JPS6168412A - Freeze-drying of medicine - Google Patents

Abstract

PURPOSE:When a medicine which crystallizes out of its aqueous solution by temperature difference is freeze-dried, the concentration of the aqueous solution to be frozen is set higher than the crystallization temperature to facilitate the drying of the frozen product and enable short-time and high-efficiency drying under milder conditions than the conventionals. CONSTITUTION:A medicine which crystallizes out of its aqueous solution by temperature difference such a sodium cefazolin (an antibiotic for injection) is made into an aqueous solution with such a concentration as it is lower than the crystallization concentration at room temperature and higher than that of precipitating eutectic crystals with water. The solution is, then cooled down to below its freezing point to effect the crystallization of the medicine. Then, the temperature is raised up to that at which ice melts, but the precipitated crystals do not dissolve and the temperature is held. Then, the solution is cooled down again to allow the crystals to grow and the whole system to freeze. The resultant frozen product is raised in its temperature and dried under reduced pressure according to a conventional method. This process are required to evaporate only water from the ice in the eutectic crystals and crystal water in the medicine, thus sublimation can be facilitated over the conventional process.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application: The present invention relates to an improvement in a method for freeze-drying pharmaceuticals, and is used in the production of freeze-dried preparations such as injections.

Prior Art: Freeze-dried pharmaceutical preparations are excellent quality preparations in that they can avoid contamination with foreign substances, and are often used particularly as single-dose forms of injections. Conventionally, this type of preparation has been produced by freeze-drying an aqueous solution having a concentration lower than the concentration of the eutectic precipitated with water.

Problems to be solved: In the conventional freeze-drying method, an aqueous solution with a concentration lower than the eutectic precipitation concentration with water was cooled, so ice first precipitated and the concentration of the drug in the aqueous solution gradually increased. It is thought that the eutectic will precipitate when its concentration reaches the eutectic precipitation concentration with water, but in reality, the eutectic does not precipitate because the freezing conditions are a dynamic process (non-equilibrium process). figure,
The aqueous solution becomes highly concentrated and finally becomes highly viscous, and the drug crystals do not precipitate and solidify in the solution state, resulting in the formation of a so-called chemical/tropic frozen product.

Since the water in this frozen body is difficult to sublimate, drying takes a long time and is not efficient. Furthermore, in order to ensure complete drying, harsh conditions such as higher temperatures and lower pressures are required compared to normal drying processes, and as a result, even the sublimable substances in the rubber stopper sublimate and adhere to the medicine. There was also the problem of lowering the quality of the freeze-dried preparation by one degree.

Means for Solving the Problem: The inventors of the present invention focused on the fact that drying is easy if the product water sublimated in the drying process is ice in the eutectic or crystal water in the pharmaceutical polishing crystal. As a result of intensive research, this invention was completed.

That is, in the method of this invention, contrary to the prior art, the concentration of the aqueous solution to be frozen is higher than the eutectic precipitation concentration, so when it is cooled, the pharmaceutical crystals first precipitate, and the concentration of the aqueous solution is lower than that of the conventional method. On the contrary, it gradually decreases, and when the eutectic precipitation concentration is reached, the eutectic is reliably precipitated. Therefore, it becomes extremely easy to dry the frozen body, and it can be dried in a shorter time and under milder conditions than in conventional methods.

The method of this invention is carried out by first preparing an aqueous solution of the drug.

The pharmaceutical used in the method of this invention is not particularly limited as long as it has the property of being precipitated from an aqueous solution due to a temperature difference, but it should be taken into consideration that it is a freeze-dried drug that is quenched by the method of this invention. Generally, injectable drugs are used, and it is most effective to apply the method of the present invention to injectable antibiotics. Examples of such injectable antibiotics include cefazolin sodium and cefazolin sodium.

Distilled water for injection is used as the water in which these pharmaceuticals are to be dissolved, when the freeze-dried preparation obtained by the method of the present invention is an injection.

The upper limit of the concentration of the drug in the aqueous solution needs to be lower than the concentration at which the drug precipitates at room temperature. This is because if the concentration of the drug in the aqueous solution exceeds this upper limit, the solution becomes a suspension rather than an aqueous solution, and the amount of the drug filled into each vial will vary.

Still, the lower limit of the concentration of the drug in an aqueous solution needs to be higher than the concentration of the precipitated eutectic of the drug and water, and the reason for this is clear from the above.

The concentration of the aqueous solution of the drug used in the method of this invention is:
It may be within the range of the above upper limit and lower limit, but it is more preferable to be closer to the upper limit because the amount of water sublimated from the frozen body is smaller. In addition, the above-mentioned upper limit concentration and lower limit concentration can be determined for each drug by a conventional method.

The aqueous pharmaceutical solution prepared in this manner is cooled to below freezing by placing the vial filled with the aqueous pharmaceutical solution in a freeze dryer. This process is a so-called pharmaceutical crystallization process, in which pharmaceutical crystals are precipitated and a portion of the water freezes.

Although the cooling temperature varies depending on the type of medicine, a temperature around -10°C is usually sufficient.

Once the cooler 1 degree reaches the target point, then the ice reaches M'U
The temperature at which the crystals dissolve and some of the crystals remain, that is, 20°C
Raise the temperature to around the same temperature and maintain it at that temperature.

Once a portion of the crystals have settled at the bottom of the vial, the contents in the vial are completely frozen and solidified by cooling to around -30° C. by a conventional method. This process is a so-called crystal growth and eutectic formation process, and the final result is a mixture of pharmaceutical crystals and ice as a frozen solid.

The frozen product thus obtained is then heated and dried under reduced pressure in a conventional manner. This process is a so-called drying process, in which the ice in the eutectic is sublimated, and if crystal water of the drug is included, the crystal water is also sublimed at the same time.

When the drying process is completed, the air in the vial is replaced with nitrogen if necessary, and the vial is tightly capped to obtain a lyophilized preparation.

Effects of the invention: According to the method of the invention, the water to be sublimed is
Since only the ice in the eutectic and the water of crystallization in the pharmaceutical crystal can be sublimated more easily than in conventional methods, the drying process can be completed in a short time and is efficient.

Furthermore, since the heating conditions and depressurization conditions are milder than in conventional methods, the quality defect of sublimable substances in the rubber stopper sublimating and adhering to medicines can also be overcome.

EXAMPLES Next, the method of the present invention will be specifically explained using examples. In addition, the temperature in Examples means the temperature of the shelf in a freeze dryer.

Example 1 A 28% aqueous solution of cefazolin sodium is prepared by dissolving cefazolin sodium (400 g strength) in distilled water for injection (1040 m/). 3.3 m of this water
Dispense into 400 vials of 1 volume and store in a freeze dryer. Next, it takes about 1 hour to cool down to around -10°C, and then it takes about 1 hour to raise the temperature to around 20'C, and is maintained at the same temperature for about 1 hour. Next, the contents were cooled to around -30°C over a period of about 2 hours and frozen, and then heated under a reduced pressure of about 150 mJo r r over a period of about 3 hours to 130°C.
Raise the temperature to around ℃. After continuing drying at the same temperature and pressure for about 14 hours, each vial was tightly stoppered and a lyophilized preparation containing 1 g of cefazolin sodium was added.

Claims (1)

[Claims] In a freeze-drying method for a pharmaceutical product that is crystallized from an aqueous solution by a temperature difference, the pharmaceutical product is made into an aqueous solution with a concentration range lower than the room temperature crystallization concentration and higher than the eutectic precipitation concentration with water;
The aqueous solution is cooled to below freezing point to crystallize the drug, then heated to a temperature range where the ice melts and the precipitated crystals do not dissolve, and after maintaining the same temperature, the solution is cooled again to grow drug crystals and the system. After completely freezing the entire
A method for freeze-drying pharmaceuticals, which is characterized by raising the temperature again and drying under reduced pressure.