JP5280813B2 - Lyophilized composition containing glycopeptides and method for producing the same - Google Patents

Description

  The present invention relates to a freeze-dried composition containing glycopeptides and a method for producing the same, and is particularly effective for improving solubility.

Conventionally, freeze-dried preparations containing glycopeptides as active ingredients have noticeable foaming peculiar to peptides when they are dissolved at the time of use. There is a problem that bubbles are easily mixed when inhaled into a syringe, and that it is difficult to transfer all the active ingredients when mixing in an infusion solution.
Japanese Patent Application Laid-Open No. 9-124481 discloses a freeze-dried preparation that uses a silicon-coated vial as a preparation container to prevent the foam generated at the time of re-dissolution from adhering to the inner surface of the vial and becomes clear quickly. In the case of a lyophilized composition containing glycopeptides, it takes time to eliminate bubbles in the solution.
Japanese Patent Application No. 2001-548134 discloses that the solubility of the preparation is improved by combining vancomycin and polyethylene glycol.
In addition, in Patent Nos. 2883890 and 2983934, an organic solvent such as ethanol, n-propanol, and isopropyl acetate is freeze-dried with vancomycin to try to make a formulation with good resolubility. There was a problem with the conversion.

Japanese Patent Laid-Open No. 9-124481 Japanese Patent Application No. 2001-548134 Japanese Patent No. 2883890 Japanese Patent No. 2989344

  The present invention provides a freeze-dried composition capable of significantly suppressing foaming that occurs when a freeze-dried composition containing glycopeptides as an active ingredient is redissolved without adding a solubilizer or solubilizing agent. And it aims at provision of the manufacturing method.

  As a result of intensive studies to achieve such an object, the present inventors have once frozen a solution containing glycopeptides without adding a solubilizer or solubilizer such as polyethylene glycol. It has been found that when a part of the product is melted and then frozen again, the cake structure of the frozen product is changed, so that it is easily dissolved again at the time of use, there is less foaming, and the defoaming time is shortened.

More specifically, the freeze-dried composition containing glycopeptides according to the present invention is obtained by partially dissolving a frozen product obtained by freezing a solution containing glycopeptides until the frozen product partially remains, Thereafter, it is obtained by freezing again and then drying under reduced pressure.
In this way, it is not necessary to add a conventional additive that exhibits a solubilizing action or a solubilizing action to a solution containing glycopeptides.
In addition, you may add the acid and base for adjusting pH to the solution containing glycopeptides as needed.

The present invention works particularly effectively when vancomycin is used as an injection as a glycopeptide.
Vancomycin is a glycopeptide antibiotic.
When vancomycin is used as an injection, the lyophilized preparation of its hydrochloride is often dissolved in water for injection and then mixed with an infusion solution for administration.
However, vancomycin freeze-dried preparations have noticeable foaming when dissolved at the time of use, and such foaming causes an error in the determination of insoluble foreign matter, and bubbles are generated when the solution is inhaled from a vial into an injection syringe. There is a problem that it takes time to prepare an injection such that it is easy to mix and it becomes difficult to transfer all the active ingredients when mixed in an infusion solution, resulting in an error in dosage.
The method for producing an injectable vancomycin lyophilized preparation according to the present invention includes a step of freezing an aqueous solution in which vancomycin hydrochloride is dissolved, and a step of heating the frozen product to partially dissolve the frozen product partially. And a step of cooling and freezing again, and a step of drying under reduced pressure.
When manufactured in this way, it is not necessary to add an acid or base other than those intended for pH adjustment to the aqueous solution in which vancomycin hydrochloride is dissolved.
The vancomycin freeze-dried preparation produced in the above process has a bulk density in the range of 0.10 to 0.20 g / mL.
Thus, the freeze-dried composition of vancomycin having a bulk density of 0.10 to 0.20 g / mL or a pharmaceutically acceptable salt thereof is excellent in antifoaming property when dissolved at the time of use.
Here, the bulk density is the 15th revised Japanese Pharmacopoeia. This is a value measured based on the 3.01 bulk density and tap density measurement method of the powder physical property measurement method.

In the present invention, foaming is effectively suppressed during dissolution during use, and the defoaming time is short.
Such an effect can be obtained by adding water for injection to a vial using the freeze-dried composition or freeze-dried preparation as, for example, a preparation container, and comparing the amount of foam generated when the freeze-dried cake is dissolved, This can be confirmed by measuring the defoaming time.

Vancomycin is a glycopeptide antibiotic and is already commercially available, and it is easy to obtain pharmaceutical grades.
Further, it can also be produced, for example, by the method described in US Pat. No. 30,670,099.
In the present invention, a free body may be used, but it is not preferable because it is hardly soluble in water.
Although it may be used as a salt such as hydrochloric acid or nitrate, it is preferable to use hydrochloride.
This is because the manufacturing cost and stability are excellent.
As a method for preparing the lyophilized composition of the present invention, vancomycin or a pharmaceutically acceptable salt thereof and, if necessary, a basic substance or an acidic substance as a pH adjuster are dissolved in an aqueous solvent.
The basic substance or acidic substance is not particularly limited as long as it is a commonly used substance, and includes hydrochloric acid, phosphoric acid, citric acid, malic acid, tartaric acid, succinic acid or salts thereof, sodium hydroxide, calcium hydroxide, etc. is there.
The lyophilized composition of the present invention can be produced according to a conventional method depending on the dosage form.
What is necessary is just to manufacture, for example with the following method, when manufacturing an injection.
Instruments and materials used in production are sterilized in advance by a conventional method (for example, high-pressure steam sterilization, dry heat sterilization, γ-ray sterilization, etc.).
The active ingredient is weighed and placed in a dissolution container, and an appropriate amount of solvent (for example, water for injection) is added and dissolved while stirring.
The concentration of the solution may be determined in consideration of the type of solvent, the solubility of the active ingredient in the solvent, and the concentration at the time of re-dissolution.
Further, a basic substance or an acidic substance (for example, 0.1 to 10 mol / L aqueous solution is used) is added to adjust the pH to 6.0 or less.
The solution thus obtained is aseptically filtered by a conventional method.
If necessary, rough filtration for the purpose of removing decomposition products, contaminants, etc. may be performed before aseptic filtration.
If the sterile filtrate is appropriately dispensed into vials, trays, etc., pre-freezing including freezing, partial thawing and re-freezing is carried out and then freeze-dried, the intended injection is obtained.
Moreover, it is also possible to produce this lyophilized composition as a so-called infusion kit preparation that is easy to prepare at the time of use.
That is, it is enclosed in a first chamber of a multi-chamber container having a partition that can communicate a freeze-dried composition or a kit preparation of a type that dissolves a vial containing a freeze-dried composition in combination with a dissolving solution (for example, JP-A-6-254136). Then, a kit preparation of a type (for example, JP-A-4-3646481) in which the lysate is sealed in the second chamber and communicated at the time of use to dissolve this lyophilized composition is exemplified.

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

50 mL of a solution prepared by dissolving 500 mg of vancomycin hydrochloride per 5 mL of water for injection and adjusting the pH to 3.3 by adding hydrochloric acid was prepared.
This solution was aseptically filtered through a membrane filter (0.22 μm), and 5 mL of the solution was filled into a vial having an internal volume of about 15 mL.
This was freeze-dried according to the following method using a shelf-like freeze dryer.
<Freeze drying method>
(1) Cool to −40 ° C. and hold for 2 hours to freeze vial contents.
(2) The temperature was raised to 0 ° C. and held for 1 hour, and then heated to 4 ° C. and held for 2 hours to dissolve a part of the frozen material.
(3) After cooling to −4 ° C. and holding for 2 hours, it was cooled to −20 ° C., further cooled to −40 ° C. and refreezing.
(4) The temperature was raised to −20 ° C. under reduced pressure and held for 1 hour, and the temperature was further raised to −15 ° C. for primary drying.
(5) The temperature was raised to 25 ° C., secondary drying was performed, the vacuum was released with nitrogen gas, and the tube was sealed to complete lyophilization.

50 mL of a solution in which 500 mg of vancomycin hydrochloride was dissolved per 5 mL of water for injection was prepared.
This solution was aseptically filtered through a membrane filter (0.22 μm), and 5 mL of the solution was filled into a vial having an internal volume of about 15 mL.
This was freeze-dried according to the following method using a shelf-like freeze dryer.
<Freeze drying method>
(1) Cool to −40 ° C. and hold for 2 hours to freeze vial contents.
(2) The temperature was raised to 4 ° C. and held for 3 hours to dissolve a part of the frozen product.
(3) After cooling to −4 ° C. and holding for 2 hours, it was cooled to −20 ° C., further cooled to −40 ° C. and refreezing.
(4) The temperature was raised to −15 ° C. under reduced pressure to perform primary drying.
(5) The temperature was raised to 25 ° C., secondary drying was performed, the vacuum was released with nitrogen gas, and the tube was sealed to complete lyophilization.

200 mL of a solution in which 500 mg of vancomycin hydrochloride was dissolved per 5 mL of water for injection was prepared.
This solution was aseptically filtered through a membrane filter (0.22 μm), and 5 mL of the solution was filled into a vial having an internal volume of about 15 mL.
This was freeze-dried according to the following method using a shelf-like freeze dryer.
<Freeze drying method>
(1) Cool to −40 ° C. and hold for 2 hours to freeze vial contents.
(2) The temperature was raised to 10 ° C. and held for 0.5 hour to dissolve a part of the frozen material.
(3) After cooling to −4 ° C. and holding for 2 hours, it was cooled to −20 ° C., further cooled to −40 ° C. and refreezing.
(4) The temperature was raised to −15 ° C. under reduced pressure to perform primary drying.
(5) The temperature was raised to 25 ° C., secondary drying was performed, the vacuum was released with nitrogen gas, and the tube was sealed to complete lyophilization.

(Comparative Example 1)
50 mL of a solution in which 500 mg of vancomycin hydrochloride was dissolved per 5 mL of water for injection was prepared.
This solution was aseptically filtered through a membrane filter (0.22 μm), and 5 mL of the solution was filled into a vial having an internal volume of about 15 mL.
This was freeze-dried according to the following method using a shelf-like freeze dryer.
<Freeze drying method>
(1) Cool to −40 ° C. and hold for 3 hours to freeze vial contents.
(2) The temperature was raised to −10 ° C. under reduced pressure and held for 1 hour, and then the temperature was raised to 10 ° C. and primary drying was performed for 10 hours.
(3) After raising the temperature to 20 ° C. and carrying out secondary drying for 5.5 hours, the vacuum was released with nitrogen gas, the tube was sealed, and freeze-drying was completed.

<Evaluation results>
As shown in FIG. 3, the freeze-dried cake before melting has a light and smooth appearance in Comparative Example 1, but Examples 1 and 2 have a frost column-like appearance in which the ice crystal structure during freezing can be observed. Presents.
Next, the solubility was compared.
Immediately after adding 10 mL of water for injection to each vial as shown in FIG. 1, in Comparative Example 1, an undissolved freeze-dried cake floated on the surface of the solution, and the portion that did not sufficiently contact with water was a solid substance in the foam. Remains as.
In Examples 1 and 2, there are few undissolved freeze-dried cakes floating on the surface of the solution, and the undissolved cake is sufficiently in contact with water, so that dissolution proceeds.
Moreover, compared with the comparative example 1, since the foaming amount at the time of melt | dissolution is also small and defoaming is also short time, it is quick that a solution becomes clear.
As shown in FIG. 1, in Examples 1 and 2, dissolution was completed within 4 minutes by adding 10 mL of water for injection and no residual bubbles were observed, but Comparative Example 1 was not dissolved in the bubbles on the solution surface. A cake is allowed.
FIG. 2 shows a comparison of defoaming after adding 10 mL of water for injection and shaking and stirring for 4 seconds after standing still for 4 minutes.

[Measurement of defoaming time]
Immediately after adding 10 mL of water for injection to the vial, dissolve with stirring for 10 seconds (stroke 40 mm, 240 spm) with a shaker (KM-SHAKER V-DN type, Iwaki Sangyo Co., Ltd.), then leave to stand until defoaming Was measured.

In Examples 1, 2, and 3, the amount of foaming was small, and defoaming was confirmed within approximately 1 minute. In Comparative Example 1, fine residual bubbles were observed even after 2 hours had passed after standing.
For reference, when 10 mL of water for injection was added to 0.5 g of vancomycin hydrochloride drug substance, it became a gel and took a long time to dissolve.

[Bulk density measurement]
Next, the bulk density was compared.
15th revision Japanese Pharmacopoeia The measurement was performed in accordance with the 3.01 bulk density and tap density measurement method (bulk density first method constant mass method) of the powder physical property measurement method.
The solid contents of Examples 1, 2, 3 and Comparative Example 1 were taken out from the vial and gently broken up using a No. 10 (1.7 mm) sieve so as not to change the properties of the sample, and then No. 16 (1000 μm). Put 3g each through the sieve into a dry 50mL glass graduated cylinder (scale: 0.5mL increments) without compaction, and after carefully touching the top of the powder layer without compaction, the minimum scale The bulk volume up to the unit was read, and the bulk density ρ _B was calculated by the following formula.
ρ _B = M / V _O
ρ _B : Bulk density by constant mass method (g / mL)
M: Mass of powder V _O : Bulk volume of powder (mL)

The bulk density of Examples 1, 2, and 3 was larger than that of Comparative Example 1.
That is, the apparent volume (bulk volume of a constant mass) appeared to be smaller in Examples 1, 2, and 3.
The bulk density of Comparative Example 1 was 0.087 to 0.092 g / mL, (average: 0.090 g / mL), whereas the bulk density of Examples 1 to 3 was the minimum value: 0.0. It is in the range of 120 g / mL, maximum value: 0.162 g / mL.
Therefore, the lyophilized composition of glycopeptides according to the present invention was generally in the range of 0.10 to 0.20 g / mL, and in this example, it was in the range of 0.12 to 0.16 g / mL.

[Measurement of particle size distribution]
Next, the particle size distributions of the powders whose bulk density was measured were compared.
The mode diameter and median diameter were measured with a laser scattering diffraction particle size distribution analyzer (LS 13 320 type, TORNADO Dry Powder System BECKMAN COULTER.).

The mode diameter and median diameter of Examples 1, 2, and 3 were larger than those of Comparative Example 1.
The particle size distribution of Example 2 was unimodal, and Examples 1, 3 and Comparative Example 1 were bimodal.
More specifically, in Examples 1 to 3, the mode diameter was about 140 to 185 μm and the median diameter was about 120 to 145 μm, whereas Comparative Example 1 was smaller than that, and the mode diameter was 38. The median diameter was 42 to 54 μm.

The photograph which compared the foaming at the time of melt | dissolution is shown. The photograph which compared the defoaming time after shaking stirring is shown. The cake comparison photograph after freeze-drying is shown.

Claims (3)

A frozen product obtained by freezing a solution containing glycopeptides is obtained by partially dissolving by heating until a part of the frozen product remains, then freezing again, and then drying under reduced pressure .
The glycopeptides are vancomycin or a pharmaceutically acceptable salt thereof, and have a bulk density in the range of 0.10 to 0.20 g / mL .   A step of freezing an aqueous solution in which vancomycin hydrochloride is dissolved, a step of heating the frozen product so that the frozen product partially remains, a step of cooling and freezing again, and drying under reduced pressure And a method for producing a vancomycin lyophilized preparation for injection, which comprises the step of: The method for producing a lyophilized preparation for injection according to claim 2 , wherein the aqueous solution in which vancomycin hydrochloride is dissolved is not added except an acid or a base for adjusting pH.