JP2015034142A - Prefilled syringe formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a technique suppressing decreased content of maxacalcitol by adsorption which is caused when filling a glass syringe, which has a gasket or a cap made of butyl rubber used for general prefilled syringe formulation, with an aqueous solution formulation with pH of 7.5-8.5 containing maxacalcitol (1α,25-dihydroxy-22-oxavitamin D) and a pH regulator.SOLUTION: The invention provides a prefilled syringe formulation filling a syringe, which has one or two kinds of components selected from a gasket and a cap subjected to the surface treatment with polytetrafluoroethylene, with an aqueous solution formulation with pH of 7.5-8.5 containing maxacalcitol and a pH regulator.

Description

  The present invention relates to a prefilled syringe preparation having high stability even when an aqueous solution preparation containing maxacalcitol is filled in a syringe.

Maxacalcitol (1α, 25-dihydroxy-22-oxavitamin D ₃ ), which is a vitamin D derivative, has a strong in vitro differentiation-inducing activity, while having a low in vivo calcium-elevating action, secondary parathyroid bodies It has been clinically tested as a candidate for therapeutic agents such as hyperfunction and psoriasis.

  However, in general, vitamin D derivatives are chemically unstable, and maxacalcitol is also unstable in an aqueous solution.

  In recent years, it has been reported that an aqueous solution formulation containing maxacalcitol and a pH regulator such as disodium hydrogen phosphate and having a pH of 7.5 to 8.5 is stable even in an aqueous solution (Patent Document 1). ).

Japanese Patent No. 3668225

  By the way, in recent years, for the convenience and safety, a prefilled syringe preparation in which the preparation is preliminarily placed in a syringe has been demanded by medical staff, but the above aqueous solution preparation is used for a general prefilled syringe preparation, When the cap is made of butyl rubber and filled into a syringe, maxacalcitol was adsorbed on the gasket or cap during storage, resulting in a new problem that the content was reduced.

  As a result of diligent research to solve the above problems, the present inventors have found that the content of maxacalcitol does not decrease during storage by changing the member constituting the syringe filled with the aqueous solution preparation. The present invention has been completed.

That is, the present invention provides an aqueous solution formulation containing maxacalcitol and a pH adjuster and having a pH of 7.5 to 8.5.
A prefilled syringe preparation characterized by filling a syringe having one or two members selected from gaskets and caps, which is surface-treated with polytetrafluoroethylene.

In addition, the present invention provides an aqueous solution formulation containing maxacalcitol and a pH adjuster and having a pH of 7.5 to 8.5.
The method for preserving the aqueous solution preparation is characterized by filling a syringe having one or two members selected from gaskets and caps, which is surface-treated with polytetrafluoroethylene.

  The prefilled syringe preparation of the present invention can suppress a decrease in the content of maxacalcitol during storage.

  The prefilled syringe preparation of the present invention can also suppress an increase in unknown impurities peculiar to a syringe preparation having a member surface-treated with polytetrafluoroethylene.

  The prefilled syringe preparation of the present invention is as stable as an aqueous preparation containing maxacalcitol encapsulated in a conventional glass ampoule.

  An aqueous solution formulation containing maxacalcitol and a pH adjuster and having a pH of 7.5 to 8.5 (hereinafter simply referred to as “the prescription syringe formulation” of the present invention). The content of maxacalcitol in the “aqueous solution formulation” is not particularly limited, and is, for example, 0.1 to 50 μg / mL, preferably 1 to 15 μg / mL.

  The pH adjuster used in the aqueous solution preparation is not particularly limited. For example, inorganic acids such as hydrochloric acid and phosphoric acid, organic acids such as acetic acid, succinic acid, tartaric acid and acidic amino acids, inorganic alkalis such as sodium hydroxide, Examples include organic alkalis such as basic amino acids, sodium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and the like. These pH adjusters can be used alone or in combination of two or more, but preferably at least sodium dihydrogen phosphate and disodium hydrogen phosphate are used.

  The aqueous solution preparation may contain a nonionic surfactant. Although it does not specifically limit as a nonionic surfactant, For example, polyoxyethylene (20) sorbitan oleate, monolauric acid polyoxyethylene sorbitan (20E.O.), etc. are mentioned. Among these nonionic surfactants, polyoxyethylene (20) sorbitan oleate is preferable because it can suppress the generation of unknown impurities derived from polytetrafluoroethylene and maxacalcitol. The content of the nonionic surfactant in the aqueous solution preparation is not particularly limited, but is, for example, 0.01 to 20 mg / mL, preferably 0.05 to 5 mg / mL.

  Further, the aqueous solution preparation may contain sodium edetate. This is preferable because generation of unknown impurities derived from polytetrafluoroethylene and known impurities derived from maxacalcitol can be suppressed. Although content of sodium edetate in an aqueous solution formulation is not specifically limited, For example, it is 0.01-20 mg / mL, Preferably it is 0.05-5 mg / mL.

  The aqueous solution preparation may further contain other components such as an isotonic agent and a solubilizing agent.

  Examples of the isotonic agent include salts such as sodium chloride and saccharides such as glucose. In an aqueous solution preparation, the isotonic agent may be added in such an amount that the osmotic pressure is the same as that of body fluid or physiological saline.

  Examples of the solubilizer include alcohols such as absolute ethanol, polyhydric alcohols such as polyethylene glycol, and the like. These solubilizers can be used alone or in combination of two or more, but are preferably absolute ethanol. Moreover, the content of the solubilizing agent in the aqueous solution preparation is not particularly limited, but is, for example, 0.01 to 100 μL / mL, preferably 0.05 to 50 μL / mL.

  The method for preparing the aqueous solution preparation is not particularly limited. For example, water such as water for injection, maxacalcitol, a pH adjuster, and if necessary, a nonionic surfactant, sodium edetate, and other components are appropriately mixed. The final pH is 7.5 to 8.5, preferably 8.0.

  The aqueous solution preparation obtained above may be further subjected to treatment such as filtration sterilization with a filter or the like.

  The preparation of the present invention is obtained by filling a syringe with the above aqueous solution preparation. The syringe has a conventionally known member such as a gasket, a cap, a barrel, a plunger, a flange, a finger clip, a luer tip, a luer slip, a luer lock, and the like. Two types, preferably both of which are surface-treated with polytetrafluoroethylene may be used. The material of the member selected from the gasket and the cap that are surface-treated with polytetrafluoroethylene is not particularly limited, but is preferably made of rubber such as butyl rubber or silicon rubber.

  In the syringe, the material of the barrel is not particularly limited. For example, cyclic polyolefin (COP), cyclic olefin copolymer (COC), polypropylene (PP), polycarbonate (PC), polyethylene terephthalate (PET), polymethylterpene (TPX) ) And the like, and glass. Among these materials, those made of resin are preferable, and those made of cyclic polyolefin are particularly preferable. Further, the barrel may be surface treated with polytetrafluoroethylene as well as the gasket and cap.

  In the above syringe, the material of the plunger, flange, finger clip, luer tip, luer slip, luer lock, etc. is not particularly limited because it does not directly contact the aqueous solution preparation.

  The gasket etc. surface-treated with the polytetrafluoroethylene demonstrated above and the syringe which has this are marketed widely, and they can be utilized without a restriction | limiting in particular. Specifically, these syringes can be purchased from Daikyo Seiko Co., Ltd. or the like.

  The preparation of the present invention can be produced in the same manner as a conventionally known prefilled syringe preparation. Specifically, it can be produced by filling an aqueous preparation prepared in advance into a capped syringe and sealing with a gasket.

  The thus-obtained preparation of the present invention can be stably stored at least at 10 ° C. for 3 years since the decrease in the content of maxacalcitol in the aqueous preparation filled therein is suppressed. .

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples at all.

In the following examples and the like, the concentration of each component was measured using UPLC (registered trademark: manufactured by waters) under the following conditions.
<Measurement conditions>
Detector: UV absorptiometer (measurement wavelength: 264 nm)
Column: Octadecylsilylated silica on stainless steel tube with inner diameter of 2.1 mm and length of 150 mm
It was filled with kagel (particle size 1.8 μm).
Column temperature: constant temperature around 40 ° C. Mobile phase: 10 mmol / L ammonium formate buffer / acetonitrile at pH 3.0
Mixed liquid (3: 2)
Flow rate: 0.3 mL / min
Measurement range: 40 minutes

Reference example 1
Preparation of aqueous formulation:
An aqueous solution preparation having the formulation shown in Table 1 below was prepared according to the following preparation method (pH 8.0).

<Preparation method>
A: Add components (4) to (6) to component (7) and stir.
B: Add (1) to component (3) and stir.
C: Add component (2) to B and stir.
D: Add A to C and stir.

Reference example 2
Ampoule preparation:
1 mL of the aqueous solution preparation prepared in Reference Example 1 was sterilized by filtration with a polyvinylidene fluoride filter, and then sealed in a glass ampule previously sterilized to obtain an ampoule preparation.

Reference example 3
Production of prefilled syringe formulations:
After 1 mL of the aqueous solution preparation prepared in Reference Example 1 was sterilized by filtration with a polyvinylidene fluoride filter, a 2.5 mL syringe consisting of a glass barrel, a butyl rubber gasket (without surface treatment), a cap, and the like ( Prefilled syringe preparation was obtained.

Example 1
Production of prefilled syringe formulations:
1 mL of the aqueous preparation prepared in Reference Example 1 was sterilized by filtration with a polyvinylidene fluoride filter, then a barrel made of cyclic polyolefin (Barrel 2.5LL: Daikyo Seiko Co., Ltd.), polytetrafluoroethylene (registered trademark: Gasket made of butyl rubber (D21-6-1) surface-treated with Teflon (3 mL Piston FR2-2S1: Daikyo Seiko Co., Ltd.), Cap made of butyl rubber surface-treated with polytetrafluoroethylene (1 mL LL Nozzle Cap) F2: Daikyo Seiko Co., Ltd.) and a plunger made of polypropylene (Plunger 2.5-2: Daikyo Seiko Co., Ltd.) were filled into a 2.5 mL syringe to obtain a prefilled syringe preparation.

Test example 1
Severe stability test:
The preparations of Example 1 and Reference Examples 2 to 3 were subjected to a severe stability test. In the severe stability test, the maxacalcitol content of each preparation was measured, and then placed in a constant temperature bath at 60 ° C. and humidity. After 7 days, the maxacalcitol content of each preparation was again measured. Was measured. For maxacalcitol, the relative content after 7 days was calculated when the content before the start was 100 (%). The results are shown in Table 2.

  In the preparation of Reference Example 3 using a gasket and cap made of butyl rubber used in a general syringe, a significant content reduction of maxacalcitol was observed. The cause was thought to be due to adsorption of maxacalcitol on the gasket and cap. Therefore, it was confirmed that the preparation of Example 1 using a gasket and cap coated with polytetrafluoroethylene for the prevention of adsorption suppressed the decrease in maxacalcitol content. However, in the preparation of Example 1, unknown impurities derived from polytetrafluoroethylene (relative retention time of about 0.83) (hereinafter simply referred to as “unknown impurities”) were confirmed.

Examples 2-5
Production of prefilled syringe formulations:
An aqueous solution preparation of each formulation described in Table 3 below was prepared according to the following preparation method (pH 8.0). Next, 1 mL of these aqueous solution preparations were sterilized by filtration with a filter made of polyvinylidene fluoride, and then filled into the same syringe as used in Example 1 to obtain prefilled syringe preparations (Examples 2 to 5).

<Preparation method>
A: Add components (5) to (9) to component (10) and stir.
B: Add (1) to component (4) and stir.
C: Components (2) to (3) are added to B and stirred.
D: Add A to C and stir.

Test example 2
Severe stability test:
The preparations of Examples 1 to 5 were subjected to a severe stability test under the same conditions as in Test Example 1, and the content of unknown impurities before and after the severe stability test was measured. The results are shown in Table 4.

  Even in the preparation of Example 2 in which the amount of surfactant polyoxyethylene sorbitan monolaurate (20E.O.) was increased, the content of unknown impurities could be reduced, but the surfactant was changed to polyoxyethylene ( 20) In the preparation of Example 3 changed to sorbitan oleate, the content of unknown impurities could be further reduced. Further, in the formulations of Examples 4 and 5 in which sodium edetate was added to the aqueous solution formulation, further reduction of unknown impurities was confirmed.

Test example 3
Severe stability test:
The present inventors, even when encapsulating maxacalcitol, encapsulates in a glass ampoule, the 9-hydroxy-iso form of maxacalcitol (hereinafter referred to as “known impurity”) during storage. ) Increased. Therefore, for the preparations of Reference Examples 2 to 3 and Examples 1, 3, and 5, a severe stability test was performed under the same conditions as in Test Example 1, and the content of known impurities before and after the severe stability test was measured. The results are shown in Table 5.

  In the preparations of Reference Examples 2 to 3 and the preparation of Example 1, the content of known impurities was comparable. However, the formulation of Example 3 in which the surfactant used in the formulation of Example 1 was changed to polyoxyethylene (20) sorbitan oleate could reduce the content of known impurities. Furthermore, the formulation of Example 5 in which sodium edetate was added to the aqueous formulation was able to further reduce the content of known impurities.

Test example 4
Accelerated stability test:
The formulations of Example 5 and Reference Example 2 were subjected to an accelerated stability test up to 6 months. In the accelerated stability test, after the maxacalcitol content of each preparation was measured, these were placed in a constant temperature bath at 25 ° C. and a humidity of 65%, before starting, after 1 month, after 3 months, and after 6 months. The content of maxacalcitol in each preparation was measured, and the relative content was calculated when the content before the start of maxacalcitol was 100 (%). The results are shown in Table 6.

  The formulation of Example 5 was found to have a lower reduction in maxacalcitol content and to be more stable than the ampoule formulation.

Example 6
Production of prefilled syringe formulations:
An aqueous solution preparation having the formulation shown in Table 7 below was prepared according to the following preparation method (pH 8.0). Next, 1 mL of this aqueous solution formulation was sterilized by filtration with a polyvinylidene fluoride filter, and then filled into the same syringe as used in Example 1 to obtain a prefilled syringe formulation (Example 6).

<Preparation method>
A: Add components (4) to (7) to component (8) and stir.
B: Add (1) to component (3) and stir.
C: Add component (2) to B and stir.
D: Add A to C and stir.

  This preparation was able to suppress the decrease in the content of maxacalcitol and to reduce the content of unknown impurities.

ADVANTAGE OF THE INVENTION According to this invention, the prefilled syringe formulation which has higher stability than the aqueous solution formulation containing the maxacalcitol encapsulated in the conventional glass ampule can be provided.

that's all

Claims (6)

An aqueous solution formulation containing maxacalcitol and a pH regulator and having a pH of 7.5-8.5,
A prefilled syringe preparation characterized by filling a syringe having one or two members selected from gaskets and caps, which is surface-treated with polytetrafluoroethylene.   The prefilled syringe preparation according to claim 1, wherein the barrel of the syringe is made of cyclic polyolefin.   The prefilled syringe preparation according to claim 1 or 2, wherein the aqueous solution preparation further contains polyoxyethylene (20) sorbitan oleate.   The prefilled syringe preparation according to any one of claims 1 to 3, wherein at least disodium hydrogen phosphate and sodium dihydrogen phosphate are used as the pH regulator.   The prefilled syringe preparation according to any one of claims 1 to 4, wherein the aqueous preparation further contains sodium edetate. An aqueous solution formulation containing maxacalcitol and a pH regulator and having a pH of 7.5-8.5,
A method for preserving the aqueous solution preparation comprising filling a syringe having one or two members selected from gaskets and caps, which is surface-treated with polytetrafluoroethylene.