RU2782538C1 - Syringe pre-filled with hydrogen peroxide with excellent preservation of hydrogen peroxide due to the silicone oil included in the oil composition - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: proposed is a pre-filled syringe with a cylinder made of a material exhibiting a high capacity for decomposition with respect to hydrogen peroxide, containing a solution of hydrogen peroxide therein and an oil composition applied to the inner wall of the cylinder, wherein the oil composition contains silicone oil.

EFFECT: ensured long-term storage of the hydrogen peroxide solution without loss of stability due to the suppressed hydrogen peroxide decomposition.

11 cl, 2 dwg, 1 ex

Description

FIELD OF TECHNOLOGY

[0001]

The present invention relates to a pre-filled syringe with an oil composition containing silicone oil pre-filled with a hydrogen peroxide solution.

BACKGROUND OF THE INVENTION

[0002]

Hydrogen peroxide solution is used in industry as a bleaching agent and as a disinfectant in the food industry. A hydrogen peroxide solution containing 2.5% to 3.5% (w/v) hydrogen peroxide (known as "oxidol" in the Japanese Pharmacopoeia) is used for medical purposes as a disinfectant.

[0003]

Such a hydrogen peroxide solution can be used as a radiosensitizer when mixed with a solution of hyaluronic acid or a salt thereof, such as sodium hyaluronate, in a predetermined ratio, to then inject said mixture into a tumor immediately before a therapeutic dose of radiation (Patent Document 1). The decomposition of hydrogen peroxide accelerates with increasing solution temperature due to its thermal decomposition. Non-Patent Document 1 describes a material suitable for hydrogen peroxide.

PRIOR ART DOCUMENTS

PATENT DOCUMENT

[0004]

Patent Document 1: WO2008/041514

NON-PATENT DOCUMENT

[0005]

Non-Patent Document 1: RYO KUSAKABE, "Production, Properties, and Handling of Hydrogen Peroxide", Japan TAPPI journal, Vol. 52, no. 5, May 1998.

DISCLOSURE OF THE INVENTION

PROBLEMS SOLVED BY THE INVENTION

[0006]

As described in Non-Patent Document 1, there are several types of storage container materials that can be used to store a hydrogen peroxide solution, and thus there are several types of storage container materials.

[0007]

Since hydrogen peroxide decomposes rapidly when removed from a special storage container that protects it from light, it must be extracted in an appropriate volume or weight and then mixed with a sodium hyaluronate solution just prior to injection when used as a radiation sensitizer, as described in Patent Document 1. This imposes an additional burden on the medical personnel who treat the patient. Either the hospital pharmacy must extract the hydrogen peroxide solution and mix it with sodium hyaluronate, or the doctor must do this at the patient's bedside. In the first case, the burden falls on the pharmacy staff, and there is a risk of delay in the delivery of the mixture for injection from the pharmacy to the patient's bedside. In the latter case, the burden falls on the medical staff at the patient's bedside, who prepares the patient for radiotherapy. In both cases, the complexity of extracting the drug and mixing the solutions increases the risk of errors that can compromise treatment or endanger the patient himself.

[0008]

In addition, if the hydrogen peroxide solution is previously placed in a conventional glass (eg, borosilicate glass) syringe, the glass syringe expands during storage of the hydrogen peroxide solution and its seal is retracted. This may prevent long-term storage of the hydrogen peroxide solution in such a glass syringe.

MEANS FOR SOLVING THE SPECIFIED TASKS

[0009]

The inventor of the present invention made intensive studies and found that an oil composition containing silicone oil has a stabilizing effect on the storage of hydrogen peroxide, and thus completed the present invention. To solve this problem, the present invention provides a syringe pre-filled with a hydrogen peroxide solution, including an oil composition for stabilizing the storage of hydrogen peroxide.

[0010]

One object of the present invention is to provide a pre-filled syringe having at least a barrel made of a material having a high degradability with respect to hydrogen peroxide, comprising: a solution of hydrogen peroxide therein and an oil composition applied to the inner wall of the barrel, the oil the composition contains silicone oil.

[0011]

By using an oil composition, the storage of hydrogen peroxide in the hydrogen peroxide solution can be stabilized. Thus, by applying the oil composition to the inner wall of the syringe, the hydrogen peroxide solution contained in the pre-filled syringe can be stored for a long time.

[0012]

Yet another object of the present invention is to provide an oil composition containing silicone oil, said oil composition for stabilizing hydrogen peroxide storage and use.

[0013]

By using said oil composition, stabilization of the storage of hydrogen peroxide in the hydrogen peroxide solution and storage of said hydrogen peroxide solution for a long time can be ensured regardless of the material of the container or syringe in which the hydrogen peroxide solution is stored.

TECHNICAL EFFECT OF THE INVENTION

[0014]

According to the present invention, a pre-filled syringe capable of storing a hydrogen peroxide solution for an extended period of time prior to use as a radiosensitizer can be provided.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015]

FIG. 1 is a schematic view of a pre-filled syringe containing a hydrogen peroxide solution according to an embodiment of the present invention.

FIG. 2 shows a graph of residual hydrogen peroxide levels for each container material according to the example shown.

IMPLEMENTATION OF THE INVENTION

[0016]

Definition

For convenience, certain terms used in the context of the present invention are collected herein. Unless otherwise indicated, all technical and scientific terms used in this document have the same meaning, which is usually understood by a person skilled in the art to which this invention pertains. The grammatical means of expressing the singular is also used herein to include references to the plural, unless the context clearly indicates otherwise.

[0017]

Although the numerical ranges and parameters defining the broad scope of the present invention are approximations, the numerical values given in the specific examples are described as precisely as possible. However, any numerical value inherently contains certain errors that inevitably arise as a result of the standard deviation found in the corresponding experimental measurements. In addition, as used herein, the term "about" generally means "within 10%, 5%, 1%, or 0.5% of a given value or range." Alternatively, the term "about" means "within the acceptable standard error of the mean considered by a person skilled in the art."

[0018]

oil composition

In the present embodiment, the oil composition contains silicone oil to stabilize the storage of hydrogen peroxide. Said oil composition can be used as an agent for stabilizing the storage of hydrogen peroxide. Said oil composition may contain a pharmaceutically acceptable component (such as sterilized water) in addition to silicone oil. Said oil composition may be applied to the inner surface of a container or syringe. Said oil composition can suppress hydrogen peroxide decomposition by a material having a high hydrogen peroxide decomposition capacity (eg, glass, a plastic having a high hydrogen peroxide decomposition capacity such as polyethylene terephthalate and stainless steel). Thus, the container or syringe can be made of a material having a high ability to decompose hydrogen peroxide.

[0019]

The silicone oil may have a kinematic viscosity of 20 cSt to 40,000 cSt, preferably 500 cSt to 30,000 cSt, more preferably 800 cSt to 20,000 cSt, and even more preferably 1000 cSt to 15,000 cSt at 25°C.

[0020]

The kinematic viscosity of silicone oil at 25°C can be measured according to JIS Z8803.

[0021]

Preferably, the linear silicone represented by the following formula (1) can be used as the silicone oil.

[0022]

[0023]

In the above formula (1), R independently represents an organic functional group containing no functional group involved in the hydrosilylation reaction, such as an alkenyl group or a silane (SiH) group, a monovalent hydrocarbon group, or a hydroxyl group. R may be the same or may be different from each other. x is an integer from 10 to 1200. R is preferably an alkyl group or an aryl group, and more preferably a methyl group, an ethyl group, or a phenyl group.

[0024]

The linear silicone represented by the above formula (1) includes a polydiorganosiloxane, both ends of which are capped with triorganosilyl groups, which are preferably a polydialkylsiloxane, a polydiarylsiloxane, a polyalkylarylsiloxane or a copolymer thereof, more preferably a polydimethylsiloxane or a polymethylphenylsiloxane, further preferably a polydimethylsiloxane in which all R are methyl groups.

[0025]

Syringe

FIG. 1 schematically shows a syringe (1) pre-filled with a hydrogen peroxide solution (50) according to one embodiment of the present invention. In the present embodiment, the syringe (10), in particular the barrel (20) of the syringe (10), has a generally cylindrical shape. In the present embodiment, the syringe (10) has at one end a needle mounting portion (30) from which a hydrogen peroxide solution (50) is discharged. In the present embodiment, the syringe (10) has a hole (80) at its other end for the plunger rod (70). In the present embodiment, the syringe (10) has a flange (90) provided around the opening (80). In the pre-filled syringe (1) shown in FIG. 1, silicone oil is applied to the inner wall of the syringe (10). To prevent leakage of the hydrogen peroxide solution (50) filling the syringe, the pre-filled syringe (1) shown in FIG. 1 has a cap (40) provided on its needle seat (30) and a plunger stem (70) inserted into the hole (80), the plunger stem (70) having a seal (60).

[0026]

In the present embodiment, the hydrogen peroxide solution syringe refers to a syringe having a low ability to decompose hydrogen peroxide in the hydrogen peroxide solution. In the present embodiment, hydrogen peroxide solution refers to a solution in which the solvent (eg water) contains hydrogen peroxide and optionally additives (eg phosphoric acid and phenacetin). In the present embodiment, the syringe may be made from a single component material or may be made from a variety of materials (including a multilayer structure such as a coating). In the case of a syringe made from a one-component material, the entire syringe is made from a material having a high hydrogen peroxide decomposability (eg, glass, a plastic having a high hydrogen peroxide decomposability such as polyethylene terephthalate, and stainless steel). In the case of a syringe made of a plurality of materials, except for a part in which the inner wall of the syringe is made of glass, the remaining parts may be made of a material having high or low hydrogen peroxide decomposability. However, all parts of the inner wall of the syringe must be made of a material that has a high ability to decompose hydrogen peroxide. Thus, the main parts, such as the inner surface of the syringe barrel, must be made of a material having a high ability to decompose hydrogen peroxide. In other words, the parts that can come into contact with the hydrogen peroxide solution, such as the plunger stem, luer lock, cap, and seal, must be made of a material that has a high ability to decompose hydrogen peroxide. In the present embodiment, the syringe may be designed for a radiosensitizer.

[0027]

The ability to decompose hydrogen peroxide can be determined from the ratio of the concentration of hydrogen peroxide in the hydrogen peroxide solution after the start of storage to the concentration of hydrogen peroxide in the hydrogen peroxide solution before storage under specific temperature conditions (residual content of hydrogen peroxide). Storage is carried out in a sealed state. Temperature conditions are not limited, but may be 35°C, 37°C, 40°C or 60°C. The shelf life is not limited, but can be one week, two weeks, three weeks, or four weeks or more. The concentration of hydrogen peroxide in the hydrogen peroxide solution before storage can be any, for example, may be in the range from 0.01% to 40% (wt./about.). In one embodiment, the hydrogen peroxide degradability of plastic is lower than that of glass. The residual content of hydrogen peroxide in the plastic container may be 70% or more, preferably 75% or more, more preferably 78% or more, even more preferably 80% or more under conditions where a solution containing 2.5% to 3. 5% (w/v) hydrogen peroxide, sealed at 60°C for 4 weeks. The amount of hydrogen peroxide in a hydrogen peroxide solution can be determined by titration with a potassium permanganate solution according to the method for determining oxidol described in the Japanese Pharmacopoeia.

[0028]

In the present embodiment, the syringe is provided as a syringe pre-filled with hydrogen peroxide solution. The syringe, pre-filled with hydrogen peroxide solution, contains a slidable sealing gasket. In addition, the needle mounting portion of the syringe pre-filled with the hydrogen peroxide solution is hermetically sealed, for example, with a cap or the like.

[0029]

In the present embodiment, the concentration of hydrogen peroxide in the hydrogen peroxide solution in the pre-filled syringe is, for example: 0.01; 0.02; 0.03; 0.04; 0.05; 0.06; 0.07; 0.08; 0.09; 0.1; 0.5; one; 5; ten; fifteen; twenty; 25; thirty; 35 or 40%, or may range between any two of the numerical values provided herein, for example, from 0.01% to 40% (w/v), preferably from 0.05% to 30% ( w/v).

[0030]

Application

The oil composition according to the present embodiment may be applied with a spray or the like. After application, the oil composition may be dissolved in a suitable solvent. When applied, the oil composition can be applied to the inner wall of the syringe in an amount of 0.02 to 0.2 mg/cm ² by spraying. After being applied to the inner wall of the syringe, the oil composition can be made uniform in thickness using a device such as a scraper or by softening the silicone oil in the oil composition by heat treatment (eg, autoclaving).

EXAMPLE

[0031]

Hydrogen peroxide solution stability test

A hydrogen peroxide solution stability test was performed using a glass container coated with silicone oil and a glass container not coated with silicone oil. The silicone oil was purchased from Dow Corning (product name: Dow Corning 360 Medical Fluid (12500 cSt)). The hydrogen peroxide solution was added to each container, sealed and then stored at 60° C. for 4 weeks. After storage, the residual hydrogen peroxide content in the hydrogen peroxide solutions was measured. The hydrogen peroxide solution used was Oxydol "KENEI" (containing 2.5% to 3.5% (w/v) hydrogen peroxide, phosphoric acid and phenacetin) manufactured by Kenei Pharmaceutical Co., Ltd. The amount of hydrogen peroxide in the hydrogen peroxide solution was determined by titration with potassium permanganate solution in accordance with the method for determining oxidol described in the Japanese Pharmacopoeia. The results are shown in FIG. 2.

[0032]

In the case of a glass container not coated with silicone oil, the residual proportion of hydrogen peroxide was about 70%. The residual proportion for the glass container coated with silicone oil was 78% or more. As a result, the glass container coated with silicone oil resisted the decomposition of hydrogen peroxide better than the glass container not coated with silicone oil.

List of elements

[0033]

1 pre-filled syringe

10 Syringes

20 Cylinder

30 Needle holder

40 cap

50 Hydrogen peroxide solution

60 Sealing gasket

70 Plunger stem

80 Hole

90 flange

Claims (18)

1. A pre-filled syringe having at least a barrel made of a material having a high ability to decompose in relation to hydrogen peroxide, containing: hydrogen peroxide solution in it and an oil composition applied to the inner wall of the cylinder, the oil composition comprising silicone oil. 2. The pre-filled syringe according to claim 1, wherein the silicone oil is a linear silicone represented by the following formula (1):

while in the above formula (1) R independently represents an organic functional group that does not contain a functional group involved in the hydrosilylation reaction, a monovalent hydrocarbon group or a hydroxyl group, R may be the same or may be different from each other, and x represents an integer from 10 to 1200. 3. The pre-filled syringe of claim 2 wherein R independently represents an alkyl group or an aryl group. 4. The pre-filled syringe of claim 3 wherein R independently represents a methyl group, an ethyl group, or a phenyl group. 5. Pre-filled syringe according to any one of paragraphs. 2-4, in which the linear silicone represented by the above formula (1) is a polydiorganosiloxane, both ends of which are capped with triorganosilyl groups. 6. The pre-filled syringe of claim 5, wherein the polydiorganosiloxane is a polydialkylsiloxane, polydiarylsiloxane, polyalkylarylsiloxane, or a copolymer thereof. 7. The pre-filled syringe of claim 6 wherein the polydiorganosiloxane is polydimethylsiloxane or polymethylphenylsiloxane. 8. The pre-filled syringe of claim 7 wherein the polydiorganosiloxane is polydimethylsiloxane and all R's are methyl groups. 9. The syringe according to any one of paragraphs. 1-8, in which the concentration of hydrogen peroxide in the hydrogen peroxide solution is in the range from 0.01% to 40% (w/v). 10. The syringe according to any one of paragraphs. 1-9, in which the material is glass. 11. The syringe according to any one of paragraphs. 1-10, wherein said syringe is used for the radiosensitizer.

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