JP5382986B2 - Heparin injection solution - Google Patents

Description

  The present invention relates to a technique for making a plastic container for a heparin injection solution in a vial. More specifically, it is filled with a preservative that is filled in a plastic bag formed from a packaging bag or a blow-molded container made of a resin layer containing a cyclic polyolefin and then sterilized at high temperature (hereinafter sometimes referred to as “high pressure steam sterilization”). The present invention relates to a heparin injection preparation and a container thereof.

  In Japan, various heparin injection solutions for medical use, such as heparin sodium injection solution and heparin calcium injection solution, treat intravascular blood coagulation syndrome and thromboembolism, and prevent blood coagulation when using hemodialysis machines. Widely used as an indication. Of these, JP Parin sodium injection solution, 1000 units / mL, 5 mL, 10 mL, 50 mL and 100 mL formulations are commercially available, and high volume (50 mL and 100 mL) formulations of this injection solution, and some In low volume (5 mL and 10 mL) preparations, benzyl alcohol is usually added at a concentration of 1 w / v% as a preservative to prevent bacterial contamination and the like due to diluting and dividing use at the time of use. In addition, as a preservative other than benzyl alcohol, a heparin sodium injection solution containing 0.026 w / v% methyl paraoxybenzoate and 0.014 w / v% propyl paraoxybenzoate is also commercially available (trade name, manufactured by Mitsubishi Pharma Corporation). : Heparin sodium injection-Wf).

  Since these preservatives permeate polyethylene containers and polypropylene containers, vials are usually used for heparin injection preparations containing preservatives and are not made into plastic containers. Furthermore, rubber plugs for sealing the vials are neoprene rubber plugs and butyl rubber plugs, and the surface is made of fluorinated polymer to prevent adsorption of preservatives such as benzyl alcohol. It is covered (see Non-Patent Document 1).

  Japanese Patent Application Laid-Open No. 2004-10596 discloses an invention (1) relating to an injection liquid preparation in which a gas-permeable plastic container is filled with a heparin sodium aqueous solution and is packaged with a gas barrier outer bag together with an oxygen scavenger, and as a stabilizer. The invention (2) relating to a heparin sodium preparation containing benzyl alcohol but not containing a pH adjuster is disclosed. However, in the case of the above invention (1), in the case of divided use, once the outer container is opened, it cannot be stored again. Therefore, the preservative may permeate the container during the period until the next use, and the content of the preservative may be reduced. There are some problems. Furthermore, in the said invention (2), after filling heparin sodium and benzyl alcohol, there exists a problem that a preservative permeate | transmits a container at the time of sterilization, and a content falls.

  On the other hand, in recent years, in large-volume infusions such as electrolyte infusions and nutrient infusions, the containers have been changed from vials to plastic containers due to problems of weight reduction and disposal. Therefore, the present inventors prepared 1 w / v% heparin sodium drug solution containing benzyl alcohol, filled it into polyethylene and polypropylene containers usually used for infusion, and sterilized under high-pressure steam. Decreased. Moreover, when it was stored at 40 ° C., the benzyl alcohol content further decreased. Thus, it has been found that polyethylene and polypropylene containers that are usually used as medical infusion containers are virtually unsuitable for preparative heparin injection formulations.

JP 2004-10596 A "Pharmaceutical Additives Handbook", edited by Japan Pharmaceutical Association, Maruzen, 1989, pp.316-318

  The present invention is a heparin injection liquid preparation containing a preservative and a container for producing the same, wherein the content of the preservative hardly decreases during high-pressure steam sterilization and storage, and has excellent flexibility and drop impact strength by making into a plastic container. The purpose is to provide.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have used a plastic bag formed from a packaging bag or a blow-molded container made of a resin layer containing a cyclic polyolefin. It was found that the preservative in the preparation was not reduced and could be applied to a heparin injection preparation containing the preservative, thereby completing the present invention.
That is, the present invention
1) A heparin injection liquid preparation characterized by containing a heparin injection liquid containing heparin and / or a salt thereof and a preservative in a container comprising a resin layer having a cyclic polyolefin layer and sterilizing at high temperature,
2) The heparin injection liquid preparation according to 1), wherein the resin layer is a laminate,
3) The heparin injection preparation according to 2), wherein the laminate has a laminate structure in which polyethylene and / or polypropylene and cyclic polyolefin are laminated with or without a layer for adhesion,
4) Any of 1) to 3), wherein the preservative is one or more preservatives selected from the group consisting of benzyl alcohol, chlorobutanol, chlorocresol, methyl paraoxybenzoate and propyl paraoxybenzoate. Heparin injection solution formulation according to
5) The heparin injection preparation according to 4), wherein the preservative is benzyl alcohol,
6) A container made of a resin layer containing a cyclic polyolefin, which is used for producing the heparin injection liquid preparation according to any one of 1) to 5), and 7) The container is a packaging bag or a blow molded container. The container is provided.

According to the above 1), the container for the heparin injection solution can be made plastic.
2) According to the invention, excellent flexibility and drop impact strength can be imparted.
According to the 3) invention, more excellent flexibility and drop impact strength can be imparted.
4) According to the invention, it is possible to prevent a decrease in the content of the preservative during autoclaving in the production process and during storage after production.
5) According to the invention, it is possible to more effectively prevent a decrease in the content of the preservative during high-pressure steam sterilization in the production process and during storage after production.
The 6) invention provides a container for heparin injection formulation having excellent flexibility and drop impact strength.
The above 7) invention provides a packaging bag or blow molded container heparin injection preparation container having excellent flexibility and drop impact strength.

  The heparin injection liquid preparation of the present invention contains heparin and / or a salt thereof and a preservative in a container composed of a resin layer containing a cyclic polyolefin.

  The resin layer having the cyclic polyolefin layer may be either a single layer or a laminate, and includes at least one resin layer formed from the cyclic polyolefin.

  The resin layer formed from the cyclic polyolefin is obtained by molding a resin obtained by polymerizing a monomer composition containing a cyclic olefin monomer into a sheet shape or a bottle shape. As the raw material monomer, only the cyclic olefin monomer may be used, or other monomers may be used in combination for copolymerization.

Specific examples of the cyclic olefin monomer include norbornene, norbornadiene, methylnorbornene, dimethylnorbornene, ethylnorbornene, chlorinated norbornene, chloromethylnorbornene, trimethylsilylnorbornene, phenylnorbornene, cyanonorbornene, dicyanonorbornene, methoxycarbonylnorbornene, pyridylnorbornene, nadic Bicyclic cycloolefins such as acid anhydrides and nadic imides; Tricyclic cycloolefins such as dicyclopentadiene, dihydrodicyclopentadiene and their alkyl, alkenyl, alkylidene, and aryl substituents; tetracyclododecene, dimethanohexahydronaphthalene Dimethanooctahydronaphthalene and its alkyl, alkenyl, alkylidene, aryl substituted Tetracyclic cycloolefins; pentacyclic cycloolefins such as tricyclopentadiene; and hexacyclic cycloolefins such as hexamethylene cycloheptanone decene and the like. Further, dinorbornene, a compound in which two norbornene rings are bonded by a hydrocarbon chain or an ester group, and a compound containing a norbornene ring such as an alkyl or aryl substituent thereof can be mentioned. The norbornene monomers may be used alone or in combination of two or more, and two or more of them are preferably used. When two or more kinds are used in combination, a resin having various physical properties can be obtained by appropriately combining a monomer having one double bond to be a thermoplastic resin and a monomer having a plurality of double bonds to be a thermosetting resin. can do. Moreover, it is because the range which can handle a monomer as a liquid may expand by the freezing point fall compared with the case of single use. In addition, these norbornene-based monomers can be copolymerized with monocyclic cycloolefins such as cyclobutene, cyclopentene, cyclooctene, and cyclododecene and derivatives thereof having a substituent.
For the purpose of the present invention, a thermoplastic saturated norbornene-based polymer consisting only of a monomer not containing the above polar group is preferred from the viewpoint of barrier properties (preservative content lowering prevention ability), but does not impair the purpose of the present invention. A polymer obtained by partially copolymerizing polar monomers may be used. In this case, the polar monomer may be a substituted product obtained by introducing a halogen group such as chlorine or bromine or an ester group into the norbornene monomers.

  The other copolymerizable monomer is not particularly limited, and examples thereof include α-olefins having 2 or more carbon atoms. Specifically, ethylene, propylene, 1-butene, 1-pentene, 1 -Hexene, 3-methyl-1-butene, 3-methyl-1-pentene, 3-ethyl-1-pentene, 4-methyl-1-pentene, 4-methyl-1-hexene, 4,4-dimethyl-1 -Hexene, 4,4-dimethyl-1-pentene, 4-ethyl-1-hexene, 3-ethyl-1-hexene, 1-octene, 1-decene, 1-dodecene, 1-tetradecene, 1-hexadecene, -Octadecene, 1-eicosene and the like. These can be used alone or in combination. Of these, ethylene or propylene is preferable, and ethylene is particularly preferable.

  Examples of the cyclic polyolefin include cyclic polyolefins obtained by polymerizing a monomer composition containing one or more of the above cyclic olefin monomers, and more specifically, the following general formula (1) or (2):

(Wherein R ₁ , R ₂ , R ₃ and R ₄ represent the same or different organic groups having 1 to 20 carbon atoms, or R ₁ and R ₂ , or R ₃ and R ₄ are the same or They may be combined with carbon atoms to which they are bonded to form a ring, m and p are the same or different and each represents 0 or an integer of 1 or more, and l and n are the same or different and represent an integer of 1 or more. It is a polymer which has the structural unit represented by this individually or in combination.

Examples of the organic group having 1 to 20 carbon atoms of R ₁ , R ₂ , R ₃ and R ₄ include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t -Butyl, i-pentyl, t-pentyl, n-hexyl, n-heptyl, n-octyl, t-octyl (1,1-dimethyl-3,3-dimethylbutyl), 2-ethylhexyl, nonyl, decyl, undecyl , Dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, etc .; cycloalkyl groups such as cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; Alkylcyclo such as methyl-4-i-propylcyclohexyl Alkyl groups; alkenyl groups such as allyl, propenyl, butenyl, 2-butenyl, hexenyl, cyclohexenyl; phenyl groups, naphthyl groups, methylphenyl groups, methoxyphenyl groups, biphenyl groups, phenoxyphenyl groups, chlorophenyl groups, sulfophenyl groups, etc. Aralkyl groups such as benzyl group, 2-phenylethyl group (phenethyl group), α-methylbenzyl group, α, α-dimethylbenzyl group, etc., but are not limited thereto. . These may be used alone or in combination of two or more.

  These cyclic polyolefins are the values of l, m, n, and p in the above general formulas (1) to (2), or the molecular weight of the cyclic polyolefin represented by these general formulas (1) to (2), the cyclic olefin monomer. It adjusts suitably by the combination of these.

  In the layer composed of the cyclic polyolefin, other resin components such as other polyolefin resins can be blended within the range not impairing the object of the present invention, and usually used additives such as ultraviolet absorbers and lubricants are blended. May be.

  Moreover, in the resin layer used for the container of the heparin injection solution of the present invention, in addition to the cyclic polyolefin layer, a synthetic resin layer usually used for a pharmaceutical infusion container can be laminated and used. Specific examples of the synthetic resin include, for example, low density polyethylene, linear low density polyethylene, ultra low density polyethylene, medium density polyethylene, high density polyethylene, polypropylene, ethylene-vinyl acetate copolymer, polyester, polyvinyl chloride. , Polybutadiene, polyamide, ethylene-methacrylate copolymer, ethylene propylene-based elastomer, and a mixture thereof. These synthetic resins may be laminated as a single layer or multiple layers on a cyclic polyolefin layer to produce a container. . Among these, in the resin layer used for the container of the heparin injection solution of the present invention, polyethylene and / or polypropylene and cyclic polyolefin were laminated with or without an adhesive layer. A laminated body having a laminated structure is preferable.

For example, the container used in the present invention has a three-layer resin layer made of polyethylene resin (PE) / cyclic polyolefin (COP) / polyethylene resin (PE) in order to avoid becoming hard due to high-pressure steam sterilization. Can be formed from The polyethylene resin used for the outermost layer preferably has a melting point higher than that of the polyethylene resin used for the innermost layer because the heat sealing operation is facilitated. Since polyethylene has a certain degree of correlation between density and melting point, it is preferable that the polyethylene resin used for the outermost layer has a higher density than the polyethylene resin used for the innermost layer. As a specific example, the polyethylene resin used for the outermost layer is a linear low density polymerized by a metallocene catalyst having a density of less than 0.910 on a linear low density polyethylene having a density of 0.910 or more. It is assumed that polyethylene is mixed in a ratio of 95: 5 to 80:20, and the polyethylene resin used in the innermost layer is a linear low density polyethylene having a density of 0.910 or more by a metallocene catalyst having a density of less than 0.910. As a mixture of polymerized linear low density polyethylene in a ratio of 90:10 to 60:40, the polyethylene resin used for the outermost layer has a higher density than the polyethylene resin used for the innermost layer. It is preferable that
In addition, by using such a container, flexibility can be imparted to the container itself even before high-pressure steam sterilization, so that the filling operation and the like are facilitated, and the impact strength of the container is increased, and the product filled in the container Safety in transportation is further increased.

  In addition, as an example of the layer structure in the case of a laminated body, as a structure of the outer layer to the inner layer, polypropylene resin (PP) / adhesive resin (AD) / cyclic polyolefin (COP), (polypropylene resin (PP) + ethylene Propylene Estramer) / Adhesive Resin (AD) / Cyclic Polyolefin (COP), High Density Polyethylene (PE) / Linear Low Density Polyethylene (PE) / Cyclic Polyolefin (COP) / Linear Low Density Polyethylene (PE) Etc. “/” Means stacking, and “+” means mixing.

  The thickness of the resin layer having a cyclic polyolefin layer is not particularly limited, and can prevent the permeation of the preservative to be contained from the container, and can be used as long as it has excellent flexibility and drop impact strength. It can be arbitrarily selected according to the properties of other synthetic resins, the layer structure, the kind of preservative, and the like. Although it is not limited, for example, in the case of a single-layer structure composed only of a cyclic polyolefin layer, the thickness is 50 to 400 μm, preferably 70 from the viewpoint of preservative permeation prevention, flexibility and drop impact strength. On the other hand, when the laminate is composed of a resin layer having at least one cyclic polyolefin layer and another synthetic resin layer, the cyclic polyolefin layer usually has a thickness of 10 to 300 μm, preferably 20 to 100 μm. Have. The total thickness in the case of a laminate is usually in the range of 60 to 500 μm.

In the present invention, as a method for producing a container, a known method can be adopted as a method for producing a normal pharmaceutical infusion container. When the container is a packaging bag, for example, a single layer or multilayer T-die is used. A single-layer or multi-layer inflation method for obtaining a tube-like sheet through a used T-die method or a circular die can be used as appropriate. Furthermore, when using a special substrate such as a stretched film to form a multilayer structure, a method of dry laminating each layer using an adhesive, a method of extrusion laminating using a meltable resin, etc. may be used in combination as appropriate. it can. The obtained sheet is heat-sealed by a known means to form a container. When the container is a blow molded container, for example, single layer or multilayer extrusion blow molding or injection blow molding is suitably employed. As a multilayer coextrusion blow molding method, a multilayer extruder having at least two extruders is used, and cyclic polyolefin and other synthetic resins and, if necessary, an adhesive resin are supplied to each extruder. Kneading and melt-extrusion are performed, and each molten resin layer is closely joined and merged inside the die for multilayer parison molding or immediately after discharging from the die to obtain a tubular multilayer parison, and then this multilayer parison is blow-molded in a molten state. A so-called direct blow molding method for obtaining a multilayer container is preferable.
In addition, as a method of multi-layer co-injection blow molding, a multi-layer parison is obtained by injection molding using a multi-layer injection molding machine having at least two extruders, and then is reheated during cooling or after cooling. A blow molding method is preferably employed. When the multilayer parison is blow-molded, stretch blow molding, particularly biaxial stretch blow molding is preferred.

  Further, as heparin or a salt thereof in the heparin injection liquid preparation of the present invention, any heparin such as heparin sodium listed in the Japanese Pharmacopoeia, heparin calcium, sodium salt of low molecular weight heparin, calcium salt, etc. can be used. Heparin sodium listed in the Japanese Pharmacopoeia is preferred. The heparin concentration in the drug solution of the preparation is not particularly limited, but is preferably 1000 to 10000 units / ml, more preferably 1000 units / ml.

  Furthermore, a preservative for divided use is added to the heparin injection solution preparation of the present invention. The preservative used is not particularly limited as long as it is a preservative usually used in pharmaceutical products, but benzyl alcohol, chlorobutanol, chlorocresol, methyl paraoxybenzoate, and paraoxy which can be used as preservatives for heparin injections are used. Propyl benzoate is used, and benzyl alcohol is particularly preferable.

  The heparin injection preparation of the present invention is heated at a high temperature after storing the chemical solution by a retort sterilization apparatus such as hot water spray (shower) sterilization, hot water injection sterilization, hot water immersion sterilization, or steam sterilization, or an autoclave sterilization apparatus. Sterilized under pressure.

  Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1
900 mL of water was heated to 40 ° C., and 9.0 g of sodium chloride, 10.0 g of benzyl alcohol, and 5.0 g of sodium heparin (about 200 units / mg) were sequentially dissolved. Next, an appropriate amount of 1 mol / L hydrochloric acid test solution and an appropriate amount of 1 mol / L sodium hydroxide solution were added, pH was adjusted to 6.5 to 7.0, an appropriate amount of water was added, and the total amount was 1000 mL to prepare a chemical solution. While filtering the chemical solution with a membrane filter with an opening diameter of 0.20 μm, each 100 mL each is a single-layered cyclic polyolefin (Zeonor made by Nippon Zeon Co., Ltd.) bag-like container (14.0 cm long × 12.6 cm wide packaging bag, sheet) 80 μm thick) and sealed with heat seal. Six bag-like containers and 3 L of water thus obtained were placed in a 5 L pressurized tank, and the liquid outlet / inlet of the tank was plugged blindly and sterilized with high pressure steam at 106 ° C. for 30 minutes. After cooling, the container was taken out from the pressurized tank, used as a test sample, and the test liquid shown in Table 1 was measured using the remaining liquid at the time of filling as a control liquid.

  The test results are shown in Table 2.

  The benzyl alcohol content is not different between the chemical solution in the sterilized cyclic polyolefin container and the control solution (residual liquid at the time of filling), and when the cyclic polyolefin container is used, the content should not be reduced by sterilization treatment It was confirmed. Similarly, there was no difference in sodium chloride content, and it was confirmed that neither sterilization dilution nor concentration phenomenon occurred.

Example 2
900 mL of water was heated to 40 ° C., and 9.0 g of sodium chloride, 10.0 g of benzyl alcohol, and 5.0 g of sodium heparin (about 200 units / mg) were sequentially dissolved. Next, an appropriate amount of 1 mol / L hydrochloric acid test solution and an appropriate amount of 1 mol / L sodium hydroxide solution were added, pH was adjusted to 6.5 to 7.0, an appropriate amount of water was added, and the total amount was 1000 mL to prepare a chemical solution. While filtering the chemical solution with a membrane filter having a diameter of 0.2 μm, each 50 mL of the solution was made into a cyclic polyolefin bag-like container AI (layer structure (thickness): PE (125 μm) / COP (Zeonor, manufactured by ZEON Corporation)) 25 μm) / PE (50 μm), overall thickness: 200 μm) and cyclic polyolefin bag-like container B (layer structure (thickness): polypropylene resin (PP) (140 μm) / adhesive resin (AD) (30 μm) / COP (Zeon Co., Ltd., ZEONOR) (30 μm, total thickness: 200 μm) was filled and sealed with a heat seal to form a packaging bag. Nine containers A-I, nine containers B and two liters of water thus obtained were placed in a 5 liter pressurized tank, and the liquid inlet / outlet of the tank was closed and sterilized by high-pressure heat at 106 ° C for 30 minutes. Sterilized by After cooling, the container was taken out from the pressurized tank, and the bags A-I and B were designated as Sample A-I and Sample B, respectively. Next, a part of these specimens A-I and B was taken, the content of benzyl alcohol was measured, the rest was placed in a constant temperature room at 40 ° C., a stability test was performed, and the content of benzyl alcohol was measured. Further, while filtering the prepared chemical solution through a membrane filter having a diameter of 0.2 μm, each 50 mL of the solution was formed into a cyclic polyolefin molded container A-II (layer structure (thickness): PE (125 μm) / COP (manufactured by Nippon Zeon Co., Ltd.). (Zeonor) (25 μm) / PE (50 μm) was filled and sealed, and the A-II container used was a container manufactured by the multilayer blow molding method. 2L of water and 2L of water are put into a 5L pressurized tank, and the liquid inlet / outlet of the tank is plugged blindly and sterilized by high-pressure heat sterilization for 30 minutes at 106 ° C. After cooling, the container is taken out of the pressurized tank, and container A- II was designated as Sample A-II, then a part of these Sample A-II was taken, the content of benzyl alcohol was measured, the rest was placed in a constant temperature room at 40 ° C., and a stability test was conducted. The content of was measured.

Comparative Example 1
1800 mL of water was heated to 40 ° C., and 18.0 g of sodium chloride, 20.0 g of benzyl alcohol, and 10.0 g of sodium heparin (about 200 units / mg) were sequentially dissolved. Next, an appropriate amount of 1 mol / L hydrochloric acid test solution and an appropriate amount of 1 mol / L sodium hydroxide solution were added, pH was adjusted to 6.5 to 7.0, an appropriate amount of water was added, and the total amount was 2000 mL to prepare a chemical solution. While filtering the chemical solution with a membrane filter having a diameter of 0.2 μm, each 50 mL of the solution is made of polyethylene container C (low density polyethylene, thickness: 400 to 500 μm, blow molding), polyethylene container D (layer structure: low density polyethylene (60 μm). ) / Ultra low density polyethylene (80 μm) / Low density polyethylene (60 μm, overall thickness: 200 μm) and polypropylene container E (layer structure: polypropylene-based resin (ethylene propylene-based elastomer) in which ethylene and propylene are reactor-polymerized) After filling a single layer structure (thickness: 200 μm), it was sealed. For container sterilization, for containers C, D, and E, 9 containers and 2 L of water were placed in a 5 L pressurized tank, the tank was closed at the inlet and outlet, and sterilized by high-pressure heat sterilization at 106 ° C for 30 minutes. After cooling, the container was taken out of the pressurized tank and used as specimens C, D, and E, respectively. Next, a part of these specimens was taken, the content of benzyl alcohol was measured, the rest was placed in a constant temperature room at 40 ° C., a stability test was performed, and the content of benzyl alcohol was measured.

  The results of Example 2 and Comparative Example 1 are shown in Table 3.

As a result, the benzyl alcohol content of specimens A-I, A-II, and B does not decrease after sterilization (during manufacture) and when stored at 40 ° C. It was confirmed that there was. In addition, all of these specimens A to E showed excellent flexibility and drop impact strength at the time of manufacture (during sterilization) and storage at 40 ° C.

  On the other hand, specimens C, D and E had a benzyl alcohol content reduced by about 10 to 20% before and after sterilization. When the benzyl alcohol in each sterilized water used at this time was measured, 0.19 g / 2 L, 0.70 g / 2 L and 0.31 g / 2 L were detected, respectively, and the amounts corresponded to the weight loss during sterilization of each specimen. From this fact, it was estimated that benzyl alcohol permeates the container during sterilization, and it has been found that there is a problem in GMP to shift to actual production. In these three samples, it was confirmed that the benzyl alcohol content significantly decreased even when stored at 40 ° C. From the above results, it was considered that Samples C, D and E had a problem that the benzyl alcohol content decreased during production (during sterilization) and during storage at 40 ° C., resulting in decreased storage efficacy.

Claims (7)

A heparin injection solution characterized by containing a drug solution containing heparin and / or a salt thereof and a preservative for divided use in a packaging bag made of a resin layer having a cyclic polyolefin layer and sterilized at high temperature. A formulation comprising:
The heparin injection liquid preparation, wherein the preservative in the preparation is not reduced during high-temperature sterilization and storage.   When the resin layer has a single-layer structure composed of only a cyclic polyolefin layer, the resin layer having the cyclic polyolefin layer has a thickness of 50 to 400 μm, and a resin layer having at least one cyclic polyolefin layer and other synthetic resins The heparin injection preparation according to claim 1, wherein, when the laminate is composed of layers, the total thickness of the laminate is 60 to 500 µm.   The heparin injection liquid preparation according to claim 1 or 2, wherein the pH is adjusted with sodium hydroxide.   The heparin injection solution preparation according to any one of claims 1 to 3, wherein the resin layer is a laminate.   The heparin injection preparation according to claim 4, wherein the laminate has a laminated structure in which polyethylene and / or polypropylene and cyclic polyolefin are laminated with or without an adhesive layer.   The preservative is one or more preservatives selected from the group consisting of benzyl alcohol, chlorobutanol, chlorocresol, methyl paraoxybenzoate and propyl paraoxybenzoate. The heparin injection liquid formulation described. The preservative, heparin injections made agent according to claim 6, wherein the benzyl alcohol.