JP2006111532A - Panipenem-containing double bag-type preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a panipenem-containing double bag-type preparation which can suppress changes caused by admixture of betamipron with panipenem and maintain stability of panipenem with time. <P>SOLUTION: The panipenem-containing double bag-type preparation 1 is equipped with a solid medicine-accommodating room 30 and a medicine solution-accommodating room 40, where the accommodating rooms 30 and 40 are isolated by an easily openable sealing part 20 formed so as to be opened by pressurizing the medicine solution-accommodating room 40 at the time of service thereby to cause the solid medicine-accommodating room 30 to communicate with the medicine solution-accommodating room 40, and the solid medicine-accommodating room 30 is filled with freeze-dried panipenem while the medicine solution-accommodating room 40 is filled with a betamipron-containing solution. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a panipenem-containing double bag type formulation useful as a carbapenem antibiotic, and more particularly to a panipenem-containing double bag type formulation in which a freeze-dried product of panipenem and a solution containing betamipron are filled in separate storage chambers. .

Panipenem is a compound widely known as a carbapenem antibiotic, including its synthesis method (Patent Document 1: Japanese Patent Publication No. 61-29357, Patent Document 2: Japanese Patent Publication No. 62-54427).
This panipenem shows nephrotoxicity when administered to humans alone, so it is necessary to administer betamipron at the same time to reduce this, but the mixture of panipenem and betamipron produces a condensate due to a change in formulation. It is known to do.

As a technique to solve this problem, a method of injecting a panipenem-containing solution onto a frozen product of betamipron, freezing it into a two-layer frozen product, and then freeze-drying the obtained two-layer frozen product at a time Has been proposed (Patent Document 3: Japanese Patent No. 2135996).
In the bilayer freeze-dried preparation obtained by this method, the betamipron layer and the panipenem layer are separated into two layers, and the above-mentioned change in the composition can be suppressed. The betamipron layer is commercially available in the form of a two-layer lyophilized preparation (Calbenin, Sankyo Co., Ltd.) having a panipenem layer as an upper layer.

However, in the method of Patent Document 3, it is difficult to completely prevent the surface of the betamipron layer from dissolving when the panipenem solution is dispensed onto the frozen betamipron layer. There is a problem that a layer in which and are dissolved and mixed is generated.
Not only is it a continuous process of dispensing betamipron solution, freezing betamipron solution, dispensing panipenem solution, freezing panipenem solution, freeze-drying of two-layer frozen product, It is difficult to set freezing / drying conditions, and a large amount of processing can be performed at the same time only by preparing a working environment using a special apparatus.

In addition, when this preparation is administered to a patient, there is a problem that the administration method is complicated because a procedure for separately preparing a solution such as physiological saline and dissolving the preparation in this solution is required. .
Therefore, it is possible to suppress changes in the combination of betamipron and panipenem, and to maintain the temporal stability of panipenem, and it is easy to administer panipenem-containing preparation, and this preparation does not require a special device and production environment. The development of a new technique that can be manufactured efficiently is desired.

Japanese Patent Publication No. 61-29357 Japanese Patent Publication No.62-54427 Japanese Patent No. 2135996

  The present invention has been made in view of such circumstances, and an object of the present invention is to provide a panipenem-containing double bag type preparation capable of suppressing a change in the composition of betamipron and panipenem and maintaining the temporal stability of panipenem. To do.

  As a result of intensive studies to achieve the above-mentioned object, the present inventor has obtained a panipenem-containing double bag-type preparation in which a panipenem freeze-dried product and a betamipron-containing solution are filled in separate storage chambers. The present invention has been found to be able to suppress the change in formulation with the above, to maintain the stability of panipenem over time, to be easily manufactured without requiring a special manufacturing apparatus and manufacturing environment, and to be easily administered with a drug. completed.

That is, the present invention
1. A solid drug storage chamber and a drug solution storage chamber are provided, and each of the storage chambers is opened by pressing the drug solution storage chamber when in use so that the solid drug storage chamber and the drug solution storage chamber can communicate with each other. The solid drug storage chamber is filled with a freeze-dried panipenem product, and the drug solution storage chamber is filled with a betamipron-containing solution. Panipenem-containing double bag formulation,
2. The panipenem lyophilized product contains a stabilizer, 1 panipenem-containing double bag type formulation,
3. Provided is one or two panipenem-containing double-bag preparations, wherein the betamipron-containing solution is a physiological saline solution of betamipron.

According to the panipenem-containing double bag type preparation of the present invention, the panipenem freeze-dried product and the betamipron-containing solution are filled in separate storage chambers, so that the mixing change can be completely suppressed and the temporal stability of panipenem Can be maintained.
That is, in this preparation, the freeze-dried product of panipenem and the solution containing betamipron are completely packaged separately, so that betamipron and panipenem are not in physical contact with each other, unlike the conventional two-layer freeze-dried preparation. Compared to the form in which each layer is closely adhered at the interface, the composition does not change at all, and the temporal stability of panipenem can be maintained.
Moreover, it is not necessary to prepare a physiological saline or the like separately as in the conventional product by using a betamipron solution as a solution, and both betamipron and panipenem are dissolved in the prepared physiological saline. It is possible to simplify the administration method of the drug without taking time and effort.

Hereinafter, the present invention will be described in more detail.
The panipenem-containing double bag type preparation according to the present invention comprises a solid drug storage chamber and a drug solution storage chamber, and each of these storage chambers is opened by pressing the drug solution storage chamber when in use, and the solid drug storage chamber And the drug solution storage chamber is isolated by an easily openable sealing portion formed so as to allow communication, the solid drug storage chamber is filled with a freeze-dried panipenem, and the drug solution storage chamber is filled with a betamipron-containing solution. It is filled.
In the present invention, panipenem means (5R, 6S, 8R) -2-[(3S) -1-acetimidoylpyrrolidin-3-ylthio] -6- (1-hydroxyethyl) -2-carbapenem-3- It is a carboxylic acid and can be produced by a known production method as described in Patent Documents 1 and 2 described above. Betamipron is N-benzoyl-β-alanine.

  The double bag used in the preparation of the present invention is particularly limited as long as it has a solid drug storage chamber and a drug solution storage chamber, and these two storage chambers are separated by the easy-open sealing portion. However, various conventionally known double bags can be used. Specifically, a bag having the same form as that of a meropen drip infusion made by Sumitomo Pharmaceutical Co., Ltd. or a pansporin intravenous bag made by Takeda Pharmaceutical Co., Ltd. may be used. can do.

The panipenem freeze-dried product is obtained by freeze-drying a panipenem-containing solution.
The panipenem-containing solution may be a solution containing at least panipenem, and can be appropriately selected from conventionally known panipenems-containing solutions. For example, a 5-10 mass% aqueous solution of panipenem can be used.
The panipenem-containing solution may be a solution containing only panipenem. However, since panipenem itself has low stability, a stabilizer is preferably added.
The stabilizer is not particularly limited as long as it has a stabilizing action of panipenem and does not adversely affect the human body, and examples thereof include sodium chloride. In this case, the compounding ratio of panipenem and sodium chloride is 1: 0.25 or more, preferably 1: 1 in molar ratio.

  The method for freeze-drying the panipenem-containing solution is not particularly limited, and it can be freeze-dried using various methods known in the art such as using a freezer, a freeze-dryer, or a refrigerant such as liquid nitrogen. That's fine. As specific conditions, for example, a method of freezing at −50 to −10 ° C., preferably −50 to −40 ° C., for 0.5 to 2 hours, preferably 1 hour, and then drying at 0 ° C. Can be used.

The form of freeze-dried panipenem is not particularly limited as long as it is solid, and various forms such as powder, granule, flake, etc. can be used, but it can be quickly dissolved at the time of use. Therefore, a powdery one is suitable.
As a method for pulverization or granulation, various known methods can be used. For example, a method of pulverizing with a pulverizer such as a power mill, a comb mill, a sample mill, a method of sieving with a sieve, or the like is used. be able to.
The average particle size of the powdery or granular material is not particularly limited, but is preferably 50 μm or more, and particularly preferably 100 to 200 μm, considering the solubility in the betamipron-containing solution.

The betamipron-containing solution may be any solution containing at least betamipron, and can be appropriately selected from conventionally known betamipron-containing solutions.
As a solvent for dissolving betamipron, water alone may be used, but in view of isotonicity when betamipron is dissolved, it is preferable to use physiological saline.
Furthermore, since betamipron itself has low solubility in water, it is preferable to incorporate a pH regulator to improve this. The pH adjuster is not particularly limited as long as it has an action of improving the solubility of betamipron in water and does not adversely affect the human body. For example, sodium hydroxide is preferable. In addition, the compounding ratio of betamiprone and sodium hydroxide is 1: 1 or more by molar ratio, preferably 1: 1.

The method for preparing the betamipron-containing solution is not particularly limited. For example, a method of dissolving betamipron and a pH regulator in a solvent such as water or physiological saline, or betamipron in a solvent such as water or physiological saline. After turbidity, a method of preparing a solution containing betamipron by adding a pH adjusting agent can be employed.
In this case, the content of betamipron can be, for example, about 0.1 to 5% by mass in the solution.
In addition, the content ratio of panipenem and betamipron in the double bag type preparation of the present invention may be equivalent to that of carbenin (manufactured by Sankyo Co., Ltd.) currently marketed, for example, 1: 1 by mass ratio. Can do.

  In the double bag type preparation of the present invention, in addition to the above-mentioned stabilizer and pH adjuster, other additives used for general injections and the like can be further blended. As specific examples, other pH adjusting agents such as hydrochloric acid, sodium hydroxide and phosphate, isotonic agents such as sodium chloride and glucose, excipients such as glucose and the like can be blended. These additives may be blended in a freeze-dried panipenem product or in a betamipron-containing solution.

Hereinafter, an embodiment of the present invention will be described with reference to the drawings.
As shown in FIG. 1, the panipenem-containing double bag type preparation 1 according to the present invention has a resin film 10 made of two substantially rectangular polyolefin resins and the like, each having a short edge 10A and a long edge 10B. A solid drug storage chamber 30 and a drug solution storage chamber 40 separated by an easy-open sealing unit 20 are provided inside the bag body 11 sealed by thermal welding or the like at the four peripheral edges. The solid drug storage chamber 30 is filled with a Panipenem lyophilized product, while the drug solution storage chamber 40 is filled with a betamipron-containing solution.

  The easy-open sealing part 20 is formed by joining the resin films 10 on the front and back with heat welding, a known adhesive, or the like. Normally, the easy-open sealing part 20 separates the panipenem freeze-dried product filled in the solid drug storage chamber 30 from the betamipron-containing solution charged in the drug solution storage chamber 40. When the drug solution storage chamber 40 is pressed, it is opened, and the solid drug storage chamber 30 and the drug solution storage chamber 40 are communicated with each other. As a result, the betamipron-containing solution and the panipenem lyophilized product are mixed and homogenized inside the bag body 11.

In addition, the medicine solution discharge port 50 that communicates the medicine solution storage chamber 40 with the outside of the bag body 11 is provided in the bag body 11 so that the medicine that has been mixed and homogenized in this manner can be taken out of the bag body 11. In the short edge 10A on the drug solution storage chamber 40 side.
The drug solution discharge port 50 is formed of a substantially cylindrical resin molded body or the like, and its opening end 50A is usually sealed with a lid member (not shown), and when the mixed drug is taken out after mixing the drug. The lid member is removed.
For example, when the short edge 10A is sealed, the chemical solution discharge port 50 is attached to the bag body 11 in a state where the chemical solution discharge port 50 is interposed between the two resin films 10. It is possible to adopt a technique such as integrating them with each other.

As a method for producing the panipenem-containing double bag type formulation 1 described above, for example, the panipenem freeze-dried layer product prepared as described above is loaded into the solid medicine storage chamber 30 by powder filling or the like, and as described above. A method of filling the drug solution storage chamber 40 with a separately prepared betamipron solution can be used. In this case, the filling method can be performed by a known method.
As an example, first, the two long edges 10B and 10B and the easy-open sealing part 20 in the resinous film 10 are sealed, the two short edges 10A are opened, and the inside is the easy-open sealing part 20. After filling the isolated chamber with the freeze-dried product containing panipenem, the short edge 10A on the side is sealed, and the other chamber is filled with the betamipron-containing solution. There is a method of sealing the short edge 10A together with the chemical solution discharge port 50, but is not limited thereto.
The order of preparing and filling the panipenem freeze-dried product and the betamipron-containing solution is arbitrary.

In the above embodiment, the bag body 11 is used which is prepared by sealing the four peripheral edges 10A and 10B of the two resin films 10 by heat welding or the like. However, the present invention is not limited to this. You may use the bag body etc. which seal two openings of the cylindrical molded object obtained by shaping | molding.
Moreover, although the chemical | medical solution discharge port 50 was provided in 10 A of short edges by the side of the chemical | medical solution storage chamber 40, it is not restricted to this, The position is arbitrary and is provided in the short edge and long edge by the side of a solid chemical | medical agent storage chamber. It may be.
In addition, specific materials, shapes, structures, and the like constituting the members are not limited to those described above, and can be appropriately changed as long as the object of the present invention can be achieved.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated more concretely, this invention is not limited to the following Example.
[Example 1]
50 g of panipenem and 10 g of sodium chloride were dissolved in 440 g of water in a 1000 mL glass container. This solution was poured into a metal vat, frozen at -40 ° C for 1 hour, and then dried at 0 ° C for 24 hours to obtain a freeze-dried panipenem product.
Separately, 50 g of betamipron was suspended in 1 L of physiological saline, 1 mol / L sodium hydroxide was added dropwise to dissolve it, adjusted to pH 7.0, and then physiological saline was added to make 10 L.
0.6 g of the freeze-dried panipenem product obtained above was powder-filled in a solid drug container, and about 100 mL of betamipron solution was liquid-filled in the drug solution container to obtain a panipenem-containing double bag type preparation.
In this preparation, the freeze-dried product of panipenem and the betamipron solution are physically completely separated at the boundary of the bag, and there is no contact between them. In addition, since betamipron is filled in a solution state, when used, it is a simple operation of opening the sealing part provided at the boundary of each chamber by pressing the drug solution storage chamber and communicating each storage chamber. Panipenem and a betamipron-containing solution can be mixed and the panipenem can be dissolved in the betamipron solution.

It is a top view which shows the panipenem containing double bag type formulation which concerns on one Embodiment of this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Double bag type formulation 20 containing panipenem Easy-open sealing part 30 Solid medicine storage chamber 40 Drug solution storage chamber

Claims (3)

A solid drug storage chamber and a drug solution storage chamber are provided, and each of the storage chambers is opened by pressing the drug solution storage chamber when in use so that the solid drug storage chamber and the drug solution storage chamber can communicate with each other. Isolated by an easy-open seal
A panipenem-containing double-bag formulation, wherein the solid drug storage chamber is filled with a freeze-dried product of panipenem, and the drug solution storage chamber is filled with a solution containing betamipron.   The double-pane formulation containing panipenem according to claim 1, wherein the freeze-dried panipenem contains a stabilizer.   The panipenem-containing double bag type preparation according to claim 1 or 2, wherein the betamipron-containing solution is a physiological saline solution of betamipron.

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