JP4802492B2 - Prefilled syringe preparation containing heparin - Google Patents

Description

  The present invention relates to a prefilled syringe preparation containing a heparin solution and a method for producing the same.

Heparin is a sulfate of mucopolysaccharide obtained from the liver, lung or intestinal mucosa of an animal, and has a structure in which uronic acid and glucosamine are alternately linked to each other. The molecular weight is about 5000 to 20000, and has effects such as blood coagulation inhibitory action and liposerum clarification action.
For this reason, a physiological saline solution containing a low concentration of heparin is used in medical institutions for the purpose of preventing blood coagulation in the catheter (referred to as heparin lock).
When a patient who has been infused for a long period of time (especially a high calorie infusion) suspends infusion for reasons such as bathing, the line may be closed aseptically with the catheter in place. There is a risk of forming a thrombus at the point of contact with the drip solution. In such a case, it is possible to suppress the formation of thrombus in the line by using a heparin solution as a liquid in contact with blood.

  As preparations of heparin used for medical purposes for such purposes, preparations containing sodium salt, calcium salt, etc. of heparin are known. As preparations containing heparin sodium, heparin sodium, a Japanese pharmacopoeia product, is known. There is an injection solution. This injection preparation contains 1000 units of heparin sodium per mL, is colorless to pale yellow and clear aqueous, has a pH of 5.5 to 8, an osmotic pressure ratio of about 1 (ratio to physiological saline), etc. It has properties.

Conventionally, such a high-concentration heparin sodium injection solution (1000 units / mL) is diluted about 10 to 100 times in a hospital (heparin concentration is about 10 to 100 units / mL), and it is necessary for use. (About 1 to 10 mL) was used.
However, such in-hospital prescriptions include bacterial contamination at the time of preparation, bacterial contamination due to divided use, complexity of dilution work / work, dilution errors during preparation, display errors after syringe dispensing, medical errors (mistakes), etc. There was a problem. In addition, since the prescription products in the hospital are simply a commercially available heparin preparation diluted with a physiological saline solution, the propagation and decay of bacteria progresses during the storage period, and the titer also decreases as the pH decreases. It was not possible to save.

Therefore, a low-concentration heparin injection preparation that can be used as it is for heparin lock or the like without any work such as dilution has been developed and already sold in Japan.
For example, Patent Documents 1 and 2 describe a heat-sterilizable heparin injection solution containing calcium lactate.
Patent Document 3 describes a heparin injection liquid preparation adjusted to pH 6-8 with citrate and enclosed in a flexible plastic container.
Patent Document 4 describes a heparin injection preparation that can be sterilized with high-pressure steam by adding citric acid or the like or a salt thereof.
Patent Document 5 describes a high pressure steam sterilized heparin injection solution containing 1 to 100 units / mL heparin, containing an isotonic agent (salts or sugars), and not containing a preservative. .
Patent Document 6 discloses a heparin injection liquid preparation containing 5-150 units / mL heparin and benzyl alcohol, packaged with a gas barrier packaging material (enclosed with an oxygen scavenger), and adjusted to a pH of about 5.5 to 8.5. Are listed.

  Furthermore, in recent years, in order to maintain convenience and sterility during use, an injection solution preparation (prefilled syringe preparation) filled in a syringe has also been developed, and there are several products (Non-patent Document 1, etc.). ).

These injection preparations are low-concentration (about 1 to 150 units) heparin preparations used for heparin locks. However, as an application different from heparin locks, they are contained in blood circuits when using extracorporeal circulation devices such as hemodialysis. There are uses aimed at preventing the formation of blood clots. At this time, since it is not preferable that the blood is diluted because it is a burden on the patient, a high-concentration heparin solution is added to the blood circuit little by little with a pump.
And the high concentration (about 160-1000 unit / mL) heparin containing formulation used at the time of such extracorporeal circulation has already been commercialized. Non-Patent Document 2 discloses a heparin injection liquid preparation (a product containing a plastic ampule) containing 250 units / mL heparin that has the effect and effect of “preventing blood coagulation when using hemodialysis and other extracorporeal circulation devices”. be written.
Moreover, the prefilled syringe formulation has also been commercialized (Non-patent Document 3).

  However, the manufacturing process of a prefilled syringe preparation is generally complicated. In particular, prefilled syringe preparations are generally sterilized by autoclaving after external packaging, and in order to store the externally packaged product in a limited space in a high-pressure sterilization chamber, once compared with ampoule products etc. The number of processed products will decrease. This has a problem that the production efficiency is lowered.

2-503199 4-507108 JP 2002-87968 JP 2002-104976 A JP 2003-183154 A JP2004-10596 Heparin Na lock 10 syringe package insert Revised June 2003 Dialysis heparin Na injection 250 units / mL package insert Revised July 2004 Heparin Na500 unit / mL syringe “NP” package insert April 2004

  The subject of this invention is providing the heparin containing prefilled syringe formulation excellent in stability, and its efficient manufacturing method.

  As a result of intensive studies in view of the above circumstances, the present inventors filled a syringe with a heparin injection solution containing a stabilizer, and after sterilizing by autoclaving, performing external packaging, The inventors have found that the above problems can be solved and have reached the present invention.

In the conventional heparin injection liquid preparation, in order to confirm that the injection needle has been punctured into the blood vessel, an operation of pulling the gasket is performed, and the inside of the gasket at the margin is also sterilized because it contacts the injection liquid. There was a need. Therefore, the sterilization process was always performed after the outer packaging. In the case of an injection solution for heparin lock, there is a possibility that the gasket is pushed back by blood pressure during injection into the catheter, and the same sterilization is necessary.
However, the heparin-containing prefilled syringe preparation used for blood extracorporeal circulation is connected to a pump of an extracorporeal circulation circuit such as a hemodialyzer and is continuously pushed out, and is not pushed back. That is, there is no need to pull the gasket at one end. Therefore, it is only necessary that the syringe after filling with the chemical solution is sterilized and only the filled chemical solution is maintained in a sterilized state.
The present inventors have found that it is possible to perform sterilization before outer packaging in this way, and have reached the present invention.

That is, the present invention
(1) A heparin-containing prefilled syringe preparation obtained by filling a syringe with a heparin solution containing about 160 to 1000 units / mL of heparin and subjecting it to autoclaving as it is,
(2) The preparation of (1) above, wherein the pH after autoclaving is about 6-9,
(3) The preparation according to (1) above, which contains any salt of citric acid, succinic acid, phosphoric acid, carbonic acid, lactic acid or an acid addition salt of trishydroxymethylaminomethane,
(4) The preparation according to the above (1), comprising sodium heparin, sodium chloride, sodium citrate, sodium hydroxide and water for injection, and subjected to autoclaving, and (5) about 160 to 1000 units / mL The present invention relates to a method for producing a heparin-containing prefilled syringe preparation, which comprises preparing a heparin solution containing heparin, filling and sealing the obtained heparin solution in a syringe, and subjecting it to autoclaving as it is.

  The heparin-containing prefilled syringe preparation of the present invention can thereby sterilize a large amount of syringe preparation at a time compared to sterilizing a syringe after outer packaging, and is a sterilization process that is a rate-limiting step in the manufacturing process. The manufacturing cost can be greatly reduced.

The prefilled syringe preparation of the present invention is a prefilled syringe preparation filled with a heparin solution containing heparin or a salt thereof.
Various known heparins can be used in the present invention. That is, it is a sulfate of mucopolysaccharide obtained from the liver, lungs or intestinal mucosa of healthy edible animals (eg, cattle, pigs, etc.), and has blood coagulation inhibitory activity and liposerum clarification activity. Uronic acid and glucosamine Have a structure in which 1,4 bonds are alternately bonded, and the molecular weight is usually about 5000 to 20000.
Heparin is prepared according to a known method. For example, the method disclosed in the 14th Japanese Pharmacopoeia can be used.

Examples of heparin salts include sodium salts and calcium salts. Sodium salt is available as a 14th Japanese Pharmacopoeia product, and calcium salt is available as a 1980 British Pharmacopoeia or 14th Japanese Pharmacopoeia product.
Moreover, low molecular weight heparin (generic name: parnaparin) is also exemplified as the heparin of the present invention. This is a depolymerized heparin obtained by decomposing heparin derived from bovine or porcine intestinal mucosa with hydrogen peroxide and cupric sulfate, and has an average relative molecular weight of 4500 to 6500, and the degree of sulfate esterification is 2 per disaccharide. 0.0 to 2.4.

  The concentration of heparin or a salt thereof in the preparation of the present invention is typically about 160 to 1000 units / mL, preferably 200 to 800 units / mL.

  The heparin solution to be filled preferably contains an isotonic agent in an amount effective for physiological isotonicity. Examples of the isotonic agent include salts such as sodium chloride and saccharides such as glucose. The osmotic pressure of the heparin solution may be a physiologically acceptable level, specifically about 0.9 to 1.1, preferably about 1 (ratio to physiological saline).

Further, the pH of the heparin solution is usually about 6 to 9, preferably about 6.0 to 7.5. This is because if the pH is less than 6, the titer of the heparin solution in the preparation decreases during autoclaving or long-term storage.
In the present invention, the pH of the heparin solution in the preparation after sterilization is usually 6 to 9, and preferably pH 6.0 to 7.5.

In order to maintain the pH of the heparin solution at about 6 to 9 in the present invention, a method using a base such as sodium hydroxide or potassium hydroxide (hereinafter, these additives are referred to as pH regulators), citric acid , Succinic acid, phosphoric acid, carbonic acid, lactic acid or acid addition salt of trishydroxymethylaminomethane, etc. And so on).
Preferred salts of the latter pH buffer are salts with strong bases such as sodium and potassium in the case of acids such as citric acid, and acid addition salts with strong acids such as hydrochloric acid in the case of trishydroxymethylaminomethane. It is. Specifically, sodium citrate, potassium citrate, disodium succinate, monosodium succinate, dipotassium succinate, monopotassium succinate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, monophosphate Examples include disodium hydrogen, monosodium dihydrogen phosphate, dipotassium monohydrogen phosphate, monopotassium dihydrogen phosphate, sodium phosphate, potassium phosphate, sodium lactate, potassium lactate, and trishydroxymethylaminomethane hydrochloride. A mixture thereof may be used as a pH buffer. Of these, sodium citrate is particularly preferably used.
These pH buffering agents may have optical isomers based on asymmetric carbon atoms (eg lactic acid), but all isomers and mixtures thereof are also included in the scope of the present invention.

In the present invention, the pH buffer may be in the form of a buffer solution (for example, a phosphate buffer solution) containing the salt. When the pH buffer is a phosphate buffer, for example, a buffer composed of a combination of disodium monohydrogen phosphate and monosodium dihydrogen phosphate is exemplified.
The addition concentration of the pH buffering agent is usually about 0.1 to 10 mM, more preferably about 1 to 10 mM.

  By blending the above pH regulator or pH buffer (hereinafter referred to as a pH regulator together), the pH of the heparin solution can be maintained at 6 or higher even after autoclaving, As a result, a decrease in the titer of the heparin solution can be prevented.

  The prefilled syringe preparation of the present invention preferably contains no preservative. An antiseptic agent refers to a drug that prevents or kills the growth of microorganisms, and examples thereof include methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, cresol, phenol, and benzyl alcohol. The prefilled syringe preparation of the present invention preferably contains no benzyl alcohol among the preservatives. A general-purpose butyl rubber stopper can be used for preserving the preparation (the conventional prefilled syringe preparation containing a heparin solution containing benzyl alcohol had to use a rubber stopper coated with Teflon (registered trademark) or the like. ) In addition, there is an advantage that it is not necessary to store the preparation under light shielding (the conventional prefilled syringe preparation containing heparin solution containing benzyl alcohol needs to be stored under light shielding because benzyl alcohol is decomposed by light. was there).

  The prefilled syringe preparation with a heparin solution of the present invention is composed of a syringe and the above heparin solution. The syringe used for the prefilled syringe preparation is not particularly limited, and a conventionally known one can be suitably used. For example, the thing of the shape etc. which were described in March 12, 1986 pharmacy trial 98 notification example 1 can be used.

  The syringe of the present invention includes a syringe (syringe) and a gasket. The syringe is a cylindrical body having a gasket fitted in an opening on one end (base end opening portion) side and a discharge port for discharging the heparin solution by pushing the gasket on the other end (tip opening portion) side. A cap is usually fitted into the discharge port before use, and a chemical solution is held together with the gasket. In addition, a plunger rod may be connected to the gasket. The length from the proximal end of the syringe to the distal end of the cap and the inner diameter of the syringe can be appropriately determined depending on the volume of the chemical solution (heparin solution) to be filled.

  Examples of the material of the syringe and plunger rod used in the present invention include ordinary plastic or glass. Examples of the plastic include polyolefin (eg, polyethylene, polypropylene) and the like. The volume can be appropriately determined according to the clinical use amount of this preparation. Specifically, those having a volume of 1 to 20 mL are exemplified. If necessary, a glass or plastic syringe can be treated with silicon or the like by baking or coating to reduce the sliding resistance of the gasket and facilitate the movement of the gasket in the syringe. It is preferable from the viewpoint of easy connection with the injection needle or the vascular catheter that the open end portion where the discharge port is formed has a luer tip shape corresponding to the shape of the device to be connected. The cap used in the present invention is not particularly limited, but is preferably an elastic cap made of rubber or a thermoplastic elastomer. The gasket may preferably be provided with means to which the plunger rod is coupled, for example a screw part. Moreover, the plunger rod and the gasket may be integrally formed.

The preparation of the present invention is produced as follows.
That is, the above pH adjuster is added to a heparin solution containing heparin or a salt thereof and an isotonic agent in an amount effective for physiological isotonicity to adjust the pH to obtain a heparin solution. The cap is attached to the open end of the syringe, and the heparin solution is filled into the syringe attached with the cap from the open end of the syringe with a nozzle. Filling the syringe with the heparin solution is performed, for example, by dispensing. After that, the gasket is attached to the base end open portion by a vacuum plugging method or a sleeve plugging method. Next, high pressure steam sterilization is applied to the prefilled syringe preparation containing the heparin solution equipped with the gasket. Thereafter, if necessary, the syringe is sealed with various known outer packaging such as blister packaging.

In the present invention, the safety of the preparation can be ensured by subjecting the prefilled syringe preparation to autoclaving. By setting the pH of the heparin solution to about 6 or more, more preferably about 6 or more after the autoclave sterilization, the pH of the heparin solution after sterilization is significantly reduced even if autoclaving is performed. As a result, it is possible to obtain a preparation which does not cause a problem that the titer of the heparin solution is lowered to such an extent that sufficient drug efficacy cannot be exhibited.
The conditions for high-pressure steam sterilization are preferably a pressure obtained by adding about 0.1 to 5 atm to the saturated steam pressure, a temperature of about 105 to 130 ° C., and a time of about 1 to 60 minutes.

The prefilled syringe preparation of the present invention removes the cap at the time of use, releases the seal on the outlet side connected to an instrument such as a hemodialyzer pump, and connects to the instrument.
When the preparation of the present invention is used for extracorporeal circulation (hemodialysis), in the case of systemic heparinization, usually about 1000 to 3000 units are administered prior to the start of dialysis. About 500-1500 units are added continuously per hour, or about 500-1500 units are added intermittently every hour. In the case of the local heparinization method, about 1500 to 2500 units are continuously infused per hour, and neutralized with promine sulfate during extracorporeal perfusion.

  The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

<In 10 mL formulation>
Active ingredient: Heparin sodium 5000 units (14th Japanese Pharmacopoeia listed product)
Isotonizing agent: Sodium chloride 99.0mg
Buffer: 2.94 mg sodium citrate
pH adjuster: Sodium hydroxide Appropriate amount Solvent: Water for injection Appropriate amount

Heparin sodium, sodium chloride, and sodium citrate were dissolved in water for injection so as to have the above composition, and an appropriate amount of sodium hydroxide was added to adjust the pH to about 7.0. The dissolved adjustment chemical was filtered through a filter (Millipore, Durapore CVGL71TP3 × 1), transferred to a liquid storage tank, and stored. After attaching a cap to a sterilized barrel made of polypropylene, 10 mL of a chemical solution was filled into the sterilized barrel from a liquid storage tank, and a gasket was plugged. The syringe filled with the chemical solution was subjected to high-pressure steam sterilization (121 ° C., 20 minutes) using a high-pressure steam sterilizer (GEV141851 AR2 manufactured by GETINGE). The pH of the sterilized drug solution was about 7.0, and the osmotic pressure ratio was about 1 (ratio to physiological saline).
Thereafter, the syringe was externally packaged by blister packaging to obtain a heparin-containing prefilled syringe preparation.

<In 20 mL formulation>
Active ingredient: Heparin sodium 10000 units (14th Japanese Pharmacopoeia listed product)
Isotonizing agent: Sodium chloride 180.0mg
Buffer: Sodium citrate 5.88mg
pH adjuster: Sodium hydroxide Appropriate amount Solvent: Water for injection Appropriate amount

Heparin sodium, sodium chloride and sodium citrate are dissolved in water for injection so as to have the above composition, an appropriate amount of sodium hydroxide is added, and pH is about 7. Adjusted to zero. The dissolved adjustment chemical solution was filtered through a filter (Millipore Corp., Durapore CVGL 7 1 TP 3 × 1), transferred to a liquid storage tank, and stored. After attaching a cap to a sterilized syringe made of polypropylene, 20 mL of a chemical solution was filled into a sterilized barrel from a liquid storage tank, and a gasket was plugged. The syringe filled with the chemical solution was subjected to high-pressure steam sterilization (12.degree. C., 20 minutes) using a high-pressure steam sterilizer (GEV 1 4 1 5 1 AR 2 manufactured by GET INGE). The pH of the sterilized chemical solution is about 7. The 0 osmotic pressure ratio was about 1 (ratio to physiological saline). Thereafter, the syringe was packaged by blister packaging to obtain a heparin injection prefilled syringe preparation.

more than

The present invention can be used for preventing blood coagulation when using an extracorporeal circulation device such as hemodialysis, and can be suitably used as an injection for continuous infusion into an extracorporeal circulation circuit.

Claims (1)

A heparin solution containing 500-1000 units / mL heparin and having a pH of 7.0 is prepared, and 10 mL to 20 mL of the resulting heparin solution is filled and sealed in a polypropylene syringe, and then subjected to high-pressure steam sterilization. A method for producing a heparin-containing prefilled syringe preparation for continuous infusion connected to a hemodialyzer pump , characterized by blister packaging.
more than