WO2006022095A1

WO2006022095A1 - Molding material for medical container and medical container

Info

Publication number: WO2006022095A1
Application number: PCT/JP2005/013129
Authority: WO
Inventors: Akira Yotsutsuji
Original assignee: Coki Engineering Inc.
Priority date: 2004-08-27
Filing date: 2005-07-15
Publication date: 2006-03-02
Also published as: JP2006061505A

Abstract

A molding material from which a medical container capable of satisfying all of the properties required of medical molded containers can be molded. The molding material for medical containers comprises 100 parts by weight of a propylene polymer and 0.001-5.0 parts by weight of a phosphoric ester compound represented by the general formula (1): (wherein R1, R2, R3, and R4 each represents hydrogen or linear, branched, or cyclic alkyl; R represents a direct bond or alkylidene; and M represents a trivalent metal) as a clarifying nucleator.

Description

Medical container molding material and medical container

Technical field

[0001] The present invention relates to a medical container molding material and a medical container.

Background art

[0002] Molded bodies that are medical containers such as syringes have excellent transparency for turbidity of drug solutions, confirmation of dosage, etc., and strength of molded bodies when filled with drug solutions and stored for a long period of time. There are required characteristics such as few eluates in the drug solution, heat resistance to withstand steam sterilization, and resistance to gamma irradiation, which is the sterilization process of molded products.

[0003] Conventionally, as a medical container such as a syringe, a molded product obtained by adding a sorbitol compound as a nucleating agent to a propylene polymer is known. However, this molded product has a problem that it cannot withstand long-term storage because there are many eluates in the drug solution and the drug may be altered.

[0004] In order to solve the above-mentioned problems, a molded body in which a phosphate ester-based transparent nucleating agent is added to a propylene-based polymer is known (see Patent Document 1). A typical compound used as a nucleating agent in this patent is methylene bis (2,4-di-tert-butylphenol) phosphate Na salt represented by the following formula.

[0005] [Chemical 1]

[0006] In addition, as the nucleating agent, a divalent metal such as Mg, Ca, Sr, Ba or the like substituted with a monovalent metal such as Li or K instead of Na in the above compound is substituted. Examples of the compound formed as a dimer and a compound formed by replacing a trivalent metal such as A1 and forming a trimer are shown.

[0007] However, the nucleating agent may have poor dispersibility with respect to the propylene-based polymer. Molded materials obtained by adding a nucleating agent to a propylene-based polymer may not have sufficient transparency and may not meet the Japanese Pharmacopoeia standard values. With problems such as low, etc.

Patent Document 1: Japanese Patent No. 3195434

Disclosure of the invention

Problems to be solved by the invention

[0008] The object of the present invention is to provide excellent transparency, low eluate, heat resistance to withstand steam sterilization, and high gamma irradiation resistance! It is an object of the present invention to provide a molding material that can form a medical container that can satisfy all of the required characteristics, and a medical container that is the molded body.

Means for solving the problem

[0009] The present inventor has diligently studied to solve the problems of moldings obtained from molding materials obtained by adding a phosphate ester-based clarification nucleating agent described in Patent Document 1 to a propylene polymer. did.

As a result, the clearing nucleating agent, which is a phosphate ester compound having a specific structure, has good dispersibility with respect to the propylene polymer, and has the ability to make the molded body transparent and to prevent elution from the molded body. It was found that the molded article obtained was excellent in heat resistance and gamma irradiation resistance. The present invention has been completed based on powerful new knowledge.

[0011] The present invention provides the following medical container molding material and medical container.

[0012] 1. 100 parts by weight of a propylene-based polymer has the general formula (1)

[0013] [Chemical 2]

[0014] (where

R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a linear, branched or cyclic alkyl group. R represents a direct bond or an alkylidene group. M represents a trivalent metal atom. A molding material for medical containers comprising 0.001 to 5.0 parts by weight of a phosphoric acid ester compound represented by the formula:

[0015] 2. The molding material according to item 1, wherein the M force is A1 in the general formula (1).

[0016] 3. A medical container obtained by molding the molding material according to item 1.

[0017] 4. The container according to item 3, wherein the medical container is a syringe.

[0018] 5. The container according to item 3, wherein the medical container is an infusion container.

[0019] 6. The container according to Item 3, wherein the medical container is an infusion container.

The invention's effect

[0020] According to the molding material of the present invention, it has excellent transparency, has a heat resistance that can withstand steam sterilization with a small amount of eluate even after being filled with a drug solution, and has a high resistance to gamma irradiation. Such a remarkable effect is obtained that a molded product for a medical container that can satisfy all of the characteristics required for the molded product for a medical container can be obtained.

[0021] Accordingly, a molded product obtained from the molding material of the present invention can be suitably used as a medical container such as a disposable syringe, a drug filling syringe, an infusion container, an infusion container, and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

[0022] The medical container molding material of the present invention includes a propylene-based polymer as a base material and a transparent nucleus It contains a phosphoric acid ester compound of general formula (1) which is an agent.

[0023] The propylene-based polymer is not limited to a propylene homopolymer, and may be a crystalline copolymer with other monomers, a crystalline polypropylene and other polymers as long as it is a polymer mainly composed of propylene. Also included are blends with these polymers. As the crystalline copolymer mainly composed of propylene, propylene / ethylene random copolymer, propylene / butene / monopolymer and the like are preferable. Examples of other polymers blended with crystalline polypropylene include ethylene / butene copolymers.

[0024] Of these propylene polymers, particularly propylene homopolymers, or from 0.5 to 7 weight ethylene propylene ^_0/0 (more preferably from 0.5 to 5 weight ^_0/0) by copolymerizing ethylene 'Propylene random copolymer is preferred in terms of transparency and resistance to gamma rays.

[0025] In the molding material of the present invention, it is necessary to use the phosphate ester compound represented by the general formula (1) as a clearing nucleating agent blended in the propylene polymer. This phosphate ester compound has a structure in which one hydroxyl group and two specific phosphate esters are bonded to a trivalent metal atom, and is highly dispersible in a propylene polymer.

In the general formula (1), the alkylidene group represented by R is preferably a lower alkylidene group having 1 to 6 carbon atoms such as a methylidene group, an ethylidene group, an isopropylidene group or a butylidene group.

Examples of the alkyl group represented by R ³ and R ⁴ include a straight chain or branched chain such as a methyl group, an ethyl group, an isopropyl group, an n propyl group, an n butyl group, an isobutyl group, an s butyl group, and a t butyl group. Or a cyclic | annular C1-C6 lower alkyl group is preferable. As the trivalent metal atom represented by M, aluminum (A1), iron (Fe), boron (B) and the like are preferable. The trivalent metal atom is most preferably aluminum, with aluminum and iron being more preferred.

[0027] Among the phosphoric acid ester compounds represented by the general formula (1), a preferred compound is a compound in which the metal atom represented by the following general formula (2) is A1, and the following general formula (3). The compound whose metal atom is Fe is shown.

[0028] [Chemical 3] [0029] [Chemical 4]

[0030] In each formula,

R ⁴ and R are the same as above.

[0031] The amount of the phosphoric acid ester compound represented by the general formula (1) to the propylene-based polymer is 0.001 to 5.0% by weight with respect to 100 parts by weight of the polymer. Part. When the blending amount is less than 0.001 part by weight, the resulting molded article may have insufficient transparency, and there may be insufficient prevention of dissolution when filled with a chemical solution. On the other hand, even if it exceeds 5.0 parts by weight, it is difficult to obtain further effects. The amount of the phosphate ester compound added is preferably about 0.01 to 3.0 parts by weight, more preferably 0.05 to 0.5 parts by weight. About a part.

[0032] An antioxidant, a neutralizing agent, an antistatic agent, an organic peroxide, and the like can be added to the molding material of the present invention as necessary.

[0033] Examples of the acid / antioxidant include phenolic acid / antioxidant and phosphite acid / antioxidant.

[0034] As typical examples of phenolic acid oxidants, tetrakis [methylene 3 (3,5 di-t-butyl 4-hydroxyphenol) propionate] methane, 1, 3, 5 tris (3,5 di-t) -Butyl-4-hydroxybenzyl) monoisocyanurate, 1,3,5 tris (3,5 di-tert-butyl-4-hydroxybenzyl) 2,4,6 trimethylbenzene and the like. Tetrakis [methylene 3 (3,5-di-tert-butyl-4-hydroxyphenol) propionate] Use “Irganox 1010” (trademark, manufactured by Ciba Specialty Chemicals Co., Ltd.) as a commercial product of methane. Can do.

[0035] As a particularly preferred example of the phosphite compound, tris (2,4-di-tert-butylphenol) phosphite can be mentioned. As a commercial product of this compound, “Ilgafos 168” (trademark, manufactured by Ciba Specialty Chemicals Co., Ltd.) can be used.

[0036] The molding material of the present invention is usually dry-blended by adding an optional component such as a nucleating agent specific to the present invention and, if necessary, an anti-oxidation agent to a propylene-based polymer, and then extruding it. Is melt-mixed and pelletized. The pelletized molding material is heated and melted again in a heating cylinder of a molding machine, and is subjected to injection molding and blow molding in a temperature range of about 180 to 280 ° C, preferably about 200 to 230 ° C. It can be formed into the desired shape by such methods.

[0037] As a result, medical containers such as disposable syringes, drug filling syringes, infusion containers, infusion containers and the like can be easily produced from the molding material of the present invention.

Example

Hereinafter, the present invention will be described more specifically with reference to examples and comparative examples.

[0039] Example 1

Polypropylene homopolymer (heat distortion temperature: 117 ° C, specific gravity: 0.90, melt index: 8. OgZlOmin) 100g, aluminum and hydroxy represented by the following formula (4) as a nucleating agent Bis [2, 4, 8, 10-Tetrakis (1,1-dimethylethyl) 1 6- (hydroxy kappa. 0) -1211-dibenzo [(1, g] [l, 3, 2] dio Xaphosfosin 6 Oxidate] Add 0.0 lg and 0.5 g of antioxidant (0.25 g each of “Ilganox 1010” and “Ilgafos 168”), dry blend with a tumbler, and use an extruder. Then, it was extruded at a temperature of 200 to 220 ° C. to obtain a pellet-shaped molding material.

[0040] [Chemical 5]

[0041] Using the above-mentioned pelletized molding material, material plasticization temperature 220 ° C, injection molding pressure 80 Okgf / cm ² , mold temperature 20 ° C, injection rate 50mlZsec, cooling time 20 seconds and injection time 5 seconds Under these molding conditions, a syringe barrel (shape: outer diameter; 14. lmm, inner diameter; 12.5 mm, length: 67 mm, inner volume: 5 ml) was injection molded.

[0042] Example 2

Polypropylene homopolymer (thermal deformation temperature: 117 ° C, specific gravity: 0.90, melt index: 8. OgZlOmin) 100 g, nucleating agent represented by the above formula (4) 0.2 g, and antioxidant 0. 5 g ("Ilganox 1010" and "Ilgaphos 168" 0.25 g each) was added, and a pellet-shaped molding material was obtained in the same manner as in Example 1.

[0043] Using the pelletized molding material, a syringe barrel having the same shape and content as in Example 1 was injection molded under the same molding conditions as in Example 1. [0044] Example 3

Polypropylene homopolymer (heat distortion temperature: 117 ° C, specific gravity: 0.90, melt index:

8.OgZlOmin) lOOg, 0.3 g of nucleating agent represented by the above formula (4), and antioxidant 0.

5g ("Ilganox 1010" and "Ilgafos 168" 0.25g each) was added,

In the same manner as in 1, a pellet-shaped molding material was obtained.

[0045] Using the pelletized molding material, a syringe barrel having the same shape and content as in Example 1 was injection molded under the same molding conditions as in Example 1.

[0046] Example 4

. Propylene ethylene random copolymer (ethylene copolymerization amount: 3 wt _{^0/0, and} the heat distortion temperature: 110.C, specific gravity: 0. 91 melt index: 25. OgZlOmin) in LOOG, represented by Formula (4) Nucleating agent 0.02g and antioxidant 0.5g ("Ilganox 1010" and "Ilgaphos 168" 0.25g each) were added and pelletized molding material in the same manner as in Example 1. It was.

[0047] A syringe barrel having the same shape and content as in Example 1 was injection-molded under the same molding conditions as in Example 1 using the above-mentioned pelletized molding material.

[0048] Comparative Example 1

Polypropylene homopolymer (heat distortion temperature: 117 ° C, specific gravity: 0.90, melt index: 8.0 g / 10min) to 100 g, nucleating agent 1,3: 2,4 oz p-methinoresidinylidene sonolebitol 0.25 g And 0.5 g of antioxidant (0.25 g each of “Ilganox 1010” and “Ilgafos 168”) were added to obtain a pellet-shaped molding material in the same manner as in Example 1.

[0049] A syringe barrel having the same shape and the same volume as in Example 1 was injection-molded using the above-mentioned molding material cast with pellets under the same molding conditions as in Example 1.

[0050] Comparative Example 2

Polypropylene homopolymer (thermal deformation temperature: 117 ° C, specific gravity: 0.90, melt index: 8. OgZlOmin) lOOg and methylene bis (2,4-di-tert-butylphenol) phosphate Na salt as nucleating agent 0. 25 g and 0.5 g of an antioxidant (0.25 g each of “Ilganox 1010” and “Ilgaphos 168”) were added, and a pellet-shaped molding material was obtained in the same manner as in Example 1. [0051] Using the pelletized molding material, a syringe barrel having the same shape and content as in Example 1 was injection molded under the same molding conditions as in Example 1.

[0052] The medical container must be free from elution of the slag additive component such as the nucleating agent and the antioxidant with respect to the water, the drug solution, and the like. For example, when the content is an injection solution, since it enters directly into the living body, various toxicities such as blood toxicity and acute toxicity due to additive components in the living body become a serious problem. Transparency is also necessary to confirm the contents.

[0053] Therefore, for each syringe obtained in Examples 1 to 4 and Comparative Examples 1 and 2, in accordance with the criteria of the plastic drug container test method prescribed in the Japanese Pharmacopoeia, (1) Transparency test And (2) The eluate test was conducted. Each test method is shown below.

[0054] (1) Transparency test

The barrel of the syringe barrel is cut to a size of about 0.9 x 4 cm, immersed in a quartz glass cell filled with pure water, and a test piece is set so that light can pass through in the thickness direction. Using a cell filled only with water as a control, the visible light transmittance (%) at 450 nm was measured. The transmittance was measured using a spectrophotometer (trade name “V-560 type”, manufactured by JASCO Corporation). A transmittance of 55% or more is acceptable.

[0055] (2) Elution test

When the syringe barrel is cut through a uniform part with as little curvature as possible and the thickness is 0.5 mm or less, the total surface area of the front and back surfaces should be about 1,200 cm ² and the thickness should be If it exceeds 0.5 mm, collect the cut pieces so that they are about 600 cm ² , further cut them into a length of about 5 cm and a width of about 0.5 cm, wash with water, and dry at room temperature. . Put this in a hard glass container of about 300mL, accurately hold 200mL of water, seal it properly, heat it at 121 ° C for 1 hour using a high-pressure steam sterilizer, and leave it to room temperature. This solution was used as a test solution. With respect to this test solution, a potassium permanganate reducing substance test, an ultraviolet absorption spectrum absorbing substance detection test, and a pH test were conducted by the following methods.

[0056] Potassium permanganate reducing substance test

Add 20 mL of the test solution to a stoppered Erlenmeyer flask, add 2 OmL of 0.002 mol ZL potassium permanganate solution and 1 mL of dilute hydrochloric acid, boil for 3 minutes, cool, and then add 0.1 g of potassium iodide solution to this. In addition, it was sealed, shaken and allowed to stand for 10 minutes, and titrated with 0. OlmolZL sodium thiosulfate solution (indicator: 5 drops of starch test solution). Separately, a blank test solution 20. OmL was used as a target, and the same operation was performed. Calculate the difference in consumption of 0.002 mol ZL potassium permanganate solution between the test solution and the blank test solution. Difference in consumption 1. Less than OmL is acceptable, 1. If it exceeds OmL, it is unacceptable.

[0057] UV absorption spectrum absorption substance detection test

When the test solution was tested with an ultraviolet absorbance measurement method for a blank test solution, the maximum absorbance in the section of wavelength 220 240 nm was 0.08 or less, and the maximum absorbance in the section of wavelength 241 350 nm was 0. The standard for success is to be below 05. Absorbance was measured using a spectrophotometer (trade name “V-560”, manufactured by JASCO Corporation).

[0058] pH test

Take 20 mL each of the test solution and the blank test solution, and add 1 mL of salt solution of 1 mL of potassium salt 1. Og to water. Measure the pH of both solutions, and measure the pH of both solutions. The difference was calculated. A difference of 1.5 or less is acceptable.

[0059] The results of the transparency test and the eluate test are shown in Table 1.

[0060] [Table 1]

table 1

[0061] Further, for each syringe obtained in Example 14 and Comparative Example 12, (3) a gamma irradiation test was performed by the following method.

[0062] (3) Gamma irradiation test

The syringe was irradiated with 25 KGy of gamma rays, and the ultraviolet absorption spectrum absorbing substance detection test was performed on this sample. [0063] Table 2 shows the results of the gamma irradiation test.

[0064] [Table 2]

Table 2

[0065] From the results in Tables 1 and 2, the following points are clear.

[0066] The syringe of Comparative Example 1 obtained by using a conventional molding material has a poor elution test and has low gamma irradiation resistance. The syringe of Comparative Example 2 has poor transparency and is resistant to gamma irradiation. Is low.

[0067] On the other hand, the syringes obtained using the molding materials of the present invention of Examples 1 to 4 are transparent, the amount of potassium permanganate solution consumed in the dissolution test, and the ultra trace dissolution based on the ultraviolet absorption spectrum. It is clear that all of the properties required for medical containers such as pH testing, which shows alteration resistance of materials and materials, and gamma irradiation resistance, are satisfied.

Claims

Claims [1] 100 parts by weight of a propylene-based polymer, as a clearing nucleating agent

[Chemical 1]

(Where

R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a linear, branched or cyclic alkyl group. R represents a direct bond or an alkylidene group. M represents a trivalent metal atom. A medical container molding material comprising 0.001 to 5.0 parts by weight of a phosphoric acid ester compound represented by the formula:

[2] The molding material according to claim 1, wherein M in the general formula (1) is A1.

[3] A medical container obtained by molding the molding material according to claim 1.

4. The container according to claim 3, wherein the medical container is a syringe barrel.

5. The container according to claim 3, wherein the medical container is an infusion container.

6. The container according to claim 3, wherein the medical container is an infusion container.