JP5118385B2 - Method for sterilizing chemical solution, prefilled syringe and method for producing the same - Google Patents

Description

  The present invention relates to a method for sterilizing a chemical solution for a prefilled syringe, a prefilled syringe and a method for producing the same.

  Conventionally, hyaluronic acid solutions have been used to treat various joint diseases such as osteoarthritis and rheumatoid arthritis. The hyaluronic acid solution is injected into a diseased joint by injection using a syringe, for example, in order to alleviate the occurrence of movement disorders and pain symptoms due to the reduction of the lubricating action of joint fluid and the protective action of the articular cartilage surface.

  In the case of the method by injection, since the hyaluronic acid solution is directly administered to the joint, it must be sterilized by some method. The hyaluronic acid solution is generally sterilized by high-pressure steam sterilization. In addition, as a method for sterilizing a hyaluronic acid solution, a method using filtration has also been studied (Patent Document 1).

On the other hand, as a method for purifying sodium hyaluronate, a method using a water-soluble organic solvent has been proposed (Patent Document 2).
JP-A-62-230801 JP 9-32001 A

  However, when a chemical solution containing hyaluronic acid is sterilized by high-pressure steam sterilization, there is a problem that the viscosity of the chemical solution changes due to decomposition of hyaluronic acid. In particular, in the case of a drug solution used as an injection for a prefilled syringe, since it is directly administered to a diseased joint part, it is important to maintain an appropriate viscosity so as to obtain a sufficient lubricating action in the joint part. In the case of the conventional high-pressure steam sterilization method, it has been difficult to perform sufficient sterilization while sufficiently suppressing the decomposition of hyaluronic acid.

  Also, in the case of the conventional method using filtration, a certain amount of heating is required to filter a viscous chemical solution, and since the filtration speed is low, the chemical solution is heated for a long time, preventing the decomposition of hyaluronic acid. In that respect, it was not satisfactory.

  Then, an object of this invention is to provide the method of sterilizing the chemical | medical solution for prefilled syringes containing hyaluronic acid or its salt by simple operation, suppressing decomposition | disassembly of hyaluronic acid or its salt. Another object of the present invention is to provide a prefilled syringe that has a sufficiently low content of a decomposition product of hyaluronic acid or a salt thereof and can be manufactured by a simple method. Furthermore, this invention aims at providing the manufacturing method which can manufacture a prefilled syringe by a simple method, suppressing decomposition | disassembly of hyaluronic acid or its salt.

  As a result of intensive studies to solve the above problems, the present inventors have surprisingly realized by combining the control of the filtration pressure within a specific range and the use of a specific filter for filtration. It was found that a very high filtration rate can be obtained even at a relatively low temperature. As a result of further studies based on such knowledge, the present invention has been completed.

  The present invention relates to a method for sterilizing a chemical solution for a prefilled syringe containing hyaluronic acid and / or a pharmaceutically acceptable salt thereof. The sterilization method according to the present invention includes a step of filtering a chemical solution with a membrane filter under conditions of a filtration temperature of 40 to 80 ° C. and a filtration pressure of 100 to 500 KPa. The membrane filter is a filter formed from at least one polymer of hydrophilic polyethersulfone and hydrophilic polyvinylidene difluoride.

  According to the sterilization method according to the present invention, since a high filtration rate is obtained, a chemical solution for a prefilled syringe containing hyaluronic acid or a salt thereof can be sufficiently sterilized while suppressing decomposition of hyaluronic acid or a salt thereof. Is possible. Further, the chemical solution may be simply filtered, and the chemical solution can be sterilized by a simple operation.

  The hyaluronic acid preferably has a mass average molecular weight of 600,000 to 1,200,000. This makes it easier to adjust the viscosity of the chemical solution so that the lubricating action when administered into the joint cavity is particularly excellent.

  The prefilled syringe according to the present invention is a prefilled syringe loaded with a drug solution sterilized by the sterilization method according to the present invention as an injection.

  The prefilled syringe according to the present invention has a sufficiently low content of a degradation product of hyaluronic acid or a salt thereof, and can be manufactured by a simple method.

  The method for producing a prefilled syringe according to the present invention comprises a step of sterilizing a chemical solution for a prefilled syringe containing a hyaluronic acid solution and / or a pharmaceutically acceptable salt thereof by the sterilization method according to the present invention, and a sterilized chemical solution Loading the unfilled prefilled syringe.

  According to the production method of the present invention, it is possible to produce a prefilled syringe by a simple method while suppressing the decomposition of hyaluronic acid or a salt thereof.

  According to the sterilization method of the present invention, it is possible to sufficiently sterilize a chemical solution for a prefilled syringe containing hyaluronic acid or a salt thereof with a simple operation while suppressing the decomposition of hyaluronic acid or a salt thereof. In the case of the present invention, since the filtration rate is high, the decomposition of hyaluronic acid hardly occurs. Therefore, it is possible for the drug solution to maintain an appropriate viscosity as an injection, and the change in characteristics of hyaluronic acid itself is also suppressed. As a result, a prefilled syringe having an excellent lubricating effect is obtained.

  The prefilled syringe of the present invention can be produced by a simple method with sufficiently reduced content of the degradation product of hyaluronic acid or a salt thereof.

  According to the production method of the present invention, it is possible to produce a prefilled syringe by a simple method while suppressing the decomposition of hyaluronic acid or a salt thereof.

  Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

  In the sterilization method according to the present embodiment, a prefilled syringe drug solution containing hyaluronic acid and / or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as “hyaluronic acid or the like”) is sterilized by filtration. The chemical solution is typically an aqueous solution containing hyaluronic acid and the like.

  Any hyaluronic acid derived from microorganisms, animals, etc. can be used. Hyaluronic acid can be obtained by, for example, isolation from vitreous, umbilical cord, joint fluid or chicken crown, or production by microorganisms such as Streptococcus pyogenes and Streptococcus ex. Among these, hyaluronic acid isolated from chicken crown is particularly preferable.

  Examples of pharmaceutically acceptable salts of hyaluronic acid include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt. Among these, sodium salt is particularly preferable.

  The mass average molecular weight of hyaluronic acid or the like is preferably 600,000 to 1,200,000. This makes it possible to easily adjust the viscosity of the drug solution to a desired range as an injection solution while maintaining the concentration of hyaluronic acid or the like in an appropriate range. The mass average molecular weight is measured by gel filtration chromatography.

  From the viewpoint of a lubricating action by administration into the joint cavity, the chemical solution preferably has a viscosity of 70 to 100 mPa · s. In addition, this viscosity is a sample measured at room temperature (25 ° C.) with a B-type viscometer (digital viscometer (model RVDV-III: manufactured by BROOKFIELD)) From the same viewpoint, hyaluronic acid and the like in a chemical solution The concentration is preferably 0.5 to 2% by mass based on the total mass of the chemical solution, and most preferably 1% by mass.

  The chemical solution often contains other components such as sodium chloride, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide, hydrochloric acid and distilled water for injection in addition to hyaluronic acid and the like. The chemical solution is preferably colorless and clear. Moreover, it is preferable to adjust normally the pH of a chemical | medical solution so that it may exist in the range of 6.8-7.8.

  Filtration temperature (temperature of the chemical solution used for filtration) is maintained at 40 to 80 ° C. If filtration temperature is 80 degrees C or less, decomposition | disassembly of hyaluronic acid etc. will fully be suppressed. If the filtration temperature is less than 30 ° C., the filtration rate tends to be slow or the membrane filter tends to be clogged.

  At a temperature within the above range, the chemical pressure is filtered through a membrane filter at a filtration pressure (pressure applied to the chemical liquid) of 100 to 500 KPa (preferably 300 to 350 kPa). When the filtration pressure is less than 100 kPa, the filtration rate is slowed, and the filtration efficiency is lowered. When the filtration pressure exceeds 500 kPa, it is difficult to obtain a sufficient sterilizing effect.

  As a membrane filter used for filtration, a filter formed from at least one of hydrophilic polyethersulfone (PES) and hydrophilic polyvinylidene difluoride (PVDF) is used. By using a porous body formed of these specific polymers as a filter, it is possible to obtain a high filtration rate without clogging a viscous chemical solution. From the viewpoint of filtration speed and sterilization effect, a hydrophilic polyethersulfone filter is particularly preferred.

  In order to obtain a high sterilization effect, the pore size of the membrane filter is preferably 0.1 to 0.3 μm.

  FIG. 1 is a perspective view showing an embodiment of a prefilled syringe. A prefilled syringe 10 shown in FIG. 1 is a double syringe type prefilled syringe loaded with two types of injection solutions.

  The prefilled syringe 10 is interposed between a barrel 11, a plunger 12 having an end stopper 12 </ b> A that seals one end of the barrel 11, and the one end and the other end of the barrel 11. A middle stopper 15 that separates into the chamber, a first chemical liquid A sealed in the front chamber, and a second chemical liquid B sealed in the rear chamber are provided. The end stopper 12A and the middle stopper 15 slide on the inner peripheral surface of the barrel 11. The first drug solution A is a lidocaine solution. The second chemical solution B is a hyaluronic acid solution containing hyaluronic acid and / or a salt thereof, that is, a chemical solution sterilized by the sterilization method described above.

  The lidocaine solution used as the 1st chemical | medical solution A is an aqueous solution which consists of compositions, such as sodium chloride, hydrochloric acid, sodium hydroxide, distilled water for injection, besides lidocaine. The viscosity of this lidocaine aqueous solution is 0.5 mPa · s to 5 mPa · s.

  As long as the lidocaine solution is a solution containing lidocaine as a main component, it may contain other components to the extent that the medicinal effect is not impaired, and also includes a solution of lidocaine hydrochloride such as lidocaine hydrochloride. . Lidocaine is known to have a pharmacological action that blocks neurotransmission by inhibiting the permeation of sodium ions and inactivating the action potential. Lidocaine solution contains lidocaine and / or a pharmaceutically acceptable salt thereof as a local anesthetic. The pH of the lidocaine solution is preferably adjusted to 5.0 to 7.0. In the present invention, the other chemical solution combined with the hyaluronic acid solution is not limited to the lidocaine solution, and can be appropriately changed according to the desired purpose.

  The plunger 12 includes a piston main body 18, and an end stopper 12 </ b> A is attached to the tip of the piston main body 18 by screwing or the like. Generally, the disposable syringe is formed of polypropylene, poly (4-methylpentene-1) or the like for the barrel and the piston, but in the syringe 10 of the present embodiment, the barrel 11 and the piston body 18 are particularly It is formed of a COP resin (cyclic olefin resin) that is heat resistant and has no contamination.

  COP resins are roughly classified into the following two types.

  The first type of COP resin is a copolymer of (a) a cyclic olefin and (b) an acyclic olefin.

  The second type of COP resin is a cyclic olefin ring-opening metathesis polymer ((a) ring-opening metathesis polymerized cyclic olefin) or a cyclic olefin ring-opening metathesis polymer hydride ((a) ring-opening metathesis. After polymerization, the polymer is hydrogenated).

  Examples of (a) cyclic olefins include polycyclic olefins having a norbornene ring (norbornenes, dicyclopentadiene, tetracyclododecene, etc.), monocyclic olefins, and cyclic diolefins.

  (B) As an acyclic olefin, the compound which has a vinyl group ((alpha) -olefin etc.) and the (meth) acryloyl group are mentioned.

  Among the above, the COP resin in the present embodiment is most preferably a cyclic olefin ring-opening metathesis polymer hydride.

  The end stopper 12A is often formed of an elastic body such as rubber or a thermoplastic elastomer in order to maintain airtightness.

  There are no particular restrictions on the rubber, but for example, synthetic rubber such as isoprene rubber, butadiene rubber, styrene butadiene rubber, ethylene propylene rubber, isoprene-isobutylene rubber, nitrile rubber, etc. And those containing an agent, a crosslinking agent and the like.

  Thermoplastic elastomers include solution-polymerized styrene butadiene rubber, (SBS block copolymer), polyester or polyether urethane rubber, polyether aromatic polyester block copolymer (polyester rubber), polyolefin block copolymer, high trans- 14-polyisoprene, polyethylene butyl graft copolymer, syndiotactic polybutadiene and the like can also be used.

  In addition to the above, relatively soft plastics, such as copolymer type polypropylene, low density polyethylene, ethylene-vinyl acetate copolymer, etc., and heat resistance almost equal to polypropylene (preferably about 130 to 140 ° C.) ) Can also be used.

  A double syringe type prefilled syringe 10 defines a front chamber and a rear chamber between a barrel 11 and an end stopper 12A of a plunger 12 having an end stopper 12A slidably inserted into the barrel 11 and the tip. A middle stopper 15 is inserted so as to form.

  The middle stopper 15 is composed of, for example, a short columnar rubber elastic body, and an elastically deformable ring-shaped lip portion 15A is slidably in contact with the inner peripheral surface of the barrel 11 at the outer periphery of the front portion. Is formed. A plurality of guide projections 15B are formed on the outer periphery of the rear end portion of the middle stopper 15 so as to be in sliding contact with the inner peripheral surface of the barrel 11 and to cooperate with the lip portion 15A to prevent the inclination of the axis of the middle stopper 15. Has been.

  The middle stopper 15 is often formed of an elastic body such as rubber or thermoplastic elastomer in order to maintain airtightness. The rubber is not particularly limited, but for example, synthetic rubber and natural rubber such as isoprene rubber, butadiene rubber, styrene butadiene rubber, ethylene propylene rubber, isoprene-isobutylene rubber, nitrile rubber, etc. are used as a main raw material, and a filler And those containing a crosslinking agent and the like.

  On the inner surface of the front end portion of the barrel 11, three pairs of bypass protrusions 11C extending radially from the periphery of the injection port 11B in the needle mounting portion 11A toward the inner peripheral surface of the barrel 11 at equal angular intervals are formed. Yes.

  FIG. 2 is a longitudinal sectional view when the prefilled syringe shown in FIG. 1 is used.

  When the prefilled syringe 10 is not used, a sealing top cap 13 (see FIG. 1) is attached to a small-diameter needle mounting portion 11A formed at the tip of the barrel 11, but the top cap 13 is removed. When the prefilled syringe 10 is used, the injection needle 14 is attached to the needle attachment portion 11 </ b> A instead of the top cap 13. In clinical practice, the injection needle 14 having a size of 22G to 23G (inner diameter of 0.48 mm to 0.40 mm) is often used.

  Further, the inner peripheral surface of the barrel 11, the surface of the end stopper 12A, and the surface of the middle stopper 15 can each be covered with a silicone gel layer. The silicone for forming the silicone gel layer 20 can be roughly classified into (a) straight silicone and (b) modified silicone depending on the type of organic group bonded to the silicon atom.

  (A) Straight silicone means what combined the methyl group and the hydrogen atom as a substituent.

  (B) Modified silicone refers to those having a constituent part derived secondarily from straight silicone, and an organopoly having at least one (preferably 2) unsaturated group such as vinyl group or (meth) acryloyl group. Examples include siloxane.

  In this embodiment, it is not limited to these silicones, and either straight silicone or modified silicone is possible. For example, Dow Corning 360 (manufactured by Dow Corning), which is a straight silicone known to be cured by gamma rays, or ThreeBond 3167, 3168 (manufactured by ThreeBond), which is commercially available as an ultraviolet curable modified silicone gel, is used. be able to. Here, optimally, Dow Corning 360 (manufactured by Dow Corning) is preferably used.

  In this syringe, since the silicone gel layer 20 is provided on the inner peripheral surface of the barrel 11 and / or the surface of the stopper (end stopper 12A, middle stopper 15), the sliding property between the barrel 11 and the stopper is ensured. Can do. Further, it is possible to reduce the possibility that the silicone is separated and peeled from the resin of the barrel 11 over time, and the liquid can be stored more stably in the barrel 11.

  When the plunger 12 having the end stopper 12A is pushed in the direction of the injection needle 14, the second drug solution B presses the middle stopper 15, the pressed middle stopper 15 presses the first drug solution A, the injection port 11B and the injection The first chemical A flows out through the needle 14. When the first medicinal solution A finishes flowing, the ridge 11C deforms the outer peripheral surface of the middle stopper 15 to form a bypass passage, and when the plunger 12 having the end stopper 12A is further pushed toward the injection needle 14, The stopper 12A presses the second chemical B, and the second chemical B flows out to the outside through the bypass passage, the injection port 11B, and the injection needle 14.

  The prefilled syringe according to the present invention is not limited to the double syringe type as in the above embodiment. For example, the prefilled syringe may be a type in which a hyaluronic acid solution is loaded alone, or three or more types of injection solutions may be used. The type to be loaded may be used.

  The prefilled syringe 10 according to the embodiment includes, for example, a step of sterilizing a second chemical solution B containing a hyaluronic acid solution and / or a pharmaceutically acceptable salt thereof by the sterilization method described above, and the first chemical solution A and the second chemical solution A. A step of obtaining a prefilled syringe loaded with the first chemical solution A and the second chemical solution B by loading the unfilled prefilled syringe 10 with the chemical solution B, and the first chemical solution A and the second chemical solution B being loaded. And sterilizing the outer surface of the prefilled syringe.

  In the case of such a method, since the second chemical solution B has already been sufficiently sterilized by the sterilization method according to the above-described embodiment, only the outer surface of the barrel 11 or the like needs to be sterilized after the chemical solution is loaded. Therefore, gas sterilization, hydrogen peroxide sterilization, or the like can be selected instead of high-pressure steam sterilization. As a result, it is possible to obtain a prefilled syringe with very little decomposition product such as hyaluronic acid as compared with the case where autoclaving is performed. Moreover, it is advantageous also when using the chemical | medical solution containing a chemical | medical agent with low heat resistance as the 1st chemical | medical solution A.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples.

(Examination 1)
Using a mixer (CLEAMIX CLM-0.8S, manufactured by M Technique Co., Ltd.), a 1% by mass sodium hyaluronate aqueous solution (mass hyaluronic acid mass average molecular weight: 1.02 million) was prepared as a chemical solution. The viscosity of the chemical solution was 80 mPa · s (25 ° C.). Next, the chemical solution was supplied onto a circular membrane filter (Super EKV (trade name), manufactured by Nippon Pole Co., Ltd.) having a pore size of 0.2 μm and a diameter of 47 mm, which is a hydrophilic polyethersulfone membrane, and the filtration temperature (chemical solution temperature) is displayed. While maintaining each temperature shown in 1, pressure filtration was performed at 300 kPa for 60 minutes. And the quantity (filtration amount) of the chemical | medical solution filtered for 60 minutes was measured.

表１に示されるように、濾過温度２５℃では濾過を行うこと自体ができなかった。これに対して、濾過温度を４０℃以上とすることにより、十分効率的な濾過が可能であることが確認された。

As shown in Table 1, the filtration itself could not be performed at a filtration temperature of 25 ° C. On the other hand, it was confirmed that sufficiently efficient filtration is possible by setting the filtration temperature to 40 ° C. or higher.

(Examination 2)
Using the following membrane filters, a test for filtering the same chemical solution as in “Review 1” was performed. Each membrane filter is a circular filter having a pore size of 0.2 μm and a diameter of 47 mm.
Membrane filter:
・ Hydrophilic PES membrane (SUPER EKV FTKEKV (trade name), manufactured by Pall Japan)
・ Hydrophilic PVDF membrane (Fluorodyne II-DFLP FTKDFL (trade name), manufactured by Nihon Pall)
・ Nylon 66 membrane (Ulchipore N66 FTKNR (trade name), manufactured by Nippon Pole)

Filtration was performed according to the following procedure.
1) Each filter was placed in a disc holder and pre-wet with water.
2) The chemical solution was heated to 60 ° C., sent to the membrane filter while being pressurized to 250 kPa, and the amount of filtration was measured over time.

親水性ＰＥＳ膜、および親水性ＰＶＤＦ膜は高い濾過効率を示した。一方、ナイロン６６膜は濾過効率が低く、濾過量は親水性ＰＥＳ膜の６８％、親水性ＰＶＤＦ膜の７５％に留まった。

The hydrophilic PES membrane and the hydrophilic PVDF membrane showed high filtration efficiency. On the other hand, the filtration efficiency of the nylon 66 membrane was low, and the filtration amount was 68% of the hydrophilic PES membrane and 75% of the hydrophilic PVDF membrane.

(Examination 3)
The chemical solution containing hyaluronic acid was sterilized by a sterilization method by filtration using a membrane filter or a sterilization method using an autoclave. The amount of degradation products (analogous substances) of hyaluronic acid contained in the chemical solution after sterilization (ratio based on the amount of hyaluronic acid before sterilization,%) was measured. The amount of the decomposed product was measured by a method of quantifying the amount of hyaluronic acid having a low molecular weight by decomposition by gel filtration chromatography.

(Examination 4)
The same chemical solution as in “Examination 1” was heated to 50 ° C., 60 ° C. or 70 ° C., and the change over time in the amount of related substances in the chemical solution was measured. The measurement results are shown in Table 4 and FIG.

  As shown in Table 4 and FIG. 4, it was confirmed that the decomposition of hyaluronic acid was sufficiently suppressed over a relatively long time if heating was performed at 80 ° C. or lower. In particular, the decomposition of hyaluronic acid was remarkably suppressed at 60 ° C. or lower.

It is a perspective view which shows one Embodiment of a prefilled syringe. It is a longitudinal cross-sectional view at the time of use of the prefilled syringe of FIG. It is a graph which shows the relationship between the amount of related substances, and heating time.

Explanation of symbols

  DESCRIPTION OF SYMBOLS 10 ... Prefilled syringe, 11 ... Barrel, 11A ... Needle mounting part, 11B ... Injection port, 11C ... Projection, 12A ... End stopper, 12 ... Plunger, 13 ... Top cap, 14 ... Injection needle, 15 ... Middle stopper, 15A ... Lip part, 15B ... Guide protrusion, 18 ... Piston body part, 20 ... Silicone gel layer, A ... 1st chemical | medical solution, B ... 2nd chemical | medical solution.

Claims (3)

A method for sterilizing a drug solution for a prefilled syringe containing hyaluronic acid and / or a pharmaceutically acceptable salt thereof,
A step of filtering the chemical solution with a membrane filter under conditions of a filtration temperature of 40 to 80 ° C. and a filtration pressure of 100 to 500 KPa,
The membrane filter is a filter formed from at least one polymer of hydrophilic polyethersulfone and hydrophilic polyvinylidene difluoride.
Sterilization method.   The sterilization method according to claim 1, wherein the hyaluronic acid has a mass average molecular weight of 600,000 to 1,200,000. Sterilizing a prefilled syringe drug solution comprising hyaluronic acid and / or a pharmaceutically acceptable salt thereof by the sterilization method according to claim 1 or 2,
Loading the sterilized drug solution into an unloaded prefilled syringe;
A method for producing a prefilled syringe.

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