WO2015147018A1

WO2015147018A1 - Injectable aqueous formulation for treating inflammatory autoimmune diseases

Info

Publication number: WO2015147018A1
Application number: PCT/JP2015/058993
Authority: WO
Inventors: 聖子福島; 宏司中村; のぞみ網; 誠司矢後
Original assignee: テルモ株式会社
Priority date: 2014-03-28
Filing date: 2015-03-24
Publication date: 2015-10-01
Also published as: JPWO2015147018A1

Abstract

An injectable aqueous formulation for treating inflammatory autoimmune diseases contains methotrexate or a pharmaceutically acceptable salt of methotrexate such that the methotrexate concentration is 25 mg/mL-100 mg/mL, and also contains a buffer and a tonicity agent. The injectable aqueous formulation has a pH of 7.0-8.0, and the osmotic pressure ratio of the injectable aqueous formulation with respect to physiological saline is 0.9-1.1.

Description

Injectable aqueous formulation for the treatment of inflammatory autoimmune diseases

The present invention relates to an injectable aqueous preparation for the treatment of inflammatory autoimmune diseases containing methotrexate.

Methotrexate is an antifolate antimetabolite and has been widely used for the treatment of various malignant tumors for a long time. Later, efficacy against rheumatoid arthritis was confirmed. As anti-rheumatic agents, “Rheumatrex (registered trademark) capsule 2 mg” (Pfizer Inc.), “Metolate (registered trademark) 2 mg” (Santen Co., Ltd.), etc. are used in Japan. Oral drugs are on sale.
The above oral drugs are usually administered at a dose of 6 mg as methotrexate per week, and if sufficient effects are not obtained even if administered for 4 to 8 weeks, the dose is increased by 2 to 4 mg. In Japan, the maximum dose is 16 mg per week. In the world, up to 30 mg per week is common. Since rheumatism is a chronic disease, it must be taken over a long period of time, and the effect may be diminished (escape phenomenon) during the course of treatment. In that case, it is said that the effect can be obtained again by increasing the amount of methotrexate (Non-patent Document 1).

It has been pointed out that oral methotrexate drugs have gastrointestinal disorders caused by the direct stimulation of the gastrointestinal mucosa, and the problem that the intestinal absorption is saturated and the bioavailability is reduced by increasing the dosage (Non-patent Document 2). ).
In addition, oral medicine may be difficult or refused to be taken by children, elderly people, etc. due to difficulty in drinking. Accordingly, a parenteral preparation capable of solving the above problems is desired.

Overseas, parenteral preparations have been proposed, and “Metoject (registered trademark)” (Medac) is a representative preparation. As for the administration method, any of subcutaneous injection, intramuscular injection, and intravenous injection is possible, but subcutaneous injection which does not need to search for a vein and does not destroy muscle tissue has become mainstream. JP 2009-544636 (Patent Document 1) relating to a parenterally administered preparation describes the use of methotrexate in the manufacture of a parenterally administered drug for treating an inflammatory autoimmune disease, wherein methotrexate is pharmaceutically acceptable. The use of which is present in a solvent at a concentration higher than 25 mg / ml. Patent Document 1 discloses an aqueous preparation using water for injection as a solvent, containing sodium chloride and sodium hydroxide, and adjusting the pH to 8.5 to 8.9.

Also, as a parenteral dosage formulation of methotrexate in Japan, an aqueous formulation having a pH of 8.0 to 9.0 containing sodium chloride and sodium hydroxide is marketed as in the case of Patent Document 1. However, in Japan, parenteral administration of methotrexate has been approved only for anticancer drugs, and has not been approved for rheumatism.

Special table 2009-544636

非 The above problems in taking can be solved by parenteral administration. However, it is said that a parenteral administration formulation of methotrexate as described above has a strong pain given to a patient at the time of injection. Pain caused by injection includes pain caused by needle puncture and pain caused by a drug solution. Pain due to puncture is not caused by the administered drug but occurs in general using the needle, and can be solved by selecting and improving the needle, such as making the needle thinner and reducing needle resistance. Is required.

The inventor of the present application diligently studied whether or not pain caused by a drug solution by injection can be reduced by improving the prescription of the drug.
As described above, in Patent Document 1 and a commercially available parenteral administration formulation of methotrexate, the pH is considerably high, and the inventor of the present application states that this high pH is a factor causing pain due to a drug solution. Found out. However, methotrexate is hardly soluble in water and is soluble in sodium hydroxide solution. However, even if it is once dissolved, it will precipitate if the pH is acidic.
Therefore, the present invention is an aqueous injection preparation for the treatment of inflammatory autoimmune diseases containing methotrexate, which has less pain due to the drug given to the patient at the time of injection, and no precipitation of methotrexate at the time of storage. The present invention provides an aqueous injectable preparation for the treatment of inflammatory autoimmune diseases that can be stored well.

What achieves the above object is as follows.
Methotrexate or a pharmaceutically acceptable salt of methotrexate containing methotrexate at a concentration of 25 mg / mL to 100 mg / mL, and further containing a buffer and an isotonic agent for the treatment of inflammatory autoimmune diseases The aqueous preparation for injection has a pH of 7.0 to 8.0, and the osmotic pressure ratio of the aqueous preparation for injection to physiological saline is 0.9 to 1.1. An injectable aqueous preparation for the treatment of inflammatory autoimmune diseases.

FIG. 1 is a front view of an example in which the aqueous injection preparation for treatment of inflammatory autoimmune disease of the present invention is applied to a prefilled syringe. FIG. 2 is a cross-sectional view of the prefilled syringe shown in FIG. FIG. 3 is an enlarged cross-sectional view of the tip portion of the prefilled syringe shown in FIG. FIG. 4 is a front view of an injectable aqueous preparation in a state where a prefilled syringe is housed and packaged. FIG. 5 is a plan view of the packaged aqueous injectable preparation shown in FIG. FIG. 6 is a front view of another embodiment in which the aqueous injection preparation for treatment of inflammatory autoimmune disease of the present invention is applied to a prefilled syringe with a needle. 7 is a cross-sectional view taken along line AA in FIG. FIG. 8 is a graph showing experimental results. FIG. 9 is a graph showing experimental results.

The aqueous injection preparation for treatment of inflammatory autoimmune diseases of the present invention will be described with reference to an example in which it is applied to a prefilled syringe with a needle.
The injectable aqueous preparation for the treatment of inflammatory autoimmune disease of the present invention contains methotrexate or a pharmaceutically acceptable salt of methotrexate as methotrexate so as to have a concentration of 25 mg / mL to 100 mg / mL, and further a buffering agent And contains an isotonic agent. The aqueous preparation for injection has a pH of 7.0 to 8.0, and the osmotic pressure ratio of the aqueous preparation for injection to physiological saline is 0.9 to 1.1.

The aqueous injectable preparation of the present invention is an injection prepared by formulating it into a state suitable for parenteral administration of methotrexate, which is an active ingredient of an oral drug already on the market, and adjusting it to be suitable for treating inflammatory autoimmune diseases. Aqueous preparation.

In the present invention, methotrexate or a pharmaceutically acceptable salt of methotrexate is used.
Methotrexat (N- {4-[(2,4-diaminopteridin-6-ylmethyl) (methyl) amino] -benzoyl} -L-glutamic acid) is a drug classified as an antifolate. In the present invention, methotrexate itself is preferably used, but a pharmaceutically acceptable salt of methotrexate may be used.

Examples of pharmaceutically acceptable salts of methotrexate include base addition salts and acid addition salts. Pharmaceutically acceptable base addition salts of methotrexate include sodium cation (Na ⁺ ), potassium cation (K ⁺ ), magnesium cation (Mg ²⁺ ), calcium cation (Ca ²⁺ ) and similar salts and N, N ′ -Salts with suitable amines such as dibenzylethylenediamine, chloroprocaine, chlorin, diethaneethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine.

Also, pharmaceutically acceptable acid addition salts of methotrexate include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and fats. Included are salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkane acids, aromatic acids, aliphatic and aromatic sulfonic acids.
In addition, as a pharmaceutically acceptable salt of methotrexate, sodium methotrexate is preferable.

The injectable aqueous preparation of the present invention is an aqueous preparation based on water (for example, purified water, water for injection, sterile purified water, etc.), and methotrexate or a pharmaceutically acceptable salt of methotrexate as methotrexate. It is contained so that the concentration is 25 mg / mL to 100 mg / mL. In addition, it is set as said density | concentration from the viewpoint of administering the exact quantity considering the residual liquid to the syringe and needle | hook used for injection as an aqueous formulation for injection which is parenteral administration, from the viewpoint of reducing pain. The content concentration is preferably 25 mg / mL to 65 mg / mL.

In addition, the aqueous preparation for injection of the present invention contains a buffer and has a pH adjusted to 7.0 to 8.0. As the buffer, a general buffer such as a phosphate buffer such as disodium hydrogen phosphate or sodium dihydrogen phosphate, a citrate buffer, or a tris buffer can be used. Moreover, the aqueous preparation for injection may contain a pH adjuster. As the pH adjuster, sodium hydroxide, hydrochloric acid or the like can be used. The pH of the aqueous preparation of the present invention is adjusted to 7.0 to 8.0.

Furthermore, the injectable aqueous preparation of the present invention contains an isotonic agent, and the osmotic pressure ratio of the injectable aqueous preparation to physiological saline is adjusted to 0.9 to 1.1. The osmotic pressure ratio can be measured, for example, according to the method described in the section of the osmotic pressure measurement method (osmolarity measurement method) of the 16th revision Japanese Pharmacopoeia.
Examples of isotonic agents include ionic tonicity agents and nonionic tonicity agents. Examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like. Examples of nonionic tonicity agents include saccharides such as sucrose and glucose, sugar alcohols such as mannitol and sorbitol, glycerin, and propylene glycol.
In addition, the decomposition product amount of the injectable aqueous preparation of the present invention is 0, which is a threshold value that requires confirmation of safety calculated from the maximum daily dose according to the International Pharmaceutical Regulation Guidelines (ICH-Q3B (R2)). The amount is preferably not more than 5%.

The aqueous injection preparation of the present invention can be prepared as follows.
Prepare water for injection, create an aqueous solution with disodium hydrogen phosphate added to it, and an aqueous solution with the same M (molar) concentration, with sodium dihydrogen phosphate added to water for injection. Prepare phosphate buffer by diluting with water for injection. It is preferable that disodium hydrogen phosphate solution: sodium dihydrogen phosphate solution = 61: 39 to 95: 5 in the phosphate buffer. The phosphate buffer is preferably 1 to 100 mM phosphate buffer.

Then, methotrexate and sodium chloride as an isotonic agent are added to the above phosphate buffer. Furthermore, the aqueous injection preparation of the present invention can be prepared by adjusting the pH with an appropriate amount of sodium hydroxide as a pH adjuster. The prepared aqueous preparation for injection is preferably filtered using a membrane filter.

And the aqueous formulation for injection produced as mentioned above is accommodated in a container body. As a container body, a thing provided with a container main body and the rubber-like elastic body (plug body) with which the container main body was equipped is used suitably. Moreover, as a container main body, the thing made from a synthetic resin is preferable. As the rubber-like elastic body (plug body), those formed of butyl rubber are suitable.
A vial and a syringe are conceivable as the container body as described above.

In the examples shown in FIGS. 1 to 3, the aqueous preparation for injection for the treatment of inflammatory autoimmune disease of the present invention is applied to a prefilled syringe.
In this example, the pre-filled syringe 1 is an aqueous injection preparation. The syringe 2 used in the prefilled syringe 1 includes an outer cylinder 21, a gasket 22 that is slidably housed in the outer cylinder 21 and seals the rear end side of the outer cylinder, and the tip of the syringe 2. And a sealing member 23 for sealing the side.

And as the outer cylinder 21, the thing made from a synthetic resin is preferable. The gasket 22 is preferably made of butyl rubber. Moreover, as an outer cylinder used for the prefilled syringe 1, what is provided with the injection needle attached to the front-end | tip part (injection needle integrated outer cylinder) may be sufficient. In this case, the outer diameter of the injection needle is preferably 0.42 mm or less.
The syringe 2 is preferably subjected to a slidability improving process for improving the slidability of the gasket 22 with respect to the inner surface of the outer cylinder 21. The slidability improving treatment is preferably performed by applying a coating or coating of a slidability improving substance on the inner surface of the outer cylinder 21 or the outer surface of the gasket 22.

The prefilled syringe 1 of the embodiment shown in FIGS. 1 to 3 includes a syringe 2 and an injection solution 3 filled in the syringe 2 as shown in FIG. For the injection solution 3, the above-described aqueous preparation for injection is used.
As shown in FIG. 1, the syringe 2 is attached to the outer cylinder 21, the gasket 22 slidably accommodated in the outer cylinder, and the injection needle mounting portion 31 of the outer cylinder 21, and is hermetically sealed. It comprises a seal cap (sealing member) 23 and a plunger 24 attached to the gasket 22.
The injection solution 3 is stored in a space formed by the outer cylinder 21, the gasket 22, and the seal member 32 stored in the seal cap 23.

The outer cylinder 21 includes an outer cylinder main body portion 30, a syringe needle attachment portion 31 provided at the distal end portion of the outer cylinder main body portion 30, and a flange portion 34 provided at the rear end portion of the outer cylinder main body portion 30. The outer cylinder 21 is transparent or translucent. The outer cylinder main body 30 is a substantially cylindrical portion that accommodates the gasket 22 in a liquid-tight and slidable manner. Further, the distal end portion (shoulder portion) of the outer cylinder main body portion 30 is tapered toward the injection needle mounting portion 31 in a tapered shape.

The injection needle mounting part 31 includes a nozzle part 35 and a collar part 36 as shown in FIGS. As shown in FIG. 2, the nozzle portion 35 is a tip portion for mounting an injection needle that decreases in diameter toward the tip. The nozzle portion 35 is provided at the distal end of the outer cylinder 21, and is provided with an opening for discharging a chemical solution or the like in the outer cylinder at the distal end, and is formed so as to be tapered toward the distal end. On the inner peripheral surface of the collar portion, a spiral groove portion 37 that can be screwed with a spiral protrusion 53 formed on the outer peripheral surface of the nozzle portion storage portion of the seal cap 23 is formed. As shown in FIGS. 1 and 2, the flange portion 34 is an elliptical donut-shaped disc portion formed so as to protrude in the vertical direction from the entire rear end circumference of the outer cylinder 21. As shown in FIGS. 1 and 2, the flange portion 34 includes two

gripping portions

34 a and 34 b that are wide and face each other.

The outer cylinder 21 is formed of a transparent or translucent material, preferably a material having low oxygen permeability and water vapor permeability. Examples of the material for forming the outer cylinder 21 include polypropylene, polyethylene, polystyrene, polyamide, polycarbonate, polyvinyl chloride, poly- (4-methylpentene-1), acrylic resin, acrylonitrile-butadiene-styrene copolymer, polyethylene terephthalate. Various resins such as polyester and cyclic polyolefin can be used, and among them, resins such as polypropylene and cyclic polyolefin are preferable because they are easy to mold and have heat resistance.

As shown in FIGS. 1 and 2, the gasket 22 includes a main body portion extending at substantially the same outer diameter, and a plurality of annular ribs 26 and 27 (two or more in this embodiment) provided on the main body portion. If necessary, the number of the

ribs

26 and 27 may be appropriately set as long as the liquid-tightness and the slidability can be satisfied. Further, the front end surface of the gasket 22 has a shape corresponding to the shape of the inner surface of the front end of the outer cylinder 21 so as not to form a gap as much as possible between the two when contacting the inner surface of the front end of the outer cylinder 21.

The material for forming the gasket 22 includes elastic rubber (eg, butyl rubber, latex rubber, silicone rubber), synthetic resin (eg, styrene elastomer such as SBS elastomer and SEBS elastomer, ethylene-α olefin copolymer). It is preferable to use an olefin-based elastomer such as an elastomer. In particular, those made of butyl rubber are preferred.

Further, the gasket 22 may have a low drug-adsorbing coating on the portion that comes into contact with the injection solution 3. As a 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 resins, fluorine resins, polyester resins, polyparaxylylene, and the like. Specifically, the polyolefin resin is preferably polypropylene, ultrahigh molecular weight polyethylene, poly (4-methylpentene-1), cyclic polyolefin, or the like, and the fluorine resin is tetrafluoroethylene-perfluoroethoxyethylene copolymer. Polymers, polytetrafluoroethylene, tetrafluoroethylene / perfluoroalkyl vinyl ether copolymers, tetrafluoroethylene / hexafluoropropylene copolymers and the like are preferable.

Also, it is preferable to apply a lubricant to the outer surface of the gasket 22, at least the surfaces of the front end side annular rib 26 and the rear end side annular rib 27. The lubricant may be applied to the inner surface of the outer cylinder. Silicone oil is suitable as the lubricant. Further, by providing a silicone resin layer formed by solidifying on the surface of the gasket main body or the outer cylinder, a lubricant such as silicone oil may not be used.

The gasket 22 is provided with a recess extending inward from the rear end thereof. The recess has a female screw shape, and is a male screw portion formed on the outer surface of the protruding portion formed at the distal end portion of the plunger 24. And can be screwed together. The plunger 24 is not detached from the gasket 22 by screwing them together. The plunger 24 is not attached and may be attached at the time of use.

The plunger 24 has a protruding portion that protrudes in a cylindrical shape at the disk portion at the tip, and a male screw that is screwed into the concave portion of the gasket 22 is formed on the outer surface of the protruding portion. The plunger 24 includes a main body portion extending in the axial direction having a cross-shaped cross section, and a pressing disk portion provided at the rear end portion.

The seal cap 23 includes a cap body 50 and a seal member 32 housed in the cap body. As shown in FIGS. 1, 2, and 3, the cap body 50 is manufactured in a cap shape, and includes a nozzle portion storage portion 51 and a collar portion storage portion 52. Further, the seal member 32 is accommodated in the nozzle portion accommodating portion 51 of the cap body 50.
The nozzle portion storage portion 51 is a cylindrical portion that is provided at the center portion of the seal cap 23 and is closed at one end and opened at the other end. The inner diameter of the nozzle part storage part 51 is substantially the same from one end to the other end. Further, an annular projecting portion 56 a that projects in the direction of the opening end from the inner surface of the closing portion 56 is formed in the central portion of the closing portion 56 of the nozzle portion storage portion 51.

And the sealing member 32 accommodated in the cap main body 50 is pinched between this annular protrusion part 56a and the front-end | tip 35a of the nozzle part 35 of the outer cylinder 21, as shown in FIG. In other words, as shown in FIG. 5, the seal member 32 is pressed against the tip 35 a of the nozzle part 35 of the outer cylinder 21 by the annular protrusion 56 a of the cap body 50, and the tip 35 a of the nozzle part 35 is brought into a liquid-tight state. Seal.

Further, a spiral protrusion 53 that can be screwed with a spiral groove 37 formed on the inner peripheral surface of the collar portion 36 of the outer cylinder 21 is formed on the outer peripheral surface of the nozzle portion storage portion 51. As a result, the injection needle mounting portion 31 and the seal cap 23 are screwed between the outer peripheral surface of the nozzle portion storage portion 51 and the collar portion 36 of the outer cylinder 21. The collar portion storage portion 52 is a cylindrical portion that is formed so as to surround the nozzle portion storage portion 51 and is closed at one end and opened at the other end. Further, as shown in FIG. 1, the outer surface of the seal cap 23 (the outer peripheral surface of the collar portion storage portion 52) is vertically cut to prevent fingers from slipping when the seal cap is rotated. Has been.

The seal cap is formed from a transparent or translucent material, preferably a material having low oxygen permeability and water vapor permeability. Examples of the material for forming the seal cap include polypropylene, polyethylene, polystyrene, polyamide, polycarbonate, polyvinyl chloride, poly- (4-methylpentene-1), acrylic resin, acrylonitrile-butadiene-styrene copolymer, polyethylene terephthalate, etc. Among these, various resins such as polyester and cyclic polyolefin are preferable. Among them, resins such as polypropylene and cyclic polyolefin are preferable because they are easy to mold and have heat resistance.

In the prefilled syringe of this embodiment, the seal member 32 is formed in a disc shape. The diameter of the seal member 32 is substantially the same as or slightly smaller than the inner diameter of the closed portion of the nozzle portion storage portion 51. The seal member 32 is preferably an elastic member so that the tip opening can be sealed in a liquid-tight manner.
As the material for forming the seal member 32, the material described for the gasket 22 can be preferably used. Moreover, you may provide the low chemical | medical agent adsorptive film mentioned above also in the part which contacts the injection solution 3 of the sealing member 32. FIG.
As described above, the seal member 32 is pressed against the tip 35a of the nozzle portion 35 of the outer cylinder 21 by the annular protrusion 56a of the cap body 50, as shown in FIG. Seal in a liquid-tight state.

As shown in FIG. 3, the prefilled syringe 1 of the present invention stores the injection solution 3, and the seal cap 23 is attached to the nozzle portion 35 of the outer cylinder 21 by screwing the spiral groove 37 and the spiral protrusion 53. Is attached, and the tip 35a of the nozzle portion 35 is in a sealed state in which it is pressed against the seal member 32. In the case where the seal cap 32 is in direct contact with the injection solution 3 in which the seal cap 32 is stored, such as when the seal member 32 is not used, it is preferable to use the same material as the formation material of the outer cylinder 21 as the formation material of the seal cap 23. .

Moreover, as a prefilled syringe, the prefilled syringe 20 with a needle | hook type as shown to FIG. 6 and FIG. 7 may be sufficient.
As shown in FIGS. 6 and 7, the prefilled syringe 20 includes an outer cylinder 72 with a needle, a sealing member (cap) 76 attached to a distal end portion (needle part) of the outer cylinder 72, and the outer cylinder 72. A gasket 75 housed and slidable in the outer cylinder, a plunger 77 attached to the gasket 75, and the above-mentioned injection solution filled in the outer cylinder 72 (for treating the inflammatory autoimmune disease of the present invention) Injectable aqueous preparation 3).

The needle tube 73 having an outer diameter of φ0.41 to 0.18 mm is used. The needle tube 73 includes a lumen that penetrates from the distal end to the proximal end. Further, the needle tube 73 includes a needle tip that is punctured by a living body at the tip. The needle tip is formed at an acute angle with a blade surface. The needle tube 73 has a distal end side portion including the needle tip protruding from the distal end of the distal end portion 78 of the outer cylinder 72, and the proximal end of the needle tube 73 passes through the needle insertion hole and reaches the inside of the outer cylinder 72. .

As the material of the metal needle tube 73, 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 73, not only a straight needle that conforms to the ISO standard as described above but also a tapered needle that is partially tapered can be used.

The outer cylinder 72 includes a main body portion 74 filled with a medicine and a distal end portion 78 having a needle insertion hole. The main body portion 74 is formed in a substantially cylindrical shape having an internal storage portion. A flange 79 is formed on the rear end side in the axial direction of the main body 74.

The tip portion 78 includes a tip bulge portion and a cylindrical portion that connects the tip bulge portion and the tip of the main body portion 74. Moreover, the front-end | tip part 78 has the needle insertion hole which penetrates an inside. The needle insertion hole is provided with the proximal end of the needle tube 73 and is formed integrally with the outer cylinder by means such as insert molding.
The cap 76 is formed in a cylindrical shape, the axial base side is open, and the axial tip is closed. The cap 76 is formed from an elastic member such as rubber or elastomer, for example. The cap 76 is attached to the distal end portion 78 of the outer cylinder 72 so as to cover the needle tip of the needle tube 73 and the distal end portion 78 of the outer cylinder 72. As shown in FIG. 7, the needle tube 73 side and the distal end portion 78 are inserted into the lumen portion 82 of the cap 76.

Note that the inner diameter of the inner cavity of the cap 76 is formed to be substantially equal to the outer diameter of the tip bulge portion of the tip portion or slightly smaller than the tip bulge portion. Therefore, when the cap 76 is attached to the tip portion 78, the outer peripheral surface of the tip bulge portion comes into close contact with the inner peripheral surface of the cap 76. Therefore, the space covering the needle tube 73 protruding from the outer cylinder 72 is sealed by the tip bulge portion and the inner peripheral surface of the cap 76. By comprising in this way, it can prevent that microbe adheres to a needle point.

The annular rib 81 provided on the inner peripheral surface of the cap 76 tightens the constricted portion at the boundary between the tip bulge portion and the taper fitting portion in the tip portion 78 by its elastic force. Thus, the inner peripheral surface of the cap 76 and the constricted portion of the tip portion 78 are engaged, and the cap 76 can be prevented from being detached from the tip portion 78 during conveyance.
The plunger 77 includes a main body portion 91, a gasket mounting portion 92 formed at the distal end of the main body portion 91, and a pressing portion 93 provided at the base end portion. Further, the gasket includes a plunger mounting portion that receives and engages with the gasket mounting portion 92 of the plunger 77.

The prefilled syringe of this example is sterilized by high-pressure steam in a state where the injection solution is filled. High-pressure steam sterilization is performed by exposing a prefilled syringe filled with an injection solution, for example, at 100 to 122 ° C. for about 15 to 30 minutes.

As shown in FIGS. 4 and 5, the injectable aqueous preparation of the present invention may be contained in a packaging container and sealed.
In the packaged aqueous injection preparation 10 of this example, a prefilled syringe 1 filled with the above-described aqueous injection preparation is used as the injection solution 3.
The package 11 used in this embodiment includes a tray 12 that houses the prefilled syringe 1 and a sealing member 13 that seals the opening of the tray 12 so that the opening can be opened.

4 and 5, the package 11 includes a tray 12 having a storage portion 41 for storing the prefilled syringe 1, and a peelable sealing sheet (sealing) for sealing the opening of the tray. Stop member) 13. The package 11 of the embodiment shown in FIGS. 4 and 5 is a blister package. The package 11 of this embodiment has a shape that can accommodate a prefilled syringe.
Specifically, the tray 12 includes a storage portion 41 and a flange 42 formed around the storage portion 41. In addition, the storage portion 41 contacts the outer peripheral surface of the outer cylinder tip storage portion that stores the vicinity of the injection needle attachment portion of the outer tube 21 without substantially contacting with the outer peripheral surface of the intermediate portion of the outer tube 21 and the outer tube 21. An outer cylinder intermediate section storage holding section for storing the intermediate section of the outer cylinder 21 so as to prevent horizontal movement of the outer cylinder 21, an outer cylinder base end storage section for storing a flange forming portion of the outer cylinder 21, and a plunger And a plunger storage section for storing 24 portions.

The material of the tray 12 is preferably water vapor hardly permeable and has a certain degree of strength and hardness. For example, a base material layer such as polyolefin such as polypropylene and polyethylene, a vinyl chloride resin, a polyester resin, a polystyrene / polypropylene resin, and a resin (for example, polyvinylidene chloride, It is preferable to provide a layer having a thickness of about 30 to 90 μm made of ethylene-vinyl alcohol copolymer (polyethylene terephthalate). Specifically, a layer composed of three layers of polyethylene terephthalate / ethylene-vinyl alcohol copolymer / polypropylene is suitable.

A sealing sheet (sealing member) 13 is airtightly fixed to the upper surface of the tray 12 so as to seal the concave portion for storing the prefilled syringe. The sealing sheet 13 includes a water vapor hardly permeable film, an adhesive resin layer fixed to at least an outer peripheral portion of the lower surface of the water vapor hardly permeable film, and a surface protective layer provided on the upper surface of the water vapor hardly permeable film. What is formed is preferable. The oxygen poorly permeable film suppresses the permeation of oxygen from the outside. As a water vapor impermeable film, a metal foil such as aluminum, silver or gold or a metal vapor deposited film with aluminum, silver or gold vapor deposited on the surface, an inorganic vapor deposited film with SiOX or the like vapor deposited on the surface, or a water vapor impermeable film Resin films such as polyvinylidene chloride, polyvinylidene chloride-polyvinyl chloride, polyvinylidene chloride-acrylic acid ester copolymer, and high-density polyethylene can be suitably used.

Specific examples of the sealing sheet 13 include four layers of polyethylene terephthalate / polyethylene / polyethylene terephthalate / adhesive resin, polyethylene terephthalate / ethylene-vinyl alcohol copolymer / stretched nylon / adhesive resin, polyethylene terephthalate / stretched. One consisting of three layers of nylon / adhesive resin is conceivable.
And in the package 11, the oxygen absorber 14 may be accommodated. Known oxygen scavengers can be used. Further, the oxygen scavenger 14 may be fixed to the inner bottom surface of the tray or the lower surface (inner surface) of the sealing sheet 13.

When the injectable aqueous preparation for the treatment of inflammatory autoimmune disease of the present invention is applied to a prefilled syringe, the liquid volume is about 0.1 to about 1.2 mL and is a small volume when calculated from the dose of the administered drug. In such a small capacity, for example, when the effective period is assumed to be as long as 3 years, it is important to prevent transpiration.
In addition, the water vapor permeability mentioned above means that the water vapor permeability is 4 g / m ² · 24 h or less, and when the container itself containing the aqueous preparation has a water vapor barrier property, for the purpose of preventing transpiration. The use of packaging containers is not required.
In addition, a package is not limited to what is provided with a tray as mentioned above. The package may be a bag having either water vapor permeability or oxygen permeability or both. As such a bag-shaped package, for example, one produced by overlapping the sealing sheets described above and sealing the peripheral edge portion can be considered. And when using such a type of package, it is preferable to fix the oxygen absorber to be stored on the inner surface of the package.

Next, specific examples of the injectable aqueous preparation for the treatment of inflammatory autoimmune disease of the present invention will be described.
Example 1
0.71 g of disodium hydrogen phosphate (anhydrous) was dissolved in 50 mL of water for injection. 0.60 g of sodium dihydrogen phosphate (anhydrous) was dissolved in 50 mL of water for injection. The mixture was mixed at a volume ratio of disodium hydrogen phosphate solution: sodium dihydrogen phosphate solution = 87: 13, and this mixture was diluted 10-fold with water for injection to obtain a 10 mM phosphate buffer. Methotrexate 125 mg and sodium chloride 27 mg were dissolved in 5 mL of 10 mM phosphate buffer, and the pH was adjusted to around 7.5 with an appropriate amount of sodium hydroxide to obtain an aqueous solution having a concentration of methotrexate of 25 mg / mL. This aqueous solution was filtered using a membrane filter having a pore size of 0.2 μm to prepare an injectable aqueous preparation for treating inflammatory autoimmune diseases.

8 and 9, the obtained aqueous preparation for injection was fixed with a 27G needle (outer diameter 0.40 mm) at the tip of a cyclic polyolefin outer cylinder and sealed with a seal member. A prefilled syringe filled with an aqueous solution for injection for inflammatory autoimmune disease treatment was prepared by filling 1 mL of a syringe with a seal and sealing with a gasket made of butyl rubber. The prefilled syringe filled with an aqueous preparation for injection is stored in a bag made of an aluminum-deposited film having a water vapor permeability of 4 g / m ² · 24 h or less, hermetically packaged by a heat seal machine, and packaged injection An aqueous preparation-filled prefilled syringe was prepared.

(Comparative Example 1)
Methotrexate (125 mg) and sodium chloride (27 mg) were dissolved in 5 mL of water for injection, and an aqueous solution having a concentration of 25 mg / mL methotrexate adjusted to a pH of around 7.5 with an appropriate amount of sodium hydroxide was obtained. This aqueous solution was filtered using a membrane filter having a pore size of 0.2 μm to prepare a methotrexate aqueous solution containing no buffer.
The obtained methotrexate aqueous solution containing no buffer was filled in 1 mL of a syringe with a cyclic polyolefin 27G needle and plugged with a butyl rubber gasket, and then a prefilled syringe containing no buffer was prepared. And like Example 1, this prefilled syringe was hermetically packaged by a heat sealer in a bag made of an aluminum vapor-deposited film having a water vapor permeability of 4 g / m ² · 24 h or less, and does not contain a buffering agent. A methotrexate-containing aqueous preparation package (Comparative Example 1) was obtained.

(Test Example 1)
The results of pH when the packaged prefilled syringes obtained in Example 1 and Comparative Example 1 were stored at 60 ° C. for 1 week were as shown in Table 1 below. In addition, the time of the start of Table 1 is the time of preparation of the injectable aqueous preparation in Example 1 and Comparative Example 1.

(Example 2)
The prefilled syringe of Example 1 was prepared by high-pressure steam sterilization by a conventional method.

Example 3
An injectable aqueous preparation containing methotrexate having a pH of 8.0 was prepared in the same manner as in Example 1 except that the amount of sodium hydroxide added in Example 1 was changed.

(Comparative Example 2)
An aqueous injection preparation containing methotrexate having a pH of 8.5 was prepared in the same manner as in Example 1 except that the amount of sodium hydroxide added in Example 1 was changed.

(Test Example 2)
The osmotic pressure ratios of Example 1, Example 3 and Comparative Example 2 were measured. The results were as shown in Table 2 below.

(Test Example 3)
The electromyogram (EMG) was measured when the injectable aqueous preparations containing methotrexate of Examples 1 and 3 and Comparative Example 2 were administered to rats. The results of the number of responding individuals and the EMG intensity were as shown in FIGS.
The administration method to rats is as follows.
Dose: 20 μL
Administration rate: 10 μL / sec
Administration method: 1mL syringe is loaded on syringe pump and 29G needle is used

Moreover, the measuring method of an electromyogram (EMG) is as follows.
Rats were anesthetized with 3% isoflurane to expose hind limb thigh muscle (half-tendon-like muscle). Anesthesia was dropped to about 1.5%, and the electrode was inserted into the tip of the foot. Electrical stimulation (40 Hz, 2 ms, 10 mA) was performed, and a recording electrode was inserted at a position where contraction was observed. The electrical stimulation intensity was reduced to 5 mA, and the anesthetic concentration was decreased until a response of about 100 μV was obtained (1 to 1.4%). After changing the anesthetic concentration, it was stabilized for 30 minutes or more, and the test was started.

(Comparative Examples 3 to 7)
Except for changing the amount of sodium hydroxide added in Comparative Example 1, the same procedure as in Comparative Example 1 was carried out, and the buffer was adjusted to pH 6.5, 7.0, 7.5, 8.0, 8.5. A methotrexate-containing aqueous preparation package containing no agent was obtained.

(Test Example 4)
Measurement of pH-dependent degradation products (area percentage (%)) by liquid chromatography when the methotrexate-containing aqueous preparation package containing no buffer of Comparative Examples 3 to 7 was stored at 60 ° C. for 3 weeks. The results were as shown in Table 3 below. In addition, the time of the start of Table 3 is the time of making a methotrexate containing aqueous formulation which does not contain a buffer.

Example 4
Instead of the film subjected to the aluminum vapor deposition treatment used in the prefilled syringe prepared in Example 1, it is hermetically packaged with a heat sealer in a bag made of an ethylene / vinyl alcohol copolymer (EVAL (registered trademark)) film, and contains methotrexate. An aqueous preparation package was obtained.

(Test Example 5)
About the prefilled syringe packaged by the film subjected to the aluminum vapor deposition treatment of Example 1 and the prefilled syringe packaged by the ethylene / vinyl alcohol copolymer (EVAL (registered trademark)) film of Example 4, The results of the water transpiration rate (%) calculated from the change in weight when stored at 60 ° C. for 1 week were as shown in Table 4 below.

From the results shown in FIG. 8, when comparing pH 7.5, 8.0, and 8.5, a large number of rats showed a pain response at pH 8.5.
From the results of FIG. 9, when comparing pH 7.5, 8.0, and 8.5, an increase in EMG intensity was confirmed depending on the pH, and the strongest pain reaction was confirmed at pH 8.5.
From the results in Table 3, the amount of decomposition products increased as the pH approached acidity, and an amount exceeding 0.5% was confirmed at pH 6.5 under storage conditions at 60 ° C.
From the results in Table 4, transpiration was hardly confirmed in the case of a package under severe storage conditions of 60 ° C.

(Test Example 5)
The results of pH when other packaged prefilled syringes obtained in Example 1 and Comparative Example 1 were stored at 60 ° C. for 3 weeks were as shown in Table 5 below. In addition, the time of the start of Table 5 is a preparation time of the injectable aqueous preparation in Example 1 and Comparative Example 1.

The aqueous injection preparation for treatment of inflammatory autoimmune diseases of the present invention is as follows.
(1) Treatment of inflammatory autoimmune disease containing methotrexate or a pharmaceutically acceptable salt of methotrexate as methotrexate to a concentration of 25 mg / mL to 100 mg / mL, and further containing a buffer and an isotonic agent An aqueous injection preparation for injection, wherein the aqueous injection preparation has a pH of 7.0 to 8.0, and an osmotic pressure ratio of the aqueous injection preparation to physiological saline of 0.9 to 1. 1. An aqueous injection preparation for the treatment of inflammatory autoimmune disease which is 1.

The aqueous preparation for injection for the treatment of inflammatory autoimmune diseases of the present invention contains methotrexate or a pharmaceutically acceptable salt of methotrexate. Further, the injectable aqueous preparation of the present invention contains methotrexate as an aqueous injectable preparation for treating inflammatory autoimmune diseases at a high concentration such that the concentration is 25 mg / mL to 100 mg / mL, and further a buffering agent. And contains an isotonic agent. The aqueous preparation for injection has a pH of 7.0 to 8.2, and the osmotic pressure ratio of the aqueous preparation for injection to physiological saline is adjusted to 0.9 to 1.1. In particular, by containing methotrexate or a salt thereof, it is effective for the treatment of inflammatory autoimmune diseases such as rheumatism, and by containing it at a high concentration, pain caused by the liquid volume at the time of injection can be reduced, In addition, since the pH is adjusted to 7.0 to 8.0 with a buffering agent, the pH during storage is stable within the above range, so that methotrexate does not precipitate, and the pain caused by injection due to the pH is small. Further, since the osmotic pressure ratio is 0.9 to 1.1, there is little pain given at the time of injection due to the osmotic pressure.

Further, the above embodiment may be as follows.
(2) The aqueous preparation for injection is stored in a syringe, and the syringe is slidably stored in the outer cylinder and the outer cylinder, and seals the rear end side of the outer cylinder. An aqueous preparation for injection according to the above (1), which is a prefilled syringe comprising a sealing member that seals the distal end side of the syringe.
(3) The said outer cylinder is equipped with the injection needle attached to the front-end | tip part, The said injection needle is an aqueous formulation for injection as described in said (2) whose outer diameter is 0.42 mm or less.
(4) The aqueous syringe preparation for injection according to the above (2) or (3), wherein the syringe is subjected to a slidability improving treatment for improving the slidability of the gasket with respect to the inner surface of the outer cylinder.
(5) The injection according to (4), wherein the slidability improving treatment is performed by applying a coating or coating of a slidability improving substance to the inner surface of the outer cylinder or the outer surface of the gasket. Aqueous preparation.
(6) The aqueous injection preparation according to any one of (1) to (5), wherein the aqueous injection preparation is housed in a packaging container and sealed.

Claims

Methotrexate or a pharmaceutically acceptable salt of methotrexate containing methotrexate at a concentration of 25 mg / mL to 100 mg / mL, and further containing a buffer and an isotonic agent for the treatment of inflammatory autoimmune diseases The aqueous preparation for injection has a pH of 7.0 to 8.0, and the osmotic pressure ratio of the aqueous preparation for injection to physiological saline is 0.9 to 1.1. An injectable aqueous preparation for the treatment of inflammatory autoimmune diseases.
The aqueous injection preparation is housed in a syringe, the syringe is slidably housed in the outer cylinder, and a gasket that seals the rear end side of the outer cylinder, The aqueous preparation for injection according to claim 1, which is a prefilled syringe comprising a sealing member for sealing the distal end side of the syringe.
The aqueous preparation for injection according to claim 2, wherein the outer cylinder includes an injection needle attached to a distal end portion, and the injection needle has an outer diameter of 0.42 mm or less.
The aqueous preparation for injection according to claim 2 or 3, wherein the syringe is subjected to a slidability improving treatment for improving the slidability of the gasket with respect to the inner surface of the outer cylinder.
The aqueous preparation for injection according to claim 4, wherein the slidability improving treatment is performed by applying a coating or coating of a slidability improving substance on the inner surface of the outer cylinder or the outer surface of the gasket.
The injectable aqueous preparation according to any one of claims 1 to 5, wherein the injectable aqueous preparation is housed in a packaging container and sealed.