SP2520" Prime Polymer), and a surface layer of 10 μm was obtained by an expansion method. 20 μm (Example 1), 30 μm (Example 2), 40 μm (Example 3) intermediate layer, and 20 μm inner surface adsorption layer.

The zeolite content of the intermediate layer was measured by an ashing test method (JIS-K7250A (ISO3451A)), and as a result, Example 1 was 0.2 mg/cm ² , Example 2 was 0.3 mg/cm ² , and Example 3 was 0.4 mg/ Cm ² .

Next, the aluminum foil of the base film was subjected to dry lamination (adhesive thickness: 3 μm) using an ester-based adhesive as opposed to the outer surface of the adsorption layer to obtain a thickness of 77 μm (Example 1) and 87 μm (Example 1). Example 2), a package film of 97 μm (Example 3). Furthermore, the layer structure of the package film is as follows.

Substrate (12 μm) / ester-based adhesive (3 μm) / aluminum foil (9 μm) / ester-based adhesive (3 μm) / adsorption layer (Example 1: 50 μm, Example 2: 60 μm, Example 3: 70 μm)

In each of the examples, the obtained package film was cut into a rectangular shape (length 60 mm × width 45 mm), and the two packaged package films were overlapped in such a manner that the adsorption layer side was opposed. Then, the sealing width of the long side was 5 mm and the sealing width of the short side was 6 mm, and the three sides were heat-sealed to obtain a package having a short side opening.

In the package, a dry syrup containing faropenem sodium hydrate as a particulate composition containing a penicillin antibiotic is contained, and the opening is heat-sealed at a sealing width of 6 mm, and then at 40 ° C, 75% RH. Save for 6 months in the environment. For the state of the drug after storage, the moisture, the price, the purity, and the purity are determined based on the method described in the Japanese Pharmacopoeia "Syrup Usage Loepnan Sodium" The next benchmark is evaluated. The results are shown in Table 2.

[moisture]

The water content of the granular composition of 80 mg was determined by coulometric titration.

When the water content is 1.5 to 2.1%, it is set to ○, and if it is not within the above range, it is set to ×.

[power price]

According to the following quantitative method, the case of faropenem (C ₁₂ H ₁₅ NO ₅ S: 285.32) corresponding to 93.0 to 106.0% of the displayed power valence is ○, and not the above case is ×.

[quantitative method]

According to the amount of display, the amount corresponding to about 25 mg (force price) of faropenem (C ₁₂ H ₁₅ NO ₅ S) is measured, and after adding 10 mL of the internal standard solution, water is added and shaken and mixed, and water is added thereto. Into 50 mL and filter. The first 10 mL of the filtrate was removed, and the subsequent filtrate was used as a sample solution. Further, an amount corresponding to about 25 mg of the faropenic sodium standard was added, and after adding 10 mL of the internal standard solution, water was added and dissolved to prepare 50 mL, which was used as a standard solution. Under the following conditions, 20 μL of the sample solution and the standard solution were tested by liquid chromatography to determine the ratio Q _T and Q _S of the peak area of faropenem to the peak area of the internal standard substance.

The amount of faropenem [mg (force price)] = W _S × Q _T / Q _S

W _S : weighing amount of faropenem sodium standard [mg (power price)]

Dissolve 0.5g of the internal standard solution of hydroxyacetophenone in 20mL of B In the nitrile, water was added to make 200 mL.

[Test conditions]

Detector: UV absorption photometer (measuring wavelength: 305 nm)

Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 25 cm was filled with 5 μm liquid chromatography using octadecyl oxime alkylated phthalocyanine.

Column temperature: 40 ° C

Mobile phase: 4.8 g of potassium dihydrogen phosphate, 5.4 g of disodium hydrogen phosphate dodecahydrate, and 1.0 g of tetra-n-butylammonium bromide were dissolved in water to prepare 1000 mL. 130 mL of acetonitrile was added to 870 mL of this solution.

Flow rate: Adjusted in such a way that the retention time of Faropenem is 11 minutes.

[System Suitability]

Performance of the system: When 20 μL of the standard solution was operated under the above conditions, the internal standard substance and faropenem were sequentially eluted, and the degree of separation was 1.5 or more.

Reproducibility of the system: When the test was repeated 6 times for 20 μL of the standard solution under the above conditions, the relative standard deviation of the ratio of the peak area of faropenem to the peak area of the internal standard substance was 1.0% or less.

[purity]

According to the purity test described below, if the amount of the lysate as the specific similar substance is 1.5% or less, and the total amount of the similar substance is 2.0% or less, it is ○, and if it is not the above, it is set to ×.

[purity test]

Depending on the amount of display, the amount corresponding to "faropenem sodium hydrate" of about 25 mg (strength) was weighed, and about 10 mL of water was added thereto, and the mixture was sufficiently shaken and mixed, and then water was added to prepare 50 mL, which was filtered. 10 mL of the initial filtrate was removed, and the subsequent filtrate was used as a sample solution. 2 mL of this solution was weighed, and water was added to prepare 200 mL, which was used as a standard solution. 20 μL of the sample solution and the standard solution were taken out, and the test was carried out by liquid chromatography under the following conditions. When the peak areas of the respective liquids were determined by the automatic integration method, the peak area of the lysate having a relative holding time of about 0.71 with respect to the sample solution was not more than 1.5 times the peak area of faropenem of the standard solution. Further, the total area of the peaks other than faropenem of the sample solution is not more than twice the peak area of faropenem of the standard solution. Among them, the peak area of the lysate having a relative holding time of about 0.71 with respect to faropenem is a value obtained by multiplying the area obtained by the automatic integration method by a sensitivity coefficient of 0.37.

[Test conditions]

Detector: UV absorption photometer (measuring wavelength: 240 nm)

Column: A stainless steel tube having an inner diameter of 4 mm and a length of 25 cm was filled with a liquid crystal of 5 μm and an octadecyl oxime alkylated gel.

Column temperature: 40 ° C

Mobile phase A: 6.12 g of potassium dihydrogen phosphate, 1.79 g of disodium hydrogen phosphate dodecahydrate, and 1.61 g of tetra-n-butylammonium bromide were dissolved in water to prepare 1000 mL.

Mobile phase B: mobile phase A/acetonitrile mixture (1:1)

Liquid feeding of mobile phase: As shown in Table 1, the mixing ratio of mobile phase A and mobile phase B was changed to control the concentration gradient.

Flow rate: 1.5mL per minute

Area measurement range: range of 2.5 times the retention time after the peak of the solvent to faropenem

[System Suitability]

Confirmation of the test: 2 mL of the standard solution was weighed and water was added to make 20 mL. It was confirmed that the peak area of faropenem obtained from 20 μL of the solution became 7 to 13% of the peak area of faropenem of the standard solution.

Performance of the system: When the standard solution of 20 μL of the quantitative method was operated under the above conditions, m-hydroxyacetophenone and faropenem were sequentially eluted, and the degree of separation was 11 or more.

Reproducibility of the system: When the test was repeated 6 times for 20 μL of the standard solution under the above conditions, the relative standard deviation of the peak area of faropenem was 3.0% or less.

<Comparative Example 1>

A package was obtained in the same manner as in Example 2 except that a zeolite-free LDPE single layer film (thickness: 60 μm) was used instead of the adsorption layer. Drug The results of the performance evaluation are shown in Table 2.

<Comparative Example 2>

A package was obtained in the same manner as in Example 2 except that the content of the zeolite in the resin for the intermediate layer was 5% by weight. The zeolite content of the intermediate layer and the evaluation results of the drug properties are shown in Table 2.

<Comparative Examples 3 and 4>

The package was obtained in the same manner as in Example 2 except that the thickness of the intermediate layer was as shown in Table 2. The zeolite content of the intermediate layer and the evaluation results of the drug properties are shown in Table 2.

<Example 4>

An ester-based adhesive (main agent: Takelac A525, hardener: Takenate A50, manufactured by Mitsui Chemicals Co., Ltd.) was fixedly coated on a PET film, and laminated aluminum foil was laminated using LDPE (made by Suntec L 1850K Asahi Kasei Co., Ltd.). A package was obtained in the same manner as in Example 2 except that the thickness of the LDPE was 15 μm. The zeolite content of the intermediate layer and the evaluation results of the drug properties are shown in Table 2.

<Examples 5 and 6, Comparative Example 5>

A package was obtained in the same manner as in Example 2 except that the thickness of the inner surface layer was as shown in Table 2 (wherein, in Example 5, the PET film and the aluminum foil were applied in the same manner as in Example 4. Perform sandwich lamination). The zeolite content of the intermediate layer and the evaluation results of the drug properties are shown in Table 2.

<Comparative Examples 6, 7>

In Comparative Example 6, "Molecular Sieve 3A" (UNION SHOWA) was used. In the comparative example 7, "molecular sieve 4A" (manufactured by UNION SHOWA Co., Ltd., pore diameter: 0.4 nm) was used as the zeolite of the intermediate layer, and A package was obtained in the same manner as in Example 2. The zeolite content of the intermediate layer and the evaluation results of the drug properties are shown in Table 2.

From the evaluation results of Table 2, the following cases were known.

The content of the zeolite in the intermediate layer of Comparative Examples 1 and 2 was less than 0.2 mg/cm ² , so that moisture was less adsorbed, the dry syrup was deteriorated, and the strength was lowered.

The thickness of the inner surface layer of Comparative Example 5 was less than 20 μm, so that the moisture in the package was excessively permeated and excessively dried, and the purity of the dry syrup was lowered.

Since the pore diameter of the zeolite of Comparative Examples 6 and 7 was less than 1 nm, the adsorption capacity was too high, and it became excessively dry, and the purity of the dry syrup was lowered.

The content of the zeolite in the intermediate layers of Comparative Examples 3 and 4 exceeded 0.4 mg/cm ² , so that compared with Comparative Examples 5 to 7, excessive adsorption of moisture caused excessive drying, and not only the purity of the dry syrup decreased, but also the moisture or the strength of the product decreased. .

On the other hand, in Examples 1 to 6, the humidity in the package was kept moderate, and as a result, the purity, moisture, and strength of the dry syrup were not lowered, and it was suitable for packaging of a dry syrup containing faropenem sodium hydrate.

Claims (4)

A pharmaceutical package in which a bag-like package is filled with a granular composition containing a penicillin antibiotic as an active ingredient, and the package comprises a substrate layer of one or more layers containing a thermoplastic resin in this order. a packaging film formed of an aluminum foil and an adsorption layer, wherein the adsorption layer is disposed on a side of the particulate material, and sequentially forms an outer surface layer, an intermediate layer and an inner surface layer from the side of the aluminum foil, the intermediate layer comprising LDPE The resin further contains 0.2 to 0.4 mg/cm ² of a zeolite having a pore diameter of 1 nm or more, and the inner surface layer contains LLDPE resin and has a layer thickness of 20 to 30 μm. The pharmaceutical package of claim 1, wherein the penem antibiotic is faropenem or a pharmaceutically acceptable salt or hydrate thereof. For example, the pharmaceutical package of claim 1 is wherein the penem antibiotic is faropenem sodium hydrate. The pharmaceutical package of claim 1, 2 or 3, wherein the granular composition is a granule, a fine granule, a powder or a dry syrup.