JPH11178887A - Resin molded container and formulation stored therein - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a container molded from such a resin that, even if a solid medicine of the type soluble at the time when it is needed is dissolved for use after being preserved for a long period in direct contact with the container, its solution will not become turbid. SOLUTION: A container storing a solid medicine of the type soluble at the time when it is needed has a medicine storage part made from a resin using as propylene polymer as its base material and having a composition containing a compound represented by the formula as a crystal nucleating agent, and the medicine of the type soluble at the time when it is needed is stored in the medicine storage part. In the formula, R1 represents hydrogen or a lower alkyl group, R2 and R3 represent each a lower alkyl group, M is an alkali metal atom or alkali earth metal atom, and (n) is the valence of the metal M.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a resin-molded container and a preparation for dissolving in use which contains a solid drug for dissolving in use in the resin-molded container.

[0002]

2. Description of the Related Art Conventionally, a drug for use at the time of use, such as an antibiotic, is filled in a glass vial, sealed, and stored until use. At the time of use, it is dissolved in a separately prepared solution and then administered to a patient by intravenous injection or the like. Glass vials prevent permeation of moisture and gas from the outside, and do not cause any interaction when they come in contact with the filled drug. It is widely used as an excellent container that does not cause turbidity and can stably store drugs for a long period of time. However, since the glass vial is heavy and easily broken, not only is it difficult to transport the glass vial, but also, after use, the glass body and the plastic flip-off stopper must be separated and discarded. Therefore, a resin vial based on a propylene-based polymer has been studied.

[0003] Further, for the purpose of easy administration and maintaining sterility, a dissolving solution in which a drug is directly filled into a plastic drug storage chamber and a dissolving solution is stored therein without using a glass vial. An infusion kit container or a pre-dissolved prefilled syringe has been proposed in which storage chambers are provided in series and a partition member or the like interposed between the two chambers is used during use to connect the two chambers.

[0004]

In these containers, a resin containing a polypropylene as a base material and blended with various additives such as a crystal nucleating agent is used as a material of a drug storage chamber for storing a drug. In these containers, the drug is stored directly in contact with the inner bottom or the inner wall of the drug storage chamber until use, but during long-term storage, the drug and the additive in the resin are mixed. There is a problem that, when the drug is dissolved at the time of use, the solution becomes turbid due to some kind of interaction.

[0005] Injectables administered to patients intravenously or the like require extremely high safety. In the Japanese Pharmacopoeia, the in-use dissolving preparations contain insoluble foreign substances that are clearly and clearly recognized by visual observation when dissolved. It is stipulated that they must not go out. Therefore, it is necessary to develop a resin material for these containers that does not cause turbidity when dissolved even when stored for a long period of time in a state in which the drug is directly in contact with the container.

[0006]

Means for Solving the Problems As a result of intensive studies, the inventors of the present invention have found that a solid-state in-use dissolving method using a polyolefin resin composition as described in JP-B-63-8980. It was found that when a solid-type dissolving-type drug was stored in a container in which a drug storage part for storing a mold drug was molded, even if the drug was dissolved during use after storage for a long period of time, the solution did not become turbid. .

In the container of the present invention, a drug storage portion of a container for storing a solid-state drug for use at the time of use has a propylene-based polymer as a base material and contains a compound represented by the following general formula as a crystal nucleating agent. It is characterized by being molded with a resin comprising the composition.

Embedded image (In the formula, R ₁ is a hydrogen or lower alkyl group, R ₂ and R ₃ are lower alkyl groups, M is an alkali metal atom or an alkaline earth metal atom, and n is a valence of the metal M.) Includes the above-mentioned vials, prefilled syringes, infusion kit containers, and the like, and the respective drug storage sections (the entire containers in vials) are molded from the resin.

[0008] The ready-to-use preparation of the present invention comprises a propylene-based polymer as a base material and a drug-containing portion of a resin molded from a resin having a composition containing a compound represented by the above general formula as a crystal nucleating agent. It contains a solid, ready-to-use drug.

The composition of the resin used in the medicine container of the container according to the present invention is characterized in that a propylene polymer is used as a base material and a compound represented by the above general formula is contained as a crystal nucleating agent. Here, the propylene-based polymer as the base material is not limited to a propylene homopolymer, and if it is a polymer mainly composed of propylene, a crystalline copolymer with another monomer or a crystalline polypropylene may be used. It may include those blended with a polymer. As a crystalline copolymer mainly composed of propylene, 0.5 to 7% by weight (more preferably 0.5 to 5% by weight) of ethylene is added to propylene.
Copolymerized propylene / ethylene random copolymer,
Propylene / butene-1 copolymer. Also,
Other polymers to be blended with the crystalline polypropylene include, for example, an ethylene / butene copolymer. Among these propylene polymers, a propylene homopolymer is preferred.

The nucleating agent used in the present invention is represented by the following general formula.

Embedded image (In the formula, R ₁ is hydrogen or a lower alkyl group, R ₂ and R ₃ are lower alkyl groups, M is an alkali metal atom or an alkaline earth metal atom, and n is a valence of the metal M.)

In the above general formula, lower alkyl groups represented by R ₁ , R ₂ and R ₃ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, Tertiary pentyl, hexyl and the like.

As the alkali metal atom represented by M,
Li, Na, K and the like can be mentioned, and as the alkaline earth metal atom, Mg, Ca, Ba and the like can be mentioned. n is M
Is 1 when is an alkali metal atom, and 2 when M is an alkaline earth metal atom.

The amount of the nucleating agent is 0.005 to 0.3 parts by weight, preferably 0.01 to 0.2 parts by weight, based on 100 parts by weight of the propylene polymer.

Specific examples of the crystal nucleating agent represented by the above general formula used in the present invention are shown below.

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Among these, the above No. Sodium-2,2'-methylenebis (4,6-di-tert-butylphenyl) phosphate (hereinafter referred to as Asahi Denka Kogyo Co., Ltd. under the trade name "NA11") , "NA11") is most preferred.

It is preferable to add a light stabilizer, an antioxidant and a neutralizer to the resin used in the container of the present invention. As the light stabilizer, for example, 2,2,6,6-tetramethyl-4-piperidyl stearate, 1,2,2,6,6-
Pentamethyl-4-piperidyl stearate, 2,2
6,6-tetramethyl-4-piperidyl benzoate,
Bis (2,2,6,6-tetramethyl-4-piperidyl) sebacate, bis (1,2,2,6,6-pentamethyl-4-piperidyl) sebacate, tetrakis (2
2,6,6-tetramethyl-4-piperidyl) butanetetracarboxylate, tetrakis (1,2,2,6)
6-pentamethyl-4-piperidyl) butanetetracarboxylate, bis (1,2,2,6,6-pentamethyl-4-piperidyl) di (tridecyl) -1,2,2
3,4-butanetetracarboxylate, bis (1,
2,2,6,6-pentamethyl-4-piperidyl) -2
-Butyl-2- (3,5-ditert-butyl-4-hydroxybenzyl) malonate, 1- (2-hydroxyethyl) -2,2,6,6-tetramethyl-4-piperidinol / diethyl succinate Polycondensate, 4-hydroxy-
2,2,6,6-tetramethyl-1-piperidinoethanol / dimethyl succinate polycondensate, 1,6-bis (2
2,6,6-tetraethyl-4-piperidylamino) hexane / dibromoethane polycondensate, 1,6-bis (2
2,6,6-tetramethyl-4-piperidylamino) hexane / 2,4-dichloro-6-morpholino-s-triazine polycondensate.

[0017] Among these light stabilizers, TINUVI
Preferred is 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinoethanol / dimethyl succinate polycondensate sold by Ciba Geigy Corporation under the trade name of N622LD.

The light stabilizer is added in an amount of 0.005 to 0.3 parts by weight, preferably 0.01 to 0.2 parts by weight, based on 100 parts by weight of the propylene polymer.

Examples of the antioxidant include an organic phosphorus antioxidant and a phenolic antioxidant. Examples of the organophosphorus antioxidant include trisnonylphenyl phosphite, tris (2,4-di-tert-butylphenyl) phosphite, distearylpentaerythritol diphosphite, and bis (2,4-dithiophene). Tertiary butylphenyl) pentaerythritol diphosphite, bis (2,6-ditert-butyl-4-methylphenyl) pentaerythritol diphosphite, 2,2′-methylenebis (4,6-ditert-butyl) Phenyl) octyl phosphate, tetrakis (2,4-ditert-butylphenyl) biphenylenediphosphonite and the like. Examples of the phenolic antioxidants include 1,3,5-
Tris (2,6-dimethyl-3-hydroxy-4-tert-butylbenzyl) isocyanurate, 1,3,5-tris (3,5-ditert-butyl-4-hydroxybenzyl) isocyanurate, 1 , 3,5-tris (3,5-
Di-tert-butyl-4-hydroxybenzyl) -2,4
6-trimethylbenzene, 1,3,5-tris [(3,
5-di-tert-butyl-4-hydroxyphenyl) propionyloxyethyl] isocyanurate; tetrakis [methylene-3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionate] methane;

Among these antioxidants, for example, MAR
Tris (2,4-di-tert-butylphenyl) phosphite sold by Asahi Denka Kogyo Co., Ltd. under the trade name of K2112, and Tetrakis [methylene] sold by Sandos under the trade name of Irganox 1010. -3- (3,
5-Di-tert-butyl-4-hydroxyphenyl) propionate] methane is preferred.

The antioxidant is added in an amount of 0.005 to 0.5 part by weight, preferably 0.01 to 0.2 part by weight, based on 100 parts by weight of the propylene polymer.

Examples of the neutralizing agent include basic double salts of alkaline earth metals. Examples of the basic double salt of an alkaline earth metal include hydrotalcites, which are hydrated basic carbonate minerals of magnesium and aluminum.

Among these neutralizing agents, for example, DHT-
Hydrotalcites such as 4A (manufactured by Kyowa Chemical Industry Co., Ltd.) are preferred.

The amount of the neutralizing agent added is 0.001 to 0.5 part by weight, preferably 0.001 to 0.05 part by weight, based on the propylene 100 polymer.

The container of the present invention can be produced, for example, by molding the resin composition produced as follows by molding means such as injection molding. For the production of the resin composition, for example, the above-mentioned propylene-based polymer is used as a base material, and a nucleating agent, a light stabilizer, a neutralizing agent, an additive such as an antioxidant, and the like are added to a Henschel mixer, a super mixer, and a ribbon. Compounded using a blender or the like, and mixed with a normal single-screw extruder, twin-screw extruder, Banbury mixer, Brabender, roll, etc.
It is carried out by melt-kneading in a temperature range of 60 to 250 ° C. and forming it into a melt pellet by an extruder. As a molding method, for example, the pellets are again heated and melted,
180-280 ° C, preferably 230 ± 10
In the range of ° C., for example, in the vial container, the entire container including the drug storage portion is formed by injection molding, and in the infusion kit container or the prefilled syringe, the drug storage chamber for storing the drug is formed into a desired shape. It is manufactured by

In the case of an infusion kit container or a prefilled syringe, when the medicine comes into contact with a communication member interposed between the two storage portions in order to make the medicine storage portion and the solution storage portion communicate with each other during use, this communication member is used. Must also be manufactured using this resin. Further, the storage portion of the dissolving solution that does not come into contact with the drug until use may be integrally manufactured using the resin used in the present invention, or manufactured using a known method using another known material, What is necessary is just to connect with the said chemical | medical agent accommodation part and a communicating member by welding etc.

Next, a method of formulating a drug using the container manufactured as described above will be described. The container manufactured as described above, for example, a drug container of a vial is filled with the following drug under aseptic conditions by powder filling or freeze-drying by a conventional method, and then stoppered to obtain a ready-to-use dissolvable preparation. In the case of an infusion kit container or the like, the medicine container is filled with a medicine, and the upper part is sealed after the medicine is filled with the medicine. To form a ready-to-use dissolving preparation by connecting to a non-woven bag by welding or the like.

The following are examples of the drug stored in the drug storage chamber of the container of the present invention, that is, one example of the active ingredient of the ready-to-use formulation. Antibiotics include cefazolin sodium, ceftizoxime sodium, cefotiam hydrochloride, cefmenoxime hydrochloride, cefacetril sodium, cefamandole sodium, cephaloridin, cefotaxime sodium, cefotetan sodium, cefoperazone sodium, cefsulodin sodium, Cephem antibiotics such as tezole sodium, cefpyramid sodium, cefmetazole sodium, cefuroxy sodium, cefocles sulfate, ampicillin sodium, carbenicillin sodium,
Penicillin antibiotics such as sodium sulbenicillin and ticarcillin, and vancomycin hydrochloride are also included. Examples of the antitumor agent include mitomycin C, fluorouracil, tegafur, and cytarabine, and examples of the antiulcer agent include famotidine, ranitidine hydrochloride, and cimetidine. Among these active ingredients, the most effective effect is obtained when an antibiotic is contained.

The dissolving solution which is prepared separately when dissolving the dissolving drug at the time of use or which is previously filled in a dissolving solution storage bag connected to the drug storage portion in an infusion kit container or the like may be a physiological solution. Examples include saline, glucose solution, water for injection, or amino acid solution to which cysteine, tryptophan and the like are added.

The drug to be filled may be a single active ingredient or a mixture of the active ingredient with, for example, lactose or mannitol. These active ingredients are dissolved in the above-mentioned dissolving solution at the time of use, and then administered to the body by intravenous administration, intravenous drip intravenous administration, intramuscular administration, subcutaneous administration, or the like.

Stability Test 1 Various resins in the form of pellets having the composition shown in Table 1 were molded into a plate and cut into a size of about 1 cm. Put 2 g (about 20 pieces) of the cut pieces in a glass vial, then add 1 g of an antibiotic (vancomycin hydrochloride), stopper, and store in a 70 ° C. thermostat. After 9 days, remove the section and add 20 cc
Add distilled water to dissolve the antibiotic. The solution was placed in a test tube, visually checked for turbidity, and the transmittance (T%) was measured at 650 nm using an absorptiometer. In stability tests 1 and 2, a propylene homopolymer (HOMO) having a MFR of 15 g / 10 min was converted to a propylene / ethylene random copolymer (RA
NDOM) having an MFR of 15 g / 10 min and an ethylene content of 2.4% by weight was used.

[Table 1] The numerical values in the table indicate the mixing ratio when the base (PP) is set to 100. Test results

[Table 2]

Stability Test 2 Using a resin having the composition shown in Table 3 and an antibiotic (cefazoline sodium), the same procedure as in Stability Test 1 was carried out at 50 ° C.
After 0 day, the appearance of the antibiotic solution was visually observed and the transmittance at 650 nm was measured.

[Table 3] Test results

[Table 4]

As is evident from these results, the resin having a composition based on the propylene polymer used in the present invention and containing NA11 as a nucleating agent was stored in direct contact with various antibiotics. Even when passed over time, no turbidity occurs when the antibiotic is dissolved.

[0034]

EXAMPLES Example 1 Propylene homopolymer (MFR 15 g / 10 min) (10
0 parts by weight), NA11 (0.10 parts by weight), TINUV
IN622LD (0.05 parts by weight), MARK2112
(0.10 parts by weight) and DHT4A (0.03 parts by weight) were dry-blended with a super mixer, and then melt-kneaded using a 50 mm diameter single screw extruder. The resin was extruded from the die at a die exit temperature of 210 ° C. and pelletized to produce a resin. This pellet is heated and melted again,
At the injection temperature in the range of 230 ° C. ± 10 ° C., the medicine container of the target container (vial) was formed by injection molding.

Example 2 Cefazoline sodium was powder-filled into the drug storage section of the vial produced in Example 1, and the solution was stoppered to obtain a ready-to-use formulation.

Example 3 Vancomycin hydrochloride was powder-filled into the drug container of the vial manufactured in Example 1 and stoppered to obtain a ready-to-use formulation.

[0037]

According to the present invention, the propylene-based polymer of the present invention is used as a base material, and a solid-state material is added to the medicine container of a container molded from a resin having a composition containing NA11 represented by the above general formula as a nucleating agent. A time-dissolved preparation containing a time-dissolved drug does not cause turbidity when dissolved after long-term storage, and is a highly stable and safe preparation. Further, the container of the present invention is excellent in long-term storage of a dissolvable drug at the time of use, since the drug storage portion is molded of the resin.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Tomohiko Kubo 3-9-3 Honjo Nishi, Kita-ku, Osaka, Osaka Prefecture Nissha Corporation (72) Inventor Mitsuru Hasegawa 3-9-, Honjo Nishi, Kita-ku, Osaka, Osaka 3 Nissha Corporation

Claims (6)

[Claims] 1. A resin comprising a propylene-based polymer as a base and a nucleating agent containing a compound represented by the following general formula: A container characterized by being molded with: Embedded image (In the formula, R ₁ is hydrogen or a lower alkyl group, R ₂ and R ₃ are lower alkyl groups, M is an alkali metal atom or an alkaline earth metal atom, and n is a valence of the metal M.) 2. The container according to claim 1, wherein the crystal nucleating agent is sodium-2,2′-methylenebis (4,6-di-tert-butylphenyl) phosphate. 3. The container according to claim 1, wherein the drug for use when used is an antibiotic. 4. A solid, ready-to-use drug in a drug container of a container molded from a resin comprising a propylene-based polymer as a base material and containing a compound represented by the following general formula as a nucleating agent: A ready-to-use dissolving preparation containing a. Embedded image (In the formula, R ₁ is hydrogen or a lower alkyl group, R ₂ and R ₃ are lower alkyl groups, M is an alkali metal atom or an alkaline earth metal atom, and n is a valence of the metal M.) 5. The preparation according to claim 4, wherein the nucleating agent is sodium-2,2'-methylenebis (4,6-ditert-butylphenyl) phosphate. 6. The preparation for dissolution in use according to claim 4, wherein the preparation for dissolution in use is an antibiotic.