WO2020027220A1

WO2020027220A1 - Method for removing silicone oil when administering protein preparation

Info

Publication number: WO2020027220A1
Application number: PCT/JP2019/030068
Authority: WO
Inventors: 努上田; 阿部　吉彦; エフ．カーペンター，ジョン
Original assignee: テルモ株式会社
Priority date: 2018-07-31
Filing date: 2019-07-31
Publication date: 2020-02-06
Also published as: JPWO2020027220A1

Abstract

[Problem] To provide a means by which, when administering a medical fluid containing a protein preparation, silicone oil that has somehow entered into the filling chamber of a syringe and clumps of the protein preparation that have been thereby generated, can be removed via a simple method. [Solution] The present disclosure provides a method for removing silicone oil from a medical fluid, which contains a protein preparation, when using a syringe comprising a syringe barrel and a gasket, which is capable of liquid-tight sliding within the syringe barrel, to administer the medical fluid, the method including passing the medical fluid through a filter, having an average pore size circle equivalent diameter of 0.6 μm or less, to thereby remove the silicone oil from the medical fluid.

Description

How to remove silicone oil when administering protein preparations

(4) The present invention relates to a method for removing silicone oil when administering a protein preparation.

Conventionally, powdered drugs such as freeze-dried products are sealed in vials, and if necessary, a drug solution is mixed and dissolved with a syringe to prepare a drug solution, and the drug in powder form can be administered and used. . As a method for producing such a drug solution, for example, a syringe filled with a solution in an outer cylinder is used, and an injection needle attached to a nozzle of an outer cylinder of the syringe is sealed with a vial containing a powdered drug. The syringe is pierced, the plunger of the syringe is pushed in the direction of the nozzle at the tip of the outer cylinder, the dissolving solution is sent into the vial, and the drug in powder form is dissolved and mixed in the vial to produce a drug solution. By performing an operation of pulling in the proximal direction, the medicinal solution prepared in the outer cylinder of the syringe is inhaled, and the medicinal solution can be administered. Further, as an injection having a different form, a prefilled syringe in which an administrable drug solution is filled in an outer cylinder in advance is also known.

Here, a gasket that seals between the inner wall of the outer cylinder and the plunger in a liquid-tight and slidable manner for accommodating a drug solution is generally attached to the tip of the plunger of the syringe on the outer cylinder nozzle side. . Then, silicone oil is applied as a lubricant to the outer surface of the gasket or the inner surface of the outer cylinder for the purpose of smoothly sliding the inner surface of the outer cylinder and the outer peripheral portion of the gasket during the preparation or administration of the drug solution. (Patent Document 1 (Japanese Patent Laid-Open No. 2-36881)). Further, Patent Document 1 discloses an adsorbent such as a fiber or a porous material having an adsorbing property to silicone oil in order to prevent silicone oil from being mixed into a liquid discharged at the time of administration of a chemical solution. There is disclosed a technique for attaching to a liquid flow path of a syringe. In addition, Patent Document 1 does not specifically describe a main drug component contained in a prepared and administered drug solution.

On the other hand, Non-Patent Document 1 (Kenji Yamane, Multiphase Flow, Vol. 29, No. 1 (2015)) discloses a cotton-like substance formed by reducing the solubility of the main drug component due to the effect of silicone oil during preparation of paclitaxel injection. Further, it is disclosed that insoluble suspended matter can be expected to be removed by filtering at a medical site. Specifically, the risk of the above insoluble suspended matter becoming a clinical problem is extremely low by administration through a drip line equipped with an in-line filter using a 0.22 μm membrane filter in the drip line. Is disclosed.

薬剤 By the way, drugs provided in the form of pre-filled syringes or freeze-dried preparations for use at the time of use include protein preparations also called bio preparations. The present inventors have particularly studied protein preparations provided as lyophilized products. During preparation (re-dissolution) of the preparation using a lysis solution, the protein components of the preparation aggregate to form aggregates. I found that sometimes. It has also been found that the formation of such aggregates occurs remarkably when the solution can come into contact with the silicone oil in the syringe filling chamber (that is, the silicone oil causes aggregation of the protein preparation). Was. Since the aggregate of the protein preparation has immunogenicity, it is not preferable to administer the aggregate as it is in a living body. Also, silicone oil itself has immunogenicity. Therefore, it is required to prevent silicone oil from being administered into a living body.

Therefore, the present invention provides a simple method for removing a silicone oil mixed into a syringe filling chamber for any reason and an aggregate of a protein preparation generated due to the silicone oil when administering a medical liquid containing the protein preparation. It is intended to provide means that can be used.

The present inventors have conducted intensive studies to solve the above-mentioned problems. As a result, surprisingly, the medical liquid containing the protein preparation and mixed with the silicone oil is passed through a filter having a predetermined pore size (equivalent diameter of the average pore diameter), whereby the protein preparation is added to the silicone oil. It has been found that it is also possible to effectively remove the aggregates. Then, based on this finding, the present invention has been completed.

That is, one embodiment of the present invention is to administer a medical liquid containing a protein preparation using a syringe including a syringe outer cylinder and a gasket that can slide inside the syringe outer cylinder in a liquid-tight manner. The method for removing silicone oil from the medical liquid. Further, the method is characterized in that the method includes removing the silicone oil from the medical liquid by passing the medical liquid through a filter having an average pore diameter equivalent to a circle of 0.6 μm or less. Note that a filter having a predetermined pore size used in the above method is also within the scope of the present invention.

Another embodiment of the present invention relates to a medical liquid administration device. The device includes a syringe outer cylinder and a gasket that can slide inside the syringe outer cylinder in a liquid-tight manner, and a silicone oil is provided on the inner peripheral surface of the syringe outer cylinder or the outer peripheral surface of the gasket. And a prefilled syringe filled with a medical liquid containing a protein preparation in a filling chamber formed inside the syringe outer cylinder and the gasket. Then, when the medical liquid is administered using the prefilled syringe, the device is used for removing silicone oil from the medical liquid, and the circle equivalent diameter of the average pore diameter is 0.6 μm or less. It is characterized in that it further has a filter.

Still another embodiment of the present invention also relates to a medical liquid administration device. The device includes a vial holding a freeze-dried product of the protein preparation therein, and a syringe outer cylinder, and a gasket slidable inside the syringe outer cylinder in a liquid-tight manner. A prefilled syringe filled with a solution for dissolving or dispersing the lyophilized product is provided in a filling chamber formed inside the outer cylinder and the gasket. Then, when administering the medical liquid in which the protein preparation is dissolved or dispersed in the dissolving solution using the prefilled syringe, used to remove silicone oil from the medical liquid, a circle equivalent diameter of an average pore diameter. Is further provided with a filter having a particle size of 0.6 μm or less.

さらに Still another embodiment of the present invention relates to a filter used in the above-mentioned “method of removing silicone oil from medical liquid”. The filter is characterized in that the circle equivalent diameter of the average pore diameter is 0.6 μm or less.

FIG. 1 is a cross-sectional view of a vial constituting a medical liquid administration device according to one embodiment of the present invention. FIG. 2 is an external view of a prefilled syringe with a needle, which constitutes the medical liquid administration device according to one embodiment of the present invention. FIG. 3 is a sectional view taken along the line AA shown in FIG. FIG. 4 is an external view of a filter constituting the medical liquid administration device according to one embodiment of the present invention.

Hereinafter, the embodiments of the present invention described above will be described with reference to the drawings. However, the technical scope of the present invention should be determined based on the description of the claims, and is not limited to the following embodiments. Note that the dimensional ratios in the drawings are exaggerated for the sake of explanation, and may differ from the actual ratios.

FIG. 1 is a cross-sectional view of a vial constituting a medical liquid administration device according to an embodiment of the present invention.

The vial 1 includes a vial body 11 having an opening, a rubber stopper 12 attached to the opening of the vial body 11 as a sealing member for sealing the opening, and a protein preparation held inside the vial body 11. And a freeze-dried product 3 of the above.

{Circle around (2)} The vial 1 is capable of injecting a solution therein. Specifically, the vial 1 includes a solution injection space 15 therein. The inside of the vial 1 is depressurized. As the lysing solution, for example, water for injection is used.

The vial body 11 may be any as long as it has an opening and can store the freeze-dried product 3 of the protein preparation therein. For example, a vial made of hard or semi-hard synthetic resin, a glass vial, or the like is used. The vial main body 11 includes a cylindrical main body 13 having a closed lower end, an opening 14 having a thick flange, and a neck having a smaller diameter than other portions formed between the opening 14 and the main body 13. , Is provided. The neck portion from the opening 14 of the vial body 11 is a storage portion for storing the in-container entry portion of the rubber stopper 12 extending with the same inner diameter. In addition, as the rubber stopper, the rubber stopper is attached to the vial body 11 so that the rubber stopper does not fall into the vial body 11 from the neck when the rubber stopper is attached to the distal end side of the container inlet part. The vial body 11 has a large diameter portion having substantially the same diameter as the outer diameter of the flange.

Examples of the hard or semi-hard synthetic resin capable of forming the vial body 11 include various commonly used hard plastic materials, for example, polyolefin such as polypropylene, polyethylene, poly (4-methylpentene-1), cyclic olefin polymer and cyclic olefin copolymer. And polyesters such as polyethylene terephthalate, polyethylene naphthalate, and amorphous polyalate, polystyrene, polyamide, polycarbonate, polyvinyl chloride, acrylic resin, acrylonitrile-butadiene-styrene copolymer, and amorphous polyetherimide. Particularly, polypropylene, poly (4-methylpentene-1), cyclic olefin polymer, cyclic olefin copolymer, polyethylene naphthalate, and amorphous polyetherimide are preferable in terms of transparency and heat sterilization resistance.

The vial 1 shown in FIG. 1 includes a covering member 16 to which a rubber stopper 12 is attached and covers the peripheral portion of the opening 14 of the vial main body 11 and the peripheral portion of the rubber stopper 12. The covering member 16 is formed of aluminum, a heat-shrinkable film, or the like, and is in close contact with the rubber stopper 12 and the vial body 11 such that the large-diameter portion of the rubber stopper 12 is compressed and fixed to the flange. Is preferred. The covering member 16 may cover the entire upper surface of the rubber stopper 12 as long as a puncture needle such as an injection needle can puncture the same. In the embodiment shown in FIG. 1, the covering member 16 includes an annular portion and a thin disk-shaped upper surface portion, and the lower end portion of the annular portion covers the annular lower surface of the opening flange portion of the vial body 11. I have.

FIG. 2 is an external view of a prefilled syringe with a needle that constitutes the medical liquid administration device according to one embodiment of the present invention. FIG. 3 is a sectional view taken along the line AA shown in FIG.

As shown in FIGS. 2 and 3, the prefilled syringe 10 includes a syringe-equipped outer cylinder 2, a sealing member (cap) 6 attached to a distal end (needle part) of the outer cylinder 2, and an outer cylinder 2. A gasket 5 housed in the inner cylinder 2 and capable of sliding inside the outer cylinder 2 in a liquid-tight manner, a plunger 7 mounted on the gasket 5, and a filling chamber formed inside the outer cylinder 2 and the gasket 5 And the above-described dissolving solution 4.

針 A needle tube 8 is fixed to the outer cylinder 2 with a needle. The outer diameter of the needle tube 8 is preferably 0.41 to 0.18 mm. The needle tube 8 has a lumen penetrating from the distal end to the proximal end. Further, the needle tube 8 has a needle tip at a distal end, which is punctured into a living body. The needle tip is formed at an acute angle with a blade surface. The distal end portion of the needle tube 8 including the needle tip protrudes from the distal end of the distal end portion 22 of the outer tube 2, and the base end of the needle tube 8 penetrates the needle insertion hole and reaches the inside of the outer tube 2. .

Needle tube 8 is preferably a metal needle tube. As the metal material, for example, stainless steel is preferable. However, the present invention is not limited to this, and aluminum, aluminum alloy, titanium, titanium alloy and other metals can be used. As the needle tube 8, not only a straight needle conforming to the ISO standard as described above, but also a tapered needle partially tapered can be used.

The outer cylinder 2 includes a main body 21 filled with a medicine, and a distal end 22 having a needle insertion hole. The main body 21 is formed in a substantially cylindrical shape having an internal storage portion. A flange 23 is formed on the rear end side of the main body 21 in the axial direction.

The distal end portion 22 includes a distal end bulging portion, and a tubular portion connecting the distal end bulging portion and the distal end of the main body portion 21. Further, the distal end portion 22 has a needle insertion hole penetrating therethrough. The needle insertion hole has a base end of the needle tube 8 and is formed integrally with the outer cylinder by means such as insert molding.

キャップ And the cap 6 is formed in a cylindrical shape, the base side in the axial direction is open, and the tip in the axial direction is closed. The cap 6 is formed from, for example, an elastic member such as rubber or elastomer. The cap 6 is attached to the distal end 22 of the outer cylinder 2 so as to cover the needle tip of the needle tube 8 and the distal end 22 of the outer cylinder 2. Then, as shown in FIG. 2, the needle tube 8 and the distal end portion 22 of the outer cylinder 2 are inserted into the lumen 62 of the cap 6.

The inner diameter of the inner cavity 62 of the cap 6 is formed to be substantially equal to the outer diameter of the tip bulge at the tip or slightly smaller than the tip bulge. Therefore, when the cap 6 is attached to the distal end portion 22 of the outer cylinder 2, the outer peripheral surface of the distal end bulging portion comes into close contact with the inner peripheral surface of the cap 6. Therefore, the space that covers the needle tube 8 protruding from the outer cylinder 2 is sealed by the distal end bulging portion and the inner peripheral surface of the cap 6. With this configuration, it is possible to prevent bacteria from adhering to the needle tip. The distal end portion 81 of the needle tube 8 is mounted so as to seal the distal end opening of the lumen with the cap 6.

環状 The annular rib 63 provided on the inner peripheral surface of the cap 6 tightens a narrow portion at the boundary between the tip bulging portion and the tapered fitting portion of the tip portion 22 of the outer cylinder 2 by its elastic force. In this manner, the inner peripheral surface of the cap 6 and the constricted portion of the distal end portion 22 of the outer cylinder 2 are engaged, and the cap 6 is prevented from detaching from the distal end portion 22 of the outer cylinder 2 during transport. The plunger 7 includes a main body 71, a gasket mounting portion 72 formed at a distal end of the main body 71, and a pressing portion 73 provided at a base end. Further, the gasket 5 includes a plunger mounting portion that receives and engages with the gasket mounting portion 72 of the plunger 7.

水 Water for injection is used as the solution 4. However, other liquids (for example, physiological saline) may be used as the dissolving liquid. The prefilled syringe according to the present embodiment is subjected to high-pressure steam sterilization while being filled with the solution. The high-pressure steam sterilization is performed by exposing a prefilled syringe filled with a solution to high-pressure steam at 100 to 122 ° C. for about 15 to 30 minutes.

The outer cylinder 2 is preferably made of a synthetic resin. Examples of the material for forming the outer cylinder 2 include transparent or translucent materials, and are preferably formed of a material having low oxygen permeability and low water vapor permeability. Examples of the material for forming the outer cylinder 2 include polypropylene, polyethylene, polystyrene, polyamide, polycarbonate, polyvinyl chloride, poly- (4-methylpentene-1), acrylic resin, acrylonitrile-butadiene-styrene copolymer, and polyethylene terephthalate. Various resins such as polyesters, cyclic olefin polymers, and cyclic olefin copolymers are exemplified. Among them, resins such as polypropylene, cyclic olefin polymers, and cyclic olefin copolymers are preferable because they are easily molded and have heat resistance.

As shown in FIG. 2, the gasket 5 has a main body portion extending with substantially the same outer diameter and an annular rib provided on the main body portion (two in this embodiment, an appropriate number if liquid-tightness and slidability are satisfied). These ribs come into contact with the inner surface of the outer cylinder 2 in a liquid-tight manner. The distal end surface of the gasket 5 has a shape corresponding to the shape of the distal end inner surface of the outer cylinder 2 so that when the gasket 5 comes into contact with the inner surface of the distal end of the outer cylinder 2, no gap is formed between them.

Examples of the material for forming the gasket 5 include rubber having elasticity (for example, butyl rubber, latex rubber, and silicone rubber), synthetic resin (for example, styrene-based elastomer such as SBS elastomer and SEBS elastomer, and ethylene-α-olefin copolymer). It is preferable to use an olefin-based elastomer such as an elastomer. In particular, those formed of butyl rubber are preferred.

(4) The gasket 5 may have a low drug-adsorbing film in a portion that comes into contact with the solution 4. As the material for forming the low drug-adsorbing film, known materials conventionally used for laminate gaskets can be used. Examples of the low drug adsorption coating material include polyolefin-based resins, fluorine-based resins, polyester-based resins, and polyparaxylylene. Specifically, the polyolefin resin is preferably polypropylene, ultra-high molecular weight polyethylene, poly (4-methylpentene-1), a cyclic olefin polymer, a cyclic olefin copolymer, or the like. Preferred are fluoroethoxyethylene copolymer, polytetrafluoroethylene, tetrafluoroethylene / perfluoroalkylvinyl ether copolymer, tetrafluoroethylene / hexafluoropropylene copolymer, and the like.

Further, in the present embodiment, a required amount of silicone oil as a lubricant is disposed on the outer peripheral surface of the gasket 5 by a method such as coating, spraying or dipping. However, the silicone oil may be arranged on the inner surface of the outer cylinder 2. Further, silicone oil may be disposed on both the outer peripheral surface of the gasket 5 and the inner surface of the outer cylinder 2. Here, "the silicone oil is disposed" means that the gasket inserted into the outer cylinder slides easily while maintaining a liquid-tight state with respect to the inner surface of the outer cylinder, as understood from the above description. To apply the silicone oil to the gasket outer peripheral surface and / or the inner surface of the outer cylinder in such a manner that the silicone oil is applied by means such as coating, spraying or dipping.

The gasket 5 is provided with a concave portion extending from the rear end to the inside. The concave portion has a female screw shape, and a male screw formed on an outer surface of a protruding portion formed on the distal end portion 72 of the plunger 7. It can be screwed with the part. The plunger 7 is fixed to the gasket 5 by screwing them together. The plunger 7 is not attached, and may be attached at the time of use.

The plunger 7 is provided with a protrusion 72 protruding in a cylindrical shape at the disk portion at the tip, and a male screw to be screwed with the recess of the gasket 5 is formed on the outer surface of the protrusion. Further, the plunger 7 includes a main body portion having a cross-shaped cross section and extending in the axial direction, and a pressing disk portion (pressing portion) 73 provided at a rear end portion.

では In the prefilled syringe 10 according to the embodiment shown in FIGS. 2 and 3, it is possible to discharge the solution by operating the plunger 7. Therefore, the lysing solution can be injected into the lysing solution injection space 15 inside the vial 1 by piercing the needle tube 8 into the rubber stopper 12 of the vial 1 and pressing the plunger in that state. The drug solution can be prepared by removing the needle tube 8 from the rubber stopper 12 after injecting the solution, or by thoroughly mixing the solution and the lyophilized product 3 of the protein preparation without removing the needle tube 8 as it is. it can. Then, with the needle tube 8 pierced into the rubber stopper 12 of the vial 1 again, the plunger is pulled while the tip of the needle tube 8 is always below the level of the drug solution, thereby filling the syringe with the drug solution. can do. In this way, the syringe is ready to administer the drug solution.

FIG. 4 is an external view of a filter constituting the medical liquid administration device according to one embodiment of the present invention.

The filter 100 includes a filter main body 110 formed of a membrane filter, an upper flow path 120 capable of supplying a substance to be filtered to the filter main body 110, and a filtration target supplied from the upper flow path 120 and filtered by the filter main body 110. And a lower passage 130 from which the fluid is discharged. In addition, the filter 100 according to the embodiment shown in FIG. 4 further includes a connection portion 140 for connecting to a catheter.

Since the membrane filter constituting the filter body has a large number of pores, it is possible to remove coarse particles contained in the material to be filtered. Here, the circle equivalent diameter of the average pore diameter of the pores is set to 0.6 μm or less. Here, the “equivalent circle diameter” is a parameter expressing the diameter of a non-circular shape, and means the diameter of a perfect circle having an area equal to the area of the shape. In addition, as a value of the circle equivalent diameter of the average pore diameter of the pores of the filter, a value calculated by a method described in the section of Examples described later is adopted. The value of the circle equivalent diameter of the average pore diameter of the pores is preferably 0.58 μm or less, more preferably 0.5 μm or less, and still more preferably 0.40 μm or less. The lower limit of this value is not particularly limited, but is preferably 0.10 μm or more, more preferably 0.20 μm or more, and further preferably 0.3 μm or more.

構成 The constituent material of the membrane filter is not particularly limited, but is generally made of resin. Especially, it is preferable to be comprised from resin, and it is preferable to be comprised from polyether sulfone (PES) or polyvinylidene fluoride (PVDF). Further, the constituent material of the membrane filter is preferably a hydrophilic material, and more preferably a hydrophilic resin. Above all, it is particularly preferable to be composed of hydrophilic PES or hydrophilic PVDF. In this specification, “a material is hydrophilic” means that a contact angle of water with respect to a sheet made of the material is 90 ° or less.

The value of the bubble point pressure of the membrane filter is not particularly limited, but is preferably 3 bar or more, more preferably 3.4 bar or more. The lower limit of the bubble point pressure is not particularly limited, but is preferably 10 bar or less.

As described above, according to the study of the present inventors, a medical liquid containing a protein preparation and mixed with silicone oil is passed through a filter having a circle equivalent diameter of the average pore diameter of the pores of 0.6 μm or less. As a result, they have found that, in addition to silicone oil, it is possible to effectively remove aggregates of protein preparations. The mechanism is not completely clear, but the following mechanism is presumed. That is, it is considered that the protein aggregate is removed by the sieving effect of the filter. On the other hand, since the silicone oil particles also show the same size distribution as the protein aggregate, it is conceivable that the silicone oil particles are captured in the same manner as the protein aggregate from the size. However, it is also assumed that the silicone oil particles are easily deformed from the original sphere by the filtration pressure and pass through the pores of the filter. The silicone oil does not wet the membrane of the hydrophilic filter due to its hydrophobic nature. Therefore, when a filter made of a hydrophilic material is used, an increase in the wetting angle of the silicone oil with respect to the pores of the filter is also considered to be a factor that traps the silicone oil.

In the medical liquid containing the protein preparation and the silicone oil mixed therein, the presence mode of the silicone oil and the protein aggregate may be either a case where both are present independently or a case where both are combined to form a complex. And both. According to the present invention, even in the latter case, it is considered that the above-described mechanism works for each substance, and even if both exist in the form of a complex, they are efficiently removed.

When the medical liquid administration device according to the embodiment shown in FIGS. 1 to 4 is used, the medical fluid is prepared as described above, and then, when the prepared medical fluid is administered, the medical fluid passes through the filter 100. Thus, the medicinal solution may be administered. As an example, the needle tube 8 is removed from the syringe outer cylinder 2 after the chemical solution is prepared, and the filter 100 is used for the syringe so that the upper channel 120 of the filter 100 is located on the side of the syringe outer cylinder 2 instead. It is joined to the outlet of the outer cylinder 2. On the other hand, the other end of the catheter having the winged needle installed at one end is connected to a connection portion 140 provided in the lower flow passage 130 of the filter 100. Thus, the medicinal solution can be administered by pressing the plunger 7 of the syringe. At this time, the medicinal solution can be administered after passing through a filter 100 having a predetermined pore size. Therefore, it is possible to effectively remove aggregates of the silicone oil and the protein preparation contained in the drug solution.

(Protein preparation)
The protein preparation is not particularly limited as long as it is a preparation containing a main drug composed of a peptide or a protein. Examples include immunoglobulin preparations such as various monoclonal antibodies (IgG, IgM, etc.), albumin preparations, blood coagulation factor preparations, interferons, various hormones (growth hormone, erythropoietin, etc.), various enzymes, glycoproteins, PEGylated proteins, etc. No. Here, blood coagulation factor preparations in particular include blood coagulation factor VIII preparation, blood coagulation factor IX preparation, fibrinogen preparation, antithrombin III preparation and the like. As described above, according to the study of the present inventors, remarkable formation of aggregates was confirmed particularly when the protein preparation was brought into contact with silicone oil. Therefore, the method for removing silicone oil using a predetermined filter according to the present invention is particularly useful for removing silicone oil and protein aggregates when administering a protein preparation. Above all, congenital blood coagulation factor VIII disorder (hemophilia A) is a type of abnormal blood coagulation, and it is estimated that there are approximately 400,000 patients worldwide. As a treatment for hemophilia A, injection of a blood coagulation factor VIII preparation is common, but two to three injections a week are required, so that home treatment and self-injection are basic. . Therefore, by applying the present invention, penetration of silicone oil into the body during self-injection at home can be prevented, and various symptoms caused by the immunogenicity of silicone oil and protein aggregates can be prevented. Becomes possible.

In the embodiment shown in FIGS. 1 to 4, an example is described in which a drug solution is prepared by re-dissolving a lyophilized protein preparation held in a vial 1 using a dissolving solution. As described above, in this embodiment, the silicone oil is disposed on the inner surface of the vial 1 or the inner surface of the rubber stopper 12 of the vial 1, not on the inner peripheral surface of the syringe outer cylinder 2 or the outer peripheral surface of the gasket 5. You may.

In addition, instead of re-dissolving the lyophilized product, it is provided as a pre-filled syringe filled in a syringe filling chamber in the form of a drug solution in which a protein preparation is dissolved in an appropriate solvent in a state where it can be administered. In this case, the present invention is applicable.

Furthermore, in the above-described embodiment, when administering the drug solution, the filter 100 is joined to the outlet of the syringe outer cylinder 2 and the catheter is further joined to the filter 100 as an example. One end of the catheter may be first joined to the 12 outlets, and the filter 100 may be joined to the other end of the catheter.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the technical scope of the present invention is not limited only to the following examples. In the following experimental examples, a freeze-dried product of a blood coagulation factor VIII preparation (Kogenate (registered trademark) FS, manufactured by Bayer AG) was used as a model drug, which was used for medical treatment shown in FIGS. The performance of removing aggregates of silicone oil and protein from a drug solution (medical liquid) obtained by re-dissolving using a liquid administration device was evaluated for filters having various specifications shown in Table 1 below. .

The value of the equivalent circle diameter of the pores of the filter was determined by observing the filter surface using an electron emission scanning electron microscope (FE-SEM) and determining the area of the pores obtained from the binarization analysis of the image. , Calculated as the diameter of a circle having an area equal to the area.

(Example 1)
The lyophilized product was redissolved using 2.5 mL of the attached lysis solution to prepare a drug solution. Next, the whole amount of the prepared drug solution was sucked into the syringe. Then, as a syringe filter, Millex (registered trademark) -GP (manufactured by Merck Millipore, SLGP033RS; manufactured by hydrophilic polyethersulfone (PES), nominal pore diameter 0.22 μm, total area 4.5 cm ² , circle of average pore diameter An equivalent diameter of 0.580 μm and a bubble point pressure of 3.8 bar or more) was attached to the outlet of the syringe. The contact angle of water with respect to the hydrophilic PES sheet used in the present syringe filter is 90 ° or less. Further, a catheter for a Surface Shielded Winged Infusion set (manufactured by Terumo, SV ^* S25BL) was connected to the outlet of the syringe filter to form a device for medical liquid administration.

薬 By pushing the plunger of the syringe that constitutes this device, the drug solution was sent through the filter and the catheter, and the solution obtained from the tip of the catheter was collected. The concentration of the silicone oil particles and the concentration of the protein aggregate particles were measured using an Archimedes analyzer (manufactured by Malvern) for the obtained recovered liquid. In addition, as a control, the same measurement was performed on the discharged liquid from the syringe before passing through the syringe filter. Then, a decrease rate to a measured concentration value when the concentration in the control was set to 100% was calculated. The results are shown in Table 2 below. In addition, this reduction ratio indicates the ratio of the difference in which the concentration of the control was reduced when the control concentration was passed through the filter and the catheter.The larger the reduction ratio, the better the silicone oil and protein aggregate removal performance. Means.

(Example 2)
The lyophilized product was redissolved using 2.5 mL of the attached lysis solution to prepare a drug solution. Next, the whole amount of the prepared drug solution was sucked into the syringe. Thereafter, a syringe filter, Millex (registered trademark) -GV (manufactured by Merck Millipore, SLGV033RS; manufactured by hydrophilic polyvinylidene fluoride (PVDF), nominal pore size 0.22 μm, total area 4.5 cm ² , circle of average pore size (Equivalent diameter: 0.389 μm, bubble point pressure: 3.4 bar or more) was attached to the outlet of the syringe. The contact angle of water with respect to the hydrophilic PVDF sheet used in the present syringe filter is 90 ° or less. Further, a catheter for a Surface Shielded Winged Infusion set (manufactured by Terumo, SV ^* S25BL) was connected to the outlet of the syringe filter to form a device for medical liquid administration.

薬 By pushing the plunger of the syringe that constitutes this device, the drug solution was sent through the filter and the catheter, and the solution obtained from the tip of the catheter was collected. The concentration of the silicone oil particles and the concentration of the protein aggregate particles were measured using an Archimedes analyzer (manufactured by Malvern) for the obtained recovered liquid. Then, the decrease rate was calculated in the same manner as above. The results are shown in Table 2 below.

(Example 3)
The lyophilized product was redissolved using 2.5 mL of the attached lysis solution to prepare a drug solution. Next, the whole amount of the prepared drug solution was sucked into the syringe. Then, as a syringe filter, Millex (registered trademark) -VV (manufactured by Merck Millipore, SLVV033RS; manufactured by hydrophilic polyvinylidene fluoride (PVDF), nominal pore size: 0.1 μm, total area: 4.5 cm ² , circle of average pore size) (Equivalent diameter 0.354 μm, bubble point pressure 4.83 bar or more) was attached to the outlet of the syringe. The contact angle of water with respect to the hydrophilic PVDF sheet used in the present syringe filter is 90 ° or less. Further, a catheter for a Surface Shielded Winged Infusion set (manufactured by Terumo, SV ^* S25BL) was connected to the outlet of the syringe filter to form a device for medical liquid administration.

(Comparative Example 1)
The lyophilized product was redissolved using 2.5 mL of the attached lysis solution to prepare a drug solution. Next, the whole amount of the prepared drug solution was sucked into the syringe. Thereafter, without attaching a syringe filter, a catheter of a Surface Shielded Wing Infusion set (manufactured by Terumo Corporation, SV ^* S25BL) was connected to the outlet of the syringe filter to configure a device for medical liquid administration.

(Comparative Example 2)
The lyophilized product was redissolved using 2.5 mL of the attached lysis solution to prepare a drug solution. Next, the whole amount of the prepared drug solution was sucked into the syringe. Thereafter, a catheter for a Surflo Winged Infusion set (manufactured by Terumo Corporation, SV-S25FL35) was connected to the outlet of the syringe to form a medical liquid administration device. This catheter was provided with an in-line filter (made of nylon-6, 6) having a nominal pore diameter of 20 μm (equivalent circle diameter: 45 μm).

From the results shown in Table 2, in Examples 1 to 3 in which the drug solution was filtered using a filter having an average pore diameter equivalent to a circle of 0.6 μm or less, the aggregates of silicone oil and protein contained in the drug solution were extremely low. It can be seen that it is effectively removed.

This application is based on US Provisional Application No. 62 / 712,568, filed July 31, 2018, the disclosure of which is incorporated by reference in its entirety.

Claims

When administering a medical liquid containing a protein preparation using a syringe including a syringe outer cylinder and a gasket capable of sliding the inside of the syringe outer cylinder in a liquid-tight manner, A method for removing silicone oil,
A method comprising removing silicone oil from the medical fluid by passing the medical fluid through a filter having an average pore diameter equivalent to a circle of 0.6 μm or less.
The method according to claim 1, wherein the syringe is a prefilled syringe stored in a state where the medical liquid is filled in a filling chamber formed inside the syringe outer cylinder and the gasket.
The method according to claim 2, wherein the silicone oil is derived from silicone oil disposed on an inner peripheral surface of the syringe outer cylinder or an outer peripheral surface of the gasket.
2. The method according to claim 1, wherein, when administering the medical liquid, the method further comprises preparing the medical liquid before use by dissolving or dispersing a lyophilized product of the protein preparation in a dissolving liquid.
The method according to claim 4, wherein the silicone oil is derived from silicone oil disposed on an inner peripheral surface of the syringe outer cylinder or an outer peripheral surface of the gasket.
Preparing the medical fluid at the time of use by introducing or dissolving or dispersing the lyophilized product into the vial holding the lyophilized product therein,
Filling the prepared medical liquid into a filling chamber formed inside the syringe outer cylinder and the gasket,
The method according to claim 4, further comprising:
7. The method of claim 6, wherein the silicone oil is derived from a silicone oil disposed on an inner surface of the vial or an inner surface of a stopper of the vial.
The method according to any one of claims 1 to 7, wherein the protein preparation is a blood coagulation factor VIII preparation.
The filter is configured to be connectable to an outlet of the syringe,
The method according to any one of claims 1 to 8, further comprising joining the filter to an outlet of the syringe when removing the silicone oil from the medical liquid.
The outlet of the syringe is configured to be connectable to one end of the catheter,
The filter is configured to be connectable to the other end of the catheter,
9. The method according to claim 1, further comprising, when removing the silicone oil from the medical liquid, joining the filter to the other end of the catheter having the one end joined to an outlet of the syringe. Item 2. The method according to item 1.
The method according to any one of claims 1 to 10, wherein the constituent material of the filter is at least one of polyethersulfone and polyvinylidene fluoride.
The method according to any one of claims 1 to 10, wherein the constituent material of the filter is at least one of hydrophilic polyethersulfone and hydrophilic polyvinylidene fluoride.
A syringe outer cylinder, and a gasket capable of sliding inside the syringe outer cylinder in a liquid-tight manner, wherein a silicone oil layer is disposed on an inner peripheral surface of the syringe outer cylinder or an outer peripheral surface of the gasket. A prefilled syringe filled with a medical liquid containing a protein preparation in a filling chamber formed inside the syringe outer cylinder and the gasket,
When administering the medical liquid using the pre-filled syringe, used to remove silicone oil from the medical liquid, a filter having a circle equivalent diameter of an average pore diameter of 0.6 μm or less,
A medical liquid administration device, comprising:
The medical liquid administration device according to claim 13, wherein the filter is configured to be connectable to an outlet of the syringe.
One end further comprises a catheter configured to be connectable to the outlet of the syringe,
The medical liquid administration device according to claim 13, wherein the filter is configured to be connectable to the other end of the catheter.
A vial holding a lyophilized protein preparation inside,
A syringe outer cylinder, and a gasket that can slide inside the syringe outer cylinder in a liquid-tight manner, wherein the lyophilized product is dissolved in a filling chamber formed inside the syringe outer cylinder and the gasket. Or a prefilled syringe filled with a dissolving solution for dispersing,
When administering the medical liquid in which the protein preparation is dissolved or dispersed in the dissolving liquid using the prefilled syringe, the circle equivalent diameter of the average pore diameter used for removing silicone oil from the medical liquid is 0. .6 μm or less;
A medical liquid administration device, comprising:
The medical liquid administration device according to claim 16, wherein the filter is configured to be connectable to an outlet of the prefilled syringe.
One end further comprises a catheter configured to be connectable to the outlet of the prefilled syringe,
The medical liquid administration device according to claim 16, wherein the filter is configured to be connectable to the other end of the catheter.
デバイス The medical liquid administration device according to any one of claims 13 to 18, wherein the protein preparation is a blood coagulation factor VIII preparation.
20. The medical liquid administration device according to any one of claims 13 to 19, wherein the constituent material of the filter is at least one of polyethersulfone and polyvinylidene fluoride.
20. The method according to claim 13, wherein a constituent material of the filter is at least one of hydrophilic polyethersulfone and hydrophilic polyvinylidene fluoride.
A filter having a circle equivalent diameter of an average pore diameter of 0.6 μm or less,
A filter used in the method according to any one of claims 1 to 12.
23. The filter according to claim 22, wherein the constituent material is at least one of polyethersulfone and polyvinylidene fluoride.
24. The filter according to claim 23, wherein the constituent material is at least one of hydrophilic polyethersulfone and hydrophilic polyvinylidene fluoride.