JP2012210315A - Fat emulsion-prefilled syringe preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a prefilled syringe preparation which holds fat emulsion containing propofol and enables stable storage, transportation and administration of the fat emulsion.SOLUTION: In the prefilled syringe preparation, fat emulsion is held within a syringe having an outer cylinder made of polypropylene and a gasket. At least a surface of the gasket that comes into contact with the fat emulsion and a surface that comes into contact with the outer cylinder are covered with a parylene layer having a membrane thickness of 0.5-1.5 μm.

Description

The present invention relates to a prefilled syringe preparation filled with a fat emulsion.

Conventionally, a glass vial is used as a medicine container. However, glass vials have been damaged due to falling accidents during transportation or handling, and due to their weight, they have given physical and mental burdens to carriers and medical workers. As a solution to this problem, plastic containers have been used. Plastics are widely used as containers for pharmaceuticals because they are lightweight, inexpensive, less damaged by dropping, and easy to mold. However, depending on the medicine to be accommodated, it may be easily adsorbed in the container. Therefore, when such a medicine is accommodated, it is necessary to give the container a function of non-adsorbing ability to the medicine.

In addition, prefilled syringe preparations that can be transported and stored in a state where an outer cylinder with the tip of the syringe sealed in advance with a chemical solution or an injection solution and the opening at the other end sealed with a gasket have been used. The prefilled syringe preparation is simple in operation and can prevent bacterial infection because it is not necessary to prepare a drug. Since prefilled syringe preparations have various advantages, preparation of prefilled syringe preparations of various drugs is desired in the medical field from the viewpoint of efficient treatment and prevention of medical errors.

The prefilled syringe preparation is provided with an outer cylinder and a gasket for sealing the outer cylinder as a container filled with a chemical solution, and they are required to have high airtightness during sterilization, transportation, and storage. On the other hand, it is necessary to slide the sealed gasket at the time of drug administration. That is, the gasket and outer cylinder of the prefilled syringe need to have contradictory functions such as airtightness and high slidability.

Propofol (2,6-diisopropylphenol) is a fat-soluble substance having hypnotic properties. Since this propofol is hardly soluble in water, it is generally prepared in the form of an oil-in-water fat emulsion that can be administered intravenously using oil components and emulsifiers, and is widely used as a general anesthetic and sedative. ing. Commercially available propofol preparations are provided in glass containers. However, when filling plastic containers, problems with strength and deterioration due to penetration of the fat and oil components of the fat emulsion into the plastic are adsorbed by propofol. Can be mentioned. Cyclic polyolefins can be cited as examples of plastics with low drug adsorption. In the case of preparations containing fat emulsions, cracks may occur due to strength deterioration. In order to prevent the occurrence of cracks, a method has been proposed in which a shielding member is provided at the chemical solution outlet and the peripheral portion (Patent Document 1).

Fat emulsions have the property of being vulnerable to oxygen. Conventionally, propofol preparations, which were glass vial-filled products, had nitrogen enclosed in a container as a countermeasure against oxidation. However, since the plastic container has oxygen permeability in the container itself, oxidation cannot be prevented only by enclosing nitrogen. On the other hand, a plastic prefilled syringe having a gas barrier property in a container has been proposed (Patent Document 2).

JP 2006-239048 JP2007-61476

As mentioned above, the active pharmaceutical ingredients contained in fat emulsions such as propofol are fat-soluble, so if they are prefilled syringes for general-purpose plastic containers, they will be adsorbed and sorbed into the containers, resulting in a decrease in titer. There is a problem of doing. Moreover, in a fat emulsion, it is necessary to suppress oxidation at the same time. However, the above-described methods proposed above are not satisfactory in terms of productivity and cost, and a fat emulsion prefilled syringe preparation having sufficient performance for the above-mentioned problems has not yet been obtained. It is not done.

The above problems are solved by the present invention described below.
(1) A prefilled syringe preparation containing a fat emulsion in a syringe having a polypropylene outer cylinder and a gasket, wherein at least the surface of the gasket that contacts the fat emulsion and the surface that contacts the outer cylinder are film thicknesses A prefilled syringe preparation which is coated with a 0.5-1.5 μm parylene layer.
(2) The prefilled syringe preparation according to (1), which is autoclaved.
(3) The prefilled syringe preparation according to (1) or (2), wherein the parylene layer is composed of parylene C represented by the following chemical formula 1 or parylene N represented by the chemical formula 2.

（４）前記脂肪乳剤がプロポフォールを含有するものである（１）乃至（３）のいずれかに記載のプレフィルドシリンジ製剤。
（５）（１）乃至（４）のいずれかに記載のプレフィルドシリンジ製剤を、酸素難透過性の包材で密封し、さらに脱酸素剤を封入したプレフィルドシリンジ製剤包装体。

(4) The prefilled syringe preparation according to any one of (1) to (3), wherein the fat emulsion contains propofol.
(5) A prefilled syringe preparation package in which the prefilled syringe preparation according to any one of (1) to (4) is sealed with a poorly oxygen permeable packaging material, and an oxygen scavenger is further enclosed.

According to the prefilled syringe preparation containing a fat emulsion of the present invention, a prefilled syringe preparation that can stably store, transport, and administer a propofol preparation over a long period of time can be provided.

FIG. 1 is a schematic diagram of a fat emulsion prefilled syringe formulation of the present invention.

Hereinafter, the prefilled syringe preparation of the present invention will be described with reference to FIG.
The prefilled syringe preparation 1 of the present invention includes an outer cylinder 2 formed of plastic, a sealing member 5 attached to a distal end opening 21 of the outer cylinder 2, and a plunger attached to or attachable to the gasket 3 and the gasket 3. 6 and a fat emulsion 4 accommodated in the outer cylinder 2. The fat emulsion 4 is liquid-tightly accommodated by the outer cylinder 2, the sealing member 5, and the gasket 3. The fat emulsion 4 can be discharged from the syringe by removing the sealing member 5, attaching an injection needle to the tip opening 21, and pressing the plunger 6.

The outer cylinder 2 of the prefilled syringe preparation of the present invention is preferably formed of a material having low water vapor permeability and air permeability. However, it is known that plastic materials such as polycarbonate and cyclic polyolefin have high affinity due to the characteristics of the dosage form of fat emulsion, resulting in strength deterioration and cracks. Also, depending on the drug dissolved in the fat emulsion, the plastic material may be adsorbed or sorbed when brought into contact with the plastic material for a long time. From these viewpoints, polypropylene is desirable as the material of the outer cylinder 2. More desirably, the polymer is a polypropylene having a small molecular weight distribution and a small number of amorphous portions polymerized using a metallocene catalyst.

The material constituting the gasket 3 of the prefilled syringe preparation of the present invention is not particularly limited, but styrene elastomer such as styrene-butylene-ethylene-styrene block copolymer, styrene-butadiene copolymer or hydrogenated product thereof, Ethylene elastomers such as ethylene-α-olefin copolymers, polyvinyl chloride elastomers, olefin elastomers, polyester elastomers, polyamide elastomers, polyurethane elastomers and any combination thereof (blend resins, polymer alloys, Laminates and the like). In addition, for the purpose of improving physical properties, polyolefin such as polyethylene, polypropylene, polybutene and α-olefin copolymer, oil such as liquid paraffin and process oil, and inorganic powder such as talc, cast and mica are mixed with this. You can also. In addition, various rubber materials (especially sulfur and Vulcanized with a peroxide) or a mixture thereof can also be used. Of these, styrenic elastomers, butyl rubber, halogenated butyl rubber, silicone rubber, and the like are desirable from the viewpoints of elastic properties, water resistance that can withstand steam sterilization, and heat resistance. In particular, butyl rubber and halogenated butyl rubber are desirable from the viewpoint of preventing adsorption.

The gasket 3 of the prefilled syringe preparation of the present invention is such that at least the surface in contact with the contained medicine and the surface in contact with the outer cylinder 2 are covered with parylene, but the entire gasket 3 may be covered with parylene. Good. From the viewpoint of ease of production, it is preferable that the entire gasket 3 is covered with parylene.

The parylene of the present invention refers to parylene C shown in chemical formula 1 and parylene N shown in chemical formula 2. Since the gasket in the present invention has elasticity, parylene C having a high elongation rate is desirable because parylene does not break.

The parylene coating method in the present invention comprises three steps. A process in which sublimation of diparaxylylene, a raw dimer of the raw material, occurs (A), a process in which diradical paraxylylene is generated by thermal decomposition of the dimer (B), and a parylene layer is formed by polymerization of radical monomers on the gasket surface. Step (C) to be performed. The processing conditions in each step A to C are shown in Table 1 below.

The obtained parylene layer has excellent heat resistance, chemical adsorption resistance, and gas barrier properties while maintaining transparency, and has a complicated shape like a gasket because it is formed by a gas phase polymerization method. Vapor deposition is also possible on the member. Furthermore, since the process is performed at room temperature in the process C, it is possible to process even a material having low heat resistance. The thickness of the parylene layer in the present invention is 0.5 to 1.5 μm, and the thickness of the parylene layer can be controlled by the temperature and pressure in Table 1 and the treatment time. If the thickness of the parylene layer is less than 0.5 μm, it is not sufficient to prevent the drug from adsorbing to the gasket, and if it exceeds 1.5 μm, the elasticity of the gasket is hindered and liquid leakage occurs during autoclave sterilization.

At the tip of the plunger 6 of the present invention, there is a means for detachably fixing the gasket 3. Further, the plunger 6 is pressed together with the gasket 3 in the direction of the tip opening 21 so that the fat emulsion 4 can be discharged from the prefilled syringe 1.

Fat emulsions are a combination of fats and oils and emulsifiers, but fatty acids may be added to these as emulsification aids. The oil and fat component used in the fat emulsion is not particularly limited as long as it is an oil and fat used in the pharmaceutical field such as vegetable oil, animal oil and mineral oil, but vegetable oil and triglyceride are preferable. These may be used alone or in combination with two or more oils or triglycerides. Examples of vegetable oils include soybean oil, sesame oil, olive oil, castor oil, corn oil, safflower oil, coconut oil, rapeseed oil, safflower oil, eucalyptus oil, and the like. Examples of triglycerides include medium chain fatty acid triglycerides and chemically synthesized triglycerides. As the emulsifier, phospholipids and surfactants such as phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidic acid, phosphatidylglycerol, and lecithin can be used alone or in combination. As the fatty acid, any of a saturated fatty acid and an unsaturated fatty acid can be used, and examples thereof include oleic acid, stearic acid, stearic acid, linoleic acid, and linolenic acid.

In the present invention, the packaging material used for sealing the prefilled syringe preparation 1 has poor oxygen permeability. Here, “difficult oxygen permeability” means that oxygen does not substantially permeate or has very low permeability. For example, aluminum foil, aluminum vapor deposition film, aluminum oxide vapor deposition film, silicon oxide vapor deposition film, Examples include laminate films having a polyvinyl alcohol, ethylene vinyl alcohol copolymer, polyethylene terephthalate, polyethylene naphthalate, polyvinylidene chloride, etc. as a gas barrier layer. When used as a package, it is necessary to see the inside from the outside of the packaging material In this case, it is preferable to employ a highly transparent gas barrier layer such as aluminum oxide vapor deposition film, silicon oxide vapor deposition film, polyvinyl alcohol, ethylene vinyl alcohol copolymer, polyethylene terephthalate, polyethylene naphthalate, polyvinylidene chloride, Necessary Flip employ aluminum foil or aluminum deposition film or the like can also be a light-shielding packaging material.

As the oxygen scavenger, those containing iron compounds such as iron hydroxide, iron oxide and iron carbide as active ingredients can be used. Examples of the commercially available products include AGELESS (registered trademark; manufactured by Mitsubishi Gas Chemical), Modulan (registered trademark; manufactured by Nippon Kayaku), Secur (registered trademark; manufactured by Nippon Soda), and the like. By sealing the oxygen scavenger with the above-mentioned poorly oxygen permeable packaging material, it is possible to provide a prefilled syringe package that suppresses an increase in pH due to oxidation of the fat emulsion and further enhances the stability of the preparation.

<Experiment 1>
A sheet having a width of 1 cm, a length of 5 cm, and a thickness of 1 mm was made of polypropylene, cyclic polyolefin, or polyethylene naphthalate pellets. A glass test tube was charged with 10 mL of 1% propofol injection (1% propofol injection “Maruishi”; Maruishi Pharmaceutical Co., Ltd.) and the above sheet, and after autoclaving, it was stored at 60 ° C. for 3 weeks. About the sheet | seat immersed at the time of a test start and after storage for 3 weeks, bending strength was measured with the small desktop testing machine EZTest (made by Shimadzu Corporation). Specifically, the upper and lower ends of the sheet are fixed to the measurement object fixing portion of a small tabletop testing machine, and the resistance value when the sheet is lowered by 20 mm at a speed of 5 mm / min is measured as the bending strength. As described above, the cyclic polyolefin and polyethylene naphthalate deteriorated in strength and still have sufficient strength, but the original strength of the material could not be maintained.

<Experiment 2>
A 20 mL polypropylene syringe is filled with 20 mL of 1% propofol injection (1% propofol injection “Marushi”; Maruishi Pharmaceutical) and coated with 0.5 to 3.0 μm parylene C and butyl rubber gasket and elastomer gasket. Sealed with no butyl rubber gasket and elastomer gasket to produce a prefilled syringe. After autoclave sterilization, leakage of the gasket sealing portion was visually confirmed. Table 3 shows the results. As shown in Table 3, regardless of butyl rubber or elastomer, it was confirmed that leakage occurred after autoclave sterilization when the film thickness was 2.0 μm or more. When the film thickness was 1.5 μm or less, no leakage occurred.

<Experiment 3>
20 mL polypropylene syringe is filled with 20 mL of 1% propofol injection (1% propofol injection “Marushi”; Maruishi Pharmaceutical) and sealed with parylene C-coated butyl rubber gasket and elastomer gasket, uncoated butyl rubber gasket and elastomer gasket The prefilled syringe was manufactured. After autoclave sterilization, an oxygen scavenger (ageless) was enclosed with a prefilled syringe in a poorly oxygen permeable packaging material to prepare a sample. This was stored at 25 ° C. for 18 months, and the content of propofol was calculated using liquid chromatography. The results are shown in Table 4. By applying parylene coating to the gasket, it was possible to suppress a decrease in propofol content.

<Experiment 4>
A 20 mL polypropylene syringe was filled with 20 mL of 1% propofol injection (1% propofol injection “Maruishi”; Maruishi Pharmaceutical) and sealed with a butyl rubber gasket coated with Parylene C. After autoclave sterilization, the sample was encapsulated with a sample containing an oxygen scavenger in a poorly oxygen permeable packaging material and the sample without encapsulation, and stored at 25 ° C for 18 months. The pH after storage was measured. The results are shown in Table 5. In the sample in which the oxygen scavenger was not encapsulated, the pH value was significantly lower than that in the encapsulated sample. Thus, it was found that the oxidation of the fat emulsion was suppressed by encapsulating the oxygen scavenger.

<Experiment 5>
When Experiment 4 was performed, the peak area ratio of the related substance / propofol was calculated from the peak appearing on the chromatograph using liquid chromatography. The results are shown in Table 6. In the sample in which the oxygen scavenger was encapsulated, the peak area ratio did not change, whereas in the sample in which the oxygen scavenger was not encapsulated, the peak area ratio increased. From this, it was found that encapsulating an oxygen scavenger can suppress the production of propofol-related substances.

1 Prefilled syringe preparation 2 Outer cylinder 21 Front end opening 22 Rear end opening 3 Gasket 4 Fat emulsion 5 Sealing member 6 Plunger

Claims (5)

A prefilled syringe preparation containing a fat emulsion in a syringe having a polypropylene outer cylinder and a gasket, wherein at least the surface of the gasket that contacts the fat emulsion and the surface that contacts the outer cylinder have a film thickness of 0.5. -A prefilled syringe preparation characterized by being coated with a 1.5 [mu] m parylene layer. The prefilled syringe preparation according to claim 1, which has been autoclaved. The prefilled syringe preparation according to claim 1 or 2, wherein the parylene layer is composed of parylene C represented by the following chemical formula 1 or parylene N represented by the chemical formula 2.

The prefilled syringe preparation according to any one of claims 1 to 3, wherein the fat emulsion contains propofol. A prefilled syringe preparation package in which the prefilled syringe preparation according to any one of claims 1 to 4 is sealed with a poorly oxygen permeable packaging material and an oxygen scavenger is further enclosed.

Images