JPH0255410B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel freeze-drying method, and its purpose is to provide a freeze-dried product containing fine mannitol with excellent solubility.

There is a demand for a lyophilized mannitol-containing product, particularly a lyophilized preparation that is a useful mannitol excipient for injections, and is finer and more soluble than conventional products.

In the freeze-drying method of an aqueous solution containing mannitol, the present inventor has determined that the cooling rate of the product temperature in the freezing step is at least 1 degree/minute, preferably 1 to 10 degrees/min.
degrees/min, more preferably 2 to 4 degrees/min in terms of energy costs for cooling.
The inventors have discovered that it is possible to obtain a product having excellent properties as described above, and have completed the present invention based on this discovery.

Freeze-drying consists of a freezing step and a subsequent drying step. However, if the cooling rate is slow, less than 1 degree per minute, which is conventionally used in the freezing process, precipitates are formed during the cooling process, and for example, It contains spherical crystals of 1 mm or more, and does not give a powder that is necessarily satisfactory in terms of appearance and solubility. On the other hand, according to the present invention, no precipitates are generated during the cooling process, and no spheroidal crystals are found. It is possible to obtain a powder that is more satisfactory in both appearance and solubility, and the present invention is extremely significant, particularly in the pharmaceutical field.

The mannitol-containing aqueous solution used in the present invention is a homogeneous solution mainly composed of water containing at least mannitol. The concentration of mannitol is, for example, about 1 to 10% of the total water. Of course, other ingredients can be included, such as pharmaceutically active ingredients. In that case, the concentration of other components is about 0.01 to 1% based on the total water content.

The freeze-drying operation in the present invention may be carried out using a method known per se.

In addition, when a sample mannitol-containing aqueous solution is placed in a weak container such as a beaker or a wide-mouth bottle and freeze-dried in a vacuum system, crystallization of mannitol may occur, especially when the mannitol concentration is 3% or more based on the total water content. Due to the recrystallization of the released hydration water, the container breaks due to the impact caused by the volumetric expansion of the contents. To avoid this, −22
The drying process may be carried out by selecting conditions under which at least 1% of the total moisture vaporizes at a temperature not exceeding .degree. C. at the beginning of the drying process.

To elaborate on this point, the freeze-drying process consists of a freezing process and a subsequent drying process, but when a mannitol-containing aqueous solution is placed in a glass container such as a beaker and subjected to the freeze-drying process, During the drying process, the containers often broke due to the impact caused by the volumetric expansion of the contents. For this reason, it was necessary to use a special container in terms of material, wall thickness, shape, etc.

As a result of intensive research to solve the above problems and develop a method that can be carried out even if a weak container is used, the inventor has determined that the moisture evaporation conditions in the drying process are set at a temperature not exceeding -22 degrees Celsius. The inventors have discovered that the problem can be solved by adopting conditions such that at least 1%, preferably at least 5%, of the total moisture at the initial stage of the process is vaporized, and based on this discovery, the present invention has been completed.

That is, as shown in Example 1, when a freeze-thaw curve was obtained for mannitol water, a specific curve was obtained, and in particular, around -22 degrees, there was a peak derived from refreezing that appeared to be due to precipitation of solutes. It was discovered that there is such a thing, and as a result of further studies taking this into consideration, the present invention was completed.

The mannitol-containing aqueous solution used in the present invention is a homogeneous solution containing at least mannitol and mainly consisting of water. The concentration of mannitol may be, for example, 1% or more based on the total water content, and the higher the concentration, the greater the impact during the drying process, so that the effects of the present invention are exhibited. In practical terms, it is about 1 to 10%. Of course, other ingredients can be included, such as pharmaceutically active ingredients. in this case,
As mentioned above, the concentration of other components is about 0.1 to 1% based on the total water content.

Hereinafter, the present invention will be explained in detail with reference to Examples.

Example 1 Changes in the amount of antifreeze water (freeze-thaw curve) during the freeze-thaw process were determined by the method shown below.

A system equipped with Nippon Bruzker's "minispec P20" NMR apparatus equipped with YHP's HP1000 minicon system was used for freezing and thawing experiments using sample tubes with an outer diameter of 7 mm.

Using 250 mg of a 9.1% mannitol aqueous solution as a sample, the results are shown in FIG. 1 when the cooling and heating rates were 6 degrees/min, and FIG. 2 shows the results when the heating rate was 0.5 degrees/min. The vertical axis is the amount of unfrozen water (g water/g dry volume), and the horizontal axis is the temperature (° C.). The solid line is the freezing curve, and the dashed line is the thawing curve.

Other sugar alcohols and sugars such as sorbitol, xylitol, glucose, fructose, lactose,
The same experiment as above was repeated for sucrose and sucrose.

As a result, it was found that the freeze-thaw curve of mannitol is specific compared to other sugar alcohols and saccharides.

As can be understood from Figure 1, when heated and thawed after being cooled and frozen at a rate of 6 degrees/minute, the temperature at around -22 degrees Celsius,
A peak derived from refreezing, which is thought to be due to solute precipitation, is observed on the curve. In Figure 1,
It was confirmed that even if the cooling rate was changed from 6 degrees/minute to 1 degree/minute, a curve similar to that shown in FIG. 1 with almost the same peaks could be obtained.

Normally, no remarkable history is observed for sugars and sugar alcohols other than gels, whereas a large freeze-thaw history loop was observed for mannitol aqueous solution.The height of the refreeze peak during thawing is Ultra-rapid freezing, such as when using liquid nitrogen, and slow freezing, less than 1 degree/min (see Figure 2).
In either case, it becomes smaller or disappears. The former produces a frozen condensate with a small cluster diameter, which is similar to matrix separation, and the amount released per unit weight is small when hydration water is released during thawing and crystallized. This is thought to be because the crystals have already formed and precipitated during the process.

Considering the above experimental results, we performed freeze-drying of the mannitol aqueous solution.

Take 20 ml of 9.1% aqueous solution of mannitol and add 100
ml beaker and dry in a natural temperature rise type freeze dryer (Refrigeration for Science, INC.,
model2281) and rotary pump (Hitachi,
Freeze-drying was performed using 160VP).

The obtained dried product was photographed using an Olympus optical stereomicroscope at a magnification of 16.

In slow freezing with a cooling rate of less than 1 degree/minute,
Large, flaky spherulites (diameter 1 mm or more) consisting of needle-like crystals were produced, which had unfavorable appearance and solubility.

On the other hand, rapid freezing at a cooling rate of 1 degree/min or more did not produce the above-mentioned large spherulites, and a more preferable product was obtained from both the appearance and solubility standpoints.

Furthermore, it was found that containers (beakers, wide-mouthed bottles, etc.) would crack during freeze-drying unless a large amount of ice was sublimated and created a gap at temperatures below -22°C, where refreezing occurs. This is because mannitol very easily releases water under freezing conditions, which turns into ice and expands in volume. Incidentally, the reason why the solubility is more favorable is thought to be closely related to the fact that this ice does not melt down to 0°C, so there is no movement of solutes, and that freeze-drying progresses as the sublimation surface recedes.
As a result, it can be understood that the freeze-drying effect of mannitol as an excipient is superior to that of other sugars and sugar alcohols.

In order to prevent the above-mentioned container from cracking, moisture vaporization conditions may be selected in the drying process such that at least 1% of the total moisture is vaporized at a temperature not exceeding -22°C.

This is comparable to the weight of the solute, i.e., Figure 1
As seen in Figure 1, it is thought that approximately 1 g of water/g of dry solute's hydration water causes refreezing during the thawing process, that is, the amount of water that causes refreezing is about the same as the weight of the solute. When the solute is 3% of the total water, the amount of hydration water to be refrozen is still 3% of the total water.
It is thought that the shock in that case can be prevented if at least 3% of the total water content of ice is sublimated, and the amount of mannitol used for freeze-drying is generally 1 to 10% of the total water content. %, it is sufficient to sublimate a minimum amount of 1% water at the beginning of the process.

According to the present invention, there is no need to use a special container in terms of material, wall thickness, shape, etc., and even if mannitol is present in a high concentration, a container that is weak against impact such as a beaker can be used. As a result, the preparation of freeze-dried products has become extremely simple.

Example 2 An aqueous solution prepared by dissolving 100 mg of mannitol, 5 mg of the anticancer polysaccharide lentinan isolated from the fruiting bodies of shiitake mushrooms, and 10 mg of "Dextran 40" in 2 ml of water was
ml vial and freeze-dried according to Example 1. In the drying process, first -35℃~25℃
Approximately 10% of the total water was vaporized at ℃. After that, it was naturally heated and dried. There were no cracks or cracks in the beaker.

125 mg of the lyophilized product thus produced was added to 5 ml of water and shaken 4 times in a vial to obtain a homogeneous aqueous solution. In contrast, the conventional method (cooling rate of product temperature in freezing process: 0.5 degrees/
The product freeze-dried (125 mg) with 5 minutes of water was colored, probably due to color reflection, and had a poor appearance.
ml and was shaken four times in a vial, no homogeneous aqueous solution was obtained, but a homogeneous aqueous solution was obtained after shaking seven times.

[Brief explanation of drawings]

1 and 2 are freeze-thaw curves obtained in Example 1. Solid line: freezing curve, dashed line: thawing curve.

Claims (1)

[Scope of Claims] 1. A freeze-drying method for an aqueous solution containing mannitol, characterized in that the cooling rate of the product temperature in the freezing step is at least 1 degree/minute. 2. The method according to claim 1, wherein the mannitol concentration in the mannitol-containing aqueous solution is 1 to 10% based on the total water content. 3. The method according to claim 1, wherein the cooling rate of the product temperature is 2 to 4 degrees/minute.