A multi-layer composite material and a pharmaceutical product

Abstract

The present application discloses a multilayer composite material and a pharmaceutical product, wherein the multilayer composite material comprises a hydrophilic polyethylene, an adhesive layer and an isolation layer in sequence; the isolation layer comprises aluminum foil; the adhesive layer comprises an adhesive material and low-density polyethylene; the adhesive material is selected from any one or more of sarin, chlorinated polypropylene and polyvinyl fluoride; the thickness ratio of the hydrophilic polyethylene, the adhesive layer and the isolation layer is (45 to 65):(15 to 45):(25 to 85).

Description

Technical Field

[0001] The present invention relates to but is not limited to the field of pharmaceutical packaging, and in particular to but is not limited to a multi-layer composite material and a pharmaceutical product. Background Art

[0002] Penem antibiotics have poor stability and are sensitive to humidity. Taking the granular composition containing faropenem sodium as an example, faropenem sodium degrades significantly at room temperature, and is prone to overdrying under high temperature conditions, causing a decrease in crystal water, and the degradation rate increases significantly. Under high humidity conditions, the granular composition containing faropenem sodium absorbs moisture quickly, causing changes in appearance and reduced quality.

[0003] Faropenem Sodium, chemical name is (+)-(5R,6S)-6-[(R)-1-hydroxyethyl]-7-oxo-3-[(R)-2-tetrahydrofuranyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate sodium. Its structural formula, molecular formula and molecular weight are as follows:

[0004] Summary of the invention

[0005] The following is an overview of the subject matter described in detail herein. This overview is not intended to limit the scope of protection of this application.

[0006] The present application provides a multilayer composite material, which can maintain constant moisture in packaged granules and slow down the degradation of faropenem sodium in the granules. The shelf life of faropenem sodium granules is usually 24 to 36 months. The use of the multilayer composite material provided by the present application can ensure product quality within the shelf life.

[0007] The present application provides a multi-layer composite material, which comprises a hydrophilic polyethylene, an adhesive layer and an isolation layer in sequence;

[0008] The isolation layer comprises aluminum foil; the adhesive layer comprises an adhesive material and low-density polyethylene; the adhesive material is selected from any one or more of sarin, chlorinated polypropylene (CPP) and polyvinyl fluoride (PVF);

[0009] The thickness ratio of the hydrophilic polyethylene, the adhesive layer and the isolation layer is (45 to 65):(15 to 45):(25 to 85).

[0010] In one embodiment provided in the present application, the moisture absorption capacity of the hydrophilic polyethylene is 0.5 g / m 2 Up to 20g / m 2 ;

[0011] In one embodiment provided in the present application, the water content of the hydrophilic polyethylene is less than 4000 ppm.

[0012] In one embodiment provided in the present application, the mass ratio of the low-density polyethylene to the adhesive material is (15 to 45):(15 to 45).

[0013] In one embodiment provided in the present application, the isolation layer includes an aluminum foil and a low-density polyethylene layer;

[0014] In one embodiment provided in the present application, the aluminum foil is located on one side of the adhesive layer.

[0015] In one embodiment provided in the present application, the thickness ratio of the aluminum foil and the low-density polyethylene layer is (10 to 60):(5 to 20).

[0016] In one embodiment provided in the present application, the thickness of the hydrophilic polyethylene is 45 μm to 65 μm.

[0017] In yet another aspect, the present application provides a pharmaceutical product, including a penicillin substance and a package containing the penicillin substance, wherein the material of the package comprises the above-mentioned multi-layer composite material;

[0018] The side of the multi-layer composite material in contact with the penicillin substance comprises hydrophilic polyethylene;

[0019] In one embodiment provided in the present application, the penicillin substance is any one or more of granules, tablets and dry suspensions.

[0020] In one embodiment provided in the present application, the penicillin substance includes any one or more of faropenem or a pharmaceutically acceptable salt thereof, meropenem or a pharmaceutically acceptable salt thereof, panipenem or a pharmaceutically acceptable salt thereof, ertapenem or a pharmaceutically acceptable salt thereof, and biapenem or a pharmaceutically acceptable salt thereof.

[0021] In one embodiment provided in the present application, the dosage of penicillins in the pharmaceutical product is 20 mg / package to 100 mg / package.

[0022] In one embodiment provided in the present application, the inner surface area of ​​the package is 1000 mm 2 Up to 5000mm 2 .

[0023] On the other hand, the present application provides a method for preparing the multi-layer composite material, comprising: using an extrusion composite process to form the multi-layer composite material by using a composite extrusion process to form the isolation layer, the adhesive layer and the hydrophilic polyethylene; a tension control device and a photoelectric correction device melt the raw materials of the adhesive layer at high temperature, and blow them into a film attached between the hydrophilic polyethylene and the isolation layer.

[0024] In one embodiment provided in the present application, aluminum foil is first extruded and compounded with low-density polyethylene and then placed in the main roll position, hydrophilic polyethylene is placed in the auxiliary roll position, melted sarin and low-density polyethylene are added for extrusion compounding, and then extruded by an extruder after passing through the compounding part and extruded into shape.

[0025] In one embodiment provided in the present application, the isolation layer and the hydrophilic polyethylene are flattened, and their relative positions are adjusted so that the hydrophilic polyethylene and the isolation layer are aligned.

[0026] In another aspect, the present application provides a method for preparing the above-mentioned pharmaceutical product;

[0027] In one embodiment provided in the present application, the heat sealing temperature of the drug product is 150°C to 200°C.

[0028] In one embodiment provided in the present application, the packaging speed of the drug product is 120 to 180 bags / min.

[0029] Other features and advantages of the present application will be described in the following description, and partly become apparent from the description, or be understood by implementing the present application. Other advantages of the present application can be invented and obtained by the schemes described in the description. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical solution and advantages of the present application more clear, the embodiments of the present application are described in detail below. It should be noted that the embodiments and features in the embodiments of the present application can be combined with each other arbitrarily without conflict.

[0031] In the examples and comparative examples provided in the present application, the multilayer composite material is prepared by extrusion compounding.

[0032] In the embodiment of the present application, the preparation method of the multilayer composite material includes: flattening the isolation layer and the hydrophilic polyethylene, and adjusting the relative positions so that the hydrophilic polyethylene and the isolation layer are aligned. Then, the isolation layer is first extruded and compounded and then placed in the main roll position, the hydrophilic polyethylene is placed in the auxiliary roll position, and the raw materials of the melted adhesive layer are added for extrusion compounding and the like, and then extruded by the extruder after the compounding part is extruded and extruded into a shape.

[0033] The isolation layer, the adhesive layer and the hydrophilic polyethylene are extruded together to form the multilayer composite material through an extrusion composite process; the tension control device and the photoelectric correction device melt the raw materials of the adhesive layer at high temperature and blow them into a film attached between the hydrophilic polyethylene and the isolation layer.

[0034] Example 1

[0035] The multilayer composite material provided in this embodiment (referred to as type A composite film) comprises, from outside to inside: a low-density polyethylene layer, an aluminum foil, an adhesive layer, and a hydrophilic polyethylene;

[0036] The thickness of the isolation layer composed of the aluminum foil and the low-density polyethylene layer is 35 μm; the thickness ratio of the low-density polyethylene layer to the aluminum foil is 15:20; the thickness of the hydrophilic polyethylene is 60 μm; and the thickness of the adhesive layer is 30 μm.

[0037] The low-density polyethylene in the bonding layer and the low-density polyethylene in the low-density polyethylene layer have the same source, which is DuPont 1520 low-density polyethylene;

[0038] The aluminum foil is a hard aluminum foil purchased from Henan Mingtai Aluminum Co., Ltd., 8011 type hard aluminum foil;

[0039] The Sarin in the adhesive layer is Sarin resin purchased from DuPont, 1702 Sarin resin; the adhesive layer is made by melting the Sarin resin and the low-density polyethylene and then blowing them into a film; the mass ratio of the Sarin and the low-density polyethylene in the adhesive layer is 1:1.

[0040] The hydrophilic polyethylene was purchased from Japan Mattai Co., Ltd., with a thickness of 55 μm to 65 μm. The dilution amount of the hydrophilic polyethylene was 10 g / m 2 Up to 15g / m 2 , the water content of the hydrophilic polyethylene is 2000±200ppm.

[0041] Example 2

[0042] The multilayer composite material provided in this embodiment (referred to as type B composite film) comprises, from outside to inside, a low-density polyethylene layer, an aluminum foil, an adhesive layer, and a hydrophilic polyethylene;

[0043] The thickness of the isolation layer composed of the low-density polyethylene layer and the aluminum foil is 65 μm; the thickness ratio of the low-density polyethylene layer to the aluminum foil is 20:45; the thickness of the hydrophilic polyethylene is 60 μm; and the thickness of the first adhesive layer is 40 μm.

[0044] The sources of other raw materials in this example are the same as those in Example 1.

[0045] Comparative Example 1

[0046] Ordinary composite film

[0047] The multilayer composite material provided in this comparative example (referred to as type C composite film) comprises from outside to inside: a first layer of low-density polyethylene, an aluminum foil and a second layer of low-density polyethylene, wherein the thickness of the first layer of low-density polyethylene is 15 μm, the thickness of the aluminum foil is 20 μm, and the thickness of the second layer of low-density polyethylene is 15 μm.

[0048] In this comparative example, the sources of various raw materials are the same as those in Example 1.

[0049] Comparative Example 2

[0050] The multilayer composite material provided in this comparative example (referred to as type D composite film) comprises, from outside to inside, a polyethylene terephthalate layer (PET), an aluminum foil and a low-density polyethylene, wherein the polyethylene terephthalate layer has a thickness of 15 μm, the aluminum foil has a thickness of 20 μm, and the low-density polyethylene has a thickness of 15 μm;

[0051] In this comparative example, the sources of low-density polyethylene and aluminum foil are the same as those in Example 1. The polyethylene terephthalate layer is FR530 from DuPont.

[0052] Comparative Example 3

[0053] The multilayer composite material provided in this comparative example (referred to as E-type composite film) comprises, from outside to inside, a low-density polyethylene layer, an aluminum foil, an adhesive layer and a hydrophilic polyethylene;

[0054] Among them, the thickness of the isolation layer composed of the low-density polyethylene layer and the aluminum foil is 45μm; the thickness ratio of the low-density polyethylene layer and the aluminum foil is 15:30; the thickness of the hydrophilic polyethylene is 20μm; the thickness of the adhesive layer is 30μm, and the adhesive layer is only composed of sarin resin.

[0055] The sources of the raw materials in this example are the same as those in Example 1.

[0056] Comparative Example 4

[0057] The multilayer composite material provided in this comparative example (referred to as type F composite film) comprises, from outside to inside, a low-density polyethylene layer, an aluminum foil, an adhesive layer and a hydrophilic polyethylene;

[0058] Among them, the thickness of the isolation layer composed of low-density polyethylene and aluminum foil is 45μm; the thickness ratio of the low-density polyethylene layer and the aluminum foil is 15:30; the thickness of the hydrophilic polyethylene is 90μm; the thickness of the adhesive layer is 30μm, and the adhesive layer is only composed of low-density polyethylene.

[0059] The sources of raw materials in this example are the same as those in Example 1.

[0060] Comparative Example 5

[0061] The multilayer composite material provided in this comparative example is recorded as a G-type composite film. The only difference between this comparative example and Example 1 is that the thickness of the adhesive layer is different. The thickness of the adhesive layer of Comparative Example 5 is 70 μm, and the raw material of the adhesive layer of Comparative Example 5 is the same as that of Example 1.

[0062] Comparative Example 6

[0063] The multilayer composite material provided in this comparative example is recorded as an H-type composite film. The only difference between this comparative example and comparative example 5 is that the material of the adhesive layer is replaced by modified low-density polyethylene instead of surin resin, that is, the modified low-density polyethylene and low-density polyethylene are evenly mixed in a mass ratio of 1:1 and blown into a film as the adhesive layer, and the modified low-density polyethylene is 1004 modified low-density polyethylene produced by Dow Chemical Company.

[0064] The granular composition containing faropenem sodium hydrate was sealed at a temperature of 180°C using a soft double aluminum light-shielding packaging machine, with a packaging speed of 180 bags / packaging, and an inner surface area of ​​each bag of 3360 mm 2 The granular composition of faropenem sodium hydrate from the same batch was packaged with type A and type B composite films, type C, type D, type E, type F, type G and type H composite films, respectively, and the difference in loading was controlled between 475 mg / bag and 525 mg / bag, and the content of penicillin was 50 mg / bag. The related substances and moisture of the original and homemade samples were detected on day 0, and then accelerated for 30 days at 40°C and 75% RH to detect the related substances and moisture in the samples before and after 30 days.

[0065] The commercially available faropenem sodium hydrate in the following table was purchased from Maruho Company in Japan, and the pediatric faropenem sodium granules. The granule composition of the same batch of faropenem sodium hydrate (prepared based on the Japanese PMDA drug database, the excipients and their amounts used in the granule composition are the same as those of the above-mentioned Japanese Maruho Company's pediatric faropenem sodium granules) was packaged with type A and type B composite films, type C, type D, type E, type F, type G and type H composite films, and the results of related substances and moisture detection before and after 30 days are shown in Table 1:

[0066] Table 1: Impurity and moisture statistics of Examples and Comparative Examples

[0067]

[0068] The impurity TFTA is R-5-(2-tetrahydrofuran)thiazole-4-carboxylic acid; the total impurities are the sum of all impurities, including the known impurity TFTA; the polymer is a polymer impurity in penem antibiotics.

[0069] The results of relevant substance and moisture detection show that the A-type and B-type composite film packaging samples prepared by extrusion composite can keep the moisture in the granules constant under the conditions of ambient temperature 40°C and ambient humidity 75% RH, slow down the degradation of faropenem sodium in the granules, and ensure the product quality within the validity period. The moisture content of the granules packaged with the ordinary composite film provided in Comparative Example 1 is significantly reduced, which does not meet the quality standard requirements; the degradation of impurities exceeds the quality standard requirements. It can be seen that the existing conventional composite film cannot guarantee the quality of the product within the validity period.

[0070] Although the embodiments disclosed in this application are as above, the contents described are only embodiments adopted to facilitate understanding of this application and are not intended to limit this application. Any technician in the field to which this application belongs can make any modifications and changes in the form and details of implementation without departing from the spirit and scope disclosed in this application, but the scope of protection of this application shall still be based on the scope defined in the attached claims.

Claims

1. A multilayer composite material, the multilayer composite material comprising, in sequence, a hydrophilic polyethylene, an adhesive layer and a barrier layer; The adhesive layer comprises an adhesive material and low-density polyethylene; the adhesive material is selected from any one or more of sarin, chlorinated polypropylene and polyvinyl fluoride; The thickness ratio of the hydrophilic polyethylene, the adhesive layer and the isolation layer is (45 to 65): (15 to 45): (25 to 85); The thickness of the hydrophilic polyethylene is 45 μm to 65 μm; The isolation layer comprises an aluminum foil and a low-density polyethylene layer, and the thickness ratio of the aluminum foil to the low-density polyethylene layer is (10 to 60): (5 to 20); The aluminum foil is located on one side of the adhesive layer; The moisture absorption of the hydrophilic polyethylene is 0.5 g / m 2 Up to 20g / m 2 ; The water content of the hydrophilic polyethylene is lower than 4000 ppm.

2. The multilayer composite material according to claim 1, wherein: The mass ratio of the low-density polyethylene to the adhesive material is (15 to 45):(15 to 45).

3. A pharmaceutical product, comprising a penicillin substance and a package containing the penicillin substance, wherein the material of the package comprises the multilayer composite material according to any one of claims 1 to 2; The side of the multi-layer composite material in contact with the penicillin substance comprises hydrophilic polyethylene.

4. The pharmaceutical product according to claim 3, wherein The penicillins are any one or more of granules, tablets and dry suspensions.

5. The pharmaceutical product according to claim 4, wherein The penicillem substances include any one or more of faropenem or a pharmaceutically acceptable salt thereof, meropenem or a pharmaceutically acceptable salt thereof, panipenem or a pharmaceutically acceptable salt thereof, ertapenem or a pharmaceutically acceptable salt thereof, and biapenem or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical product according to claim 5, wherein The dosage of penicillins in the drug product is 20 mg / package to 100 mg / package.

7. The pharmaceutical product according to any one of claims 3 to 6, wherein The inner surface area of ​​the package is 1000mm 2 Up to 5000mm 2 .

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