JP2013203675A - Diluted dexmedetomidine preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a diluted dexmedetomidine preparation stably storable for a long term while suppressing increase of impurities and stored in a plastic medicinal solution container.SOLUTION: A diluted dexmedetomidine preparation is produced by filling a medicinal solution container having a plastic container body and a butyl rubber plug body with a dexmedetomidine injection solution diluted to a concentration allowing direct administration to a living body, in particular to 1-10 μg/mL. Preferably, the preparation is a prefilled syringe preparation stored in a syringe having a plastic outer cylinder and a butyl rubber gasket.

Description

  The present invention relates to a dexmedetomidine diluted preparation filled in a container.

  Dexmedetomidine is a potent and highly selective central α2 adrenergic receptor agonist and is a compound having a sedative effect (Patent Document 1).

  The dexmedetomidine injection formulation currently marketed is a vial formulation (100 μg / mL) containing 200 μg of dexmedetomidine hydrochloride in 2 mL of one vial, and diluted to 50 mL with physiological saline (4 μg / mL) when used. There is a need. Therefore, there is a work burden at the time of preparation of a chemical solution and a risk of bacterial contamination, and development of a preparation diluted in advance is awaited.

  On the other hand, in recent years, prefilled syringes, which are pre-filled drug products, have been used from the viewpoints of preventing drug mix-ups and hospital infections, improving disposal, and reducing the burden on medical staff. ing. Glass or various plastics are used as the material for the chemical solution storage part of the prefilled syringe, that is, the outer cylinder. A prefilled syringe made of plastic is lighter and harder to break than a glass-made syringe, and has an advantage over a glass-made one in that a dispensing operation can be performed more safely at a medical site.

  From the above viewpoint, it is desirable that the dexmedetomidine diluted injection solution be a plastic prefilled syringe preparation. However, diluting the drug may reduce the stability of the preparation, and the plastic that is the material of the outer cylinder of the syringe, or the rubber or elastomer that is the material of the gasket, and the drug have some interaction, that is, the plastic Careful examination is necessary to make a pre-diluted prefilled syringe formulation because it may cause drug adsorption and elution of material components of the outer cylinder or gasket into the chemical solution.

  Lexomedetomidine, an optical isomer, has been reported as an impurity in dexmedetomidine, which is the main component of this preparation. As a result of the examination by the applicant of the present application, the undiluted dexmedetomidine injection solution showed almost no increase in impurities even when filled in a plastic syringe and stored for a long period of time. On the other hand, it has been clarified that impurities may increase over time when a diluted dexmedetomidine injection preparation is filled in a plastic syringe and stored for a long period of time.

Japanese Patent Publication No. 6-25138

  The present invention relates to a pre-diluted dexmedetomidine preparation stored in a plastic pharmaceutical container that can be stably stored for a long period of time while suppressing an increase in impurities, in particular, an existing syringe stored in a syringe having a plastic outer cylinder. It is an object to provide a diluted dexmedetomidine prefilled syringe formulation.

What solves the above-mentioned problems is the following present invention.
(1) A pre-diluted dexmedetomidine preparation in which a drug solution container having a plastic container body and a butyl rubber stopper is filled with dexmedetomidine hydrochloride injection solution diluted to a concentration capable of being directly administered to a living body.
(2) The already diluted dexmedetomidine preparation according to (1), wherein the dexmedetomidine hydrochloride concentration is 1 to 10 μg / mL.
(3) The pre-diluted dexmedetomidine preparation according to (1) or (2), which is a prefilled syringe preparation housed in a syringe having a plastic outer cylinder and a butyl rubber gasket.
(4) The already diluted dexmedetomidine preparation according to any one of (1) to (3), wherein the plastic is polypropylene or cyclic polyolefin.
(5) The already diluted dexmedetomidine preparation according to any one of (1) to (4), further sterilized by autoclaving.

  The already diluted dexmedetomidine injection formulation of the present invention is diluted to a concentration that can be directly administered to the living body, and is contained in a plastic container, but the generation of impurities is suppressed even during long-term storage at room temperature, and the formulation is stable. A highly potent formulation is provided. Therefore, it is possible to reduce the work burden when preparing the dexmedetomidine preparation at the medical site, and at the same time, eliminate the risk of bacterial contamination.

  The already diluted dexmedetomidine injection solution preparation of the present invention will be described in detail.

  The container body used in the present invention is formed of a plastic excellent in steam sterilization resistance, transparency, moldability and versatility. Examples of such plastics include polypropylene, polyethylene, polystyrene, polyamide, polycarbonate, polyvinyl chloride, poly- (4-methylpentene-1), acrylic resin, acrylonitrile-butadiene-styrene copolymer, and polyethylene terephthalate. Various resins such as polyester and cyclic polyolefin can be mentioned. Among them, polypropylene (PP), cyclic olefin polymer (COP) and cyclic olefin copolymer (COC) are preferred from the viewpoint of ease of molding, heat resistance, and chemical stability. And the like are preferred.

  The chemical solution container may be a plastic vial or a plastic syringe, but for the purpose of the present invention, a plastic syringe is more preferable. That is, the already diluted dexmedetomidine injection liquid preparation of the present invention is preferably a prefilled syringe preparation.

  Butyl rubber is used as the material of the stopper of the chemical container. If an elastomer is used as the material of the plug body, it is not preferable because impurities are formed over time during storage of the preparation. The stopper is used as a plastic vial seal or a plastic syringe gasket. The stopper may be of any known form, and if it is a gasket for a syringe, it is in close contact with the inside of the syringe outer cylinder and seals the rear end opening side of the syringe internal space, and easily slides inside the syringe. It is preferable that it is movable and a plunger can be attached to the rear end.

  The already diluted dexmedetomidine injection liquid preparation of the present invention contains an injection liquid in which dexmedetomidine is diluted to a concentration capable of being directly administered to a living body. Here, the direct bioadministration means that administration can be started to a patient without performing a dispensing operation such as dilution after the preparation is opened at a medical site. The concentration of such dexmedetomidine injection solution is preferably 1 μg / mL to 10 μg / mL. Dexmedetomidine injection needs to be administered slowly and continuously using a syringe pump or the like that can adjust the administration rate appropriately. If the volume of the drug solution becomes too large, and if it exceeds 10 μg / mL, fine adjustment of the administration rate becomes difficult. Moreover, since the dexmedetomidine injection formulation currently marketed shall be diluted and administered to 4 microgram / mL, it is still more preferable that it is 4 microgram / mL also in the already diluted injection formulation of this invention.

  The pH of the already diluted dexmedetomidine injection solution of the present invention is preferably 4.5 to 7 and more preferably 5 to 6 from the viewpoint of drug stability. The pH may be adjusted using an acid such as hydrochloric acid or an alkali such as sodium hydroxide, but a pharmaceutically acceptable buffer may also be used. Moreover, you may further add sodium chloride, glucose, etc. as an additive of an injection.

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

Example 1
Dexmedetomidine hydrochloride 4 mg and sodium chloride 9.0 g were dissolved in 1000 mL of water for injection to obtain an aqueous solution of dexmedetomidine hydrochloride 4 μg / mL (pH about 6). This aqueous solution is aseptically filtered using a 0.2 μm pore size filter (ADVANTEC, CELLULOSE ACETATE MEMBRANE FILTER), and then 50 mL in a 50 mL plastic syringe (outer cylinder: polypropylene (PP), gasket: butyl rubber). Filled one by one and sealed. Thereafter, autoclaving was performed according to a conventional method to obtain a pre-filled syringe preparation of an already diluted dexmedetomidine injection solution.

(Example 2)
A dilute dexmedetomidine injection solution prefilled syringe preparation was obtained in the same manner as in Example 1 except that an outer cylinder made of cyclic olefin polymer (COP) was used as the plastic syringe.

(Comparative Example 1)
A dilute dexmedetomidine injection solution prefilled syringe preparation was obtained in the same manner as in Example 1 except that a thermoplastic elastomer gasket was used as the gasket for the plastic syringe.

(Comparative Example 2)
100 mg of dexmedetomidine hydrochloride and 9.0 g of sodium chloride were dissolved in 1000 mL of water for injection to obtain a 100 μg / mL aqueous solution of dexmedetomidine hydrochloride (pH about 6). This aqueous solution is aseptically filtered using a 0.2 μm pore size filter (ADVANTEC, CELLULOSE ACETATE MEMBRANE FILTER), and then put into a 2.5 mL plastic syringe (outer cylinder: polypropylene, gasket: butyl rubber). Each 5 mL was filled and sealed. Thereafter, high-pressure steam sterilization was performed in the same manner as described above to obtain an undiluted dexmedetomidine injection solution prefilled syringe preparation.

(Comparative Example 3)
An undiluted dexmedetomidine injection solution prefilled syringe preparation was obtained in the same manner as in Comparative Example 2, except that the same elastomer gasket as in Comparative Example 1 was used as the plastic syringe gasket.

(Reference Example 1)
Dexmedetomidine hydrochloride 4 mg and sodium chloride 9.0 g were dissolved in 1000 mL of water for injection to obtain an aqueous solution of dexmedetomidine hydrochloride 4 μg / mL (pH about 6). After aseptic filtration, each 50 mL glass ampoule was filled and sealed. Thereafter, high-pressure steam sterilization was performed in the same manner as described above to obtain a pre-diluted dexmedetomidine injection solution glass ampoule preparation.

  The above Examples, Comparative Examples and Reference Examples are summarized in Table 1 below.

(Test Example 1) Stability test Each dexmedetomidine injection solution obtained in Example 1 and Comparative Examples 1 and 2 was stored at 60 ° C, and at the start of the test, after 1 week and after 3 weeks. The dexmedetomidine residual rate (%) at the time was measured by high performance liquid chromatography (HPLC) (values in the table are average values of n = 3). This test follows a general protocol for measuring dexmedetomidine content. However, since levomedetomidine, which is an optical isomer of dexmedetomidine, is detected as the same peak, d-form and l-form are added together. The medetomidine residual rate is defined as dexmedetomidine residual rate. The results are shown in Table 2.

(Measurement method of dexmedetomidine content)
To 10 mL of this product, 4 mL of internal standard solution and 6 mL of mobile phase were added to obtain a total of 20 mL of sample solution. Separately, water for injection is added to 10 mg of dexmedetomidine hydrochloride to make 100 mL of 0.1 mg / mL dexmedetomidine hydrochloride aqueous solution. 2 mL of this aqueous solution was collected, and water for injection was further added to make 50 mL to obtain a 4 μg / mL dexmedetomidine hydrochloride aqueous solution. 10 mL of this aqueous solution was weighed, and 4 mL of internal standard solution and 6 mL of mobile phase were added to make a total of 20 mL to obtain a standard solution. 50 μL each of the sample solution and the standard solution was subjected to HPLC under the following conditions. The peak area of each sample was measured by an automatic integration method, and the amount of dexmedetomidine was determined from the ratio of the peak area of dexmedetomidine to the peak area of the internal standard substance.
Detection condition Detector: UV absorption photometer (measurement wavelength: 220 nm)
Column: A stainless steel tube having an inner diameter of 4.0 mm and a length of 12.5 cm is filled with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: 20 ° C
Mobile phase: methanol / pH 7.0 5 mM phosphate buffer mixed solution (3: 2)
Flow rate: About 1.0mL / min
Internal standard solution: Isoamyl paraoxybenzoate (1 → 50000)

  From the results of Test Example 1, it can be seen that the diluted dexmedetomidine formulation is kept stable when stored in a plastic (polypropylene) container (syringe) and almost the same as when stored in a glass ampoule. .

(Test Example 2) Quantitative determination of levomedetomidine Each dexmedetomidine injection solution obtained in Examples 1 and 2 and Comparative Examples 2 to 4 was stored at 60 ° C., 1 week after and 3 weeks after the start of the test. The amount of levomedetomidine (ratio of levomedetomidine to dexmedetomidine) at each subsequent time point was determined (values in the table are average values of n = 2, units are%). The results are shown in Table 3.

(Measurement method of ratio of levomedetomidine to dexmedetomidine)
A sample solution of 50 μL was subjected to HPLC under the following conditions. The peak area of dexmedetomidine and the impurity levomedetomidine in each sample was measured by an automatic integration method, and the percentage of the ratio of the peak area of levomedetomidine to the peak area of dexmedetomidine was determined.
Detection condition Detector: UV absorption photometer (measurement wavelength: 220 nm)
Column: A stainless steel tube having an inner diameter of 4.0 mm and a length of 10.0 cm is filled with 5 μm of α1-acid glycoproteinated silica gel.
Column temperature: constant temperature around 25 ° C. Mobile phase: 2-propanol / pH 5.0 0.02 M acetate buffer mixed solution (1:99)
Flow rate: About 0.9mL / min

  From the results of Test Example 2, it was found that the pre-diluted dexmedetomidine injection solution prefilled syringe preparation using a thermoplastic elastomer for the gasket produced levomedetomidine when stored at 60 ° C. for 3 weeks. Although almost no decrease in the content of dexmedetomidine (total amount of d-form and l-form) was observed in Test Example 1, the results of Test Example 2 showed that when dexmedetomidine was formulated into an already diluted preparation, It shows that a unique problem of the formation of certain levomedetomidines can occur. On the other hand, the pre-diluted dexmedetomidine injection solution prefilled syringe preparation of the present invention using butyl rubber as a gasket is a preparation over a long period of time, although the production of levomedetomidine is suppressed despite being diluted to a concentration capable of direct bioadministration. It was shown that stability was maintained.

Claims (5)

A pre-diluted dexmedetomidine preparation in which a drug solution container having a plastic container body and a plug made of butyl rubber is filled with dexmedetomidine hydrochloride injection solution diluted to a concentration capable of being directly administered to a living body. The already diluted dexmedetomidine preparation according to claim 1, wherein the concentration of dexmedetomidine hydrochloride is 1 to 10 µg / mL. The pre-diluted dexmedetomidine preparation according to claim 1 or 2, which is a prefilled syringe preparation housed in a syringe having a plastic outer cylinder and a butyl rubber gasket. The pre-diluted dexmedetomidine preparation according to any one of claims 1 to 3, wherein the plastic is polypropylene or cyclic polyolefin. The already diluted dexmedetomidine preparation according to any one of claims 1 to 4, further sterilized by autoclaving.