JPH02207092A - Method for producing lyophilized preparations of anthracycline compounds or their salts - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

BACKGROUND OF THE INVENTION Technical Field The present invention relates to the use of anthracycline compounds, such as 3'-deamino-3'-(4-morpholinyl)13-, as active drug substances with excellent anti-tumor properties. Deoxo
10-hydroxy-carminomycin or 3'-
Relating to a method for producing a freeze-dried preparation containing deamino-3'-(4-morpholinyl)-11-deoxy-13-deoxo-carminomycin or a pharmaceutically acceptable salt thereof, having good shape, thermal stability, and solubility. It is something.

PRIOR ART The active drug substances which are the subject of the process according to the invention are anthracycline compounds, such as 3'deamino-3'
-(4-morpholinyl)-13-deoxo-10-hydroxy-carminomycin or 3'-deamino-3'-(4-morpholinyl)-11-deoxy-
It is clear that 13-deoxo-carminomycin or a pharmaceutically acceptable salt thereof, particularly those exemplified above, exhibit remarkable antitumor properties against animal tumors, particularly malignant tumors. (Special application 1986-1971)
(See specification No. 96 and Japanese Patent Application No. 60-40866).

When these active drug substances are used in the form of a solution, they are generally dried by lyophilization and redissolved by adding water for injection before use. However, these active drug substances have reduced activity upon drying, or have poor storage stability in a dry state or in a solution state after reconstitution, and also have drawbacks in the shape and solubility of lyophilized preparations. From this point of view, a more excellent freeze-drying method is desired.

[Summary of the invention]

Summary The present invention aims to solve the above problems by adding an excipient and setting the temperature conditions during freezing of the solution and the reduced pressure and temperature conditions during drying to a specific range. It is an attempt to achieve a goal.

That is, the method for producing a freeze-dried preparation of an anthracycline compound or a salt thereof according to the present invention includes adding at least one or more excipients to an anthracycline compound or a pharmaceutically acceptable salt thereof; Step (I) of obtaining an aqueous solution, and the aqueous solution obtained in step (I) are pre-frozen, the frozen product is heated to a predetermined temperature while maintaining the frozen state, and then the temperature is raised again to the above-mentioned pre-freezing temperature. The step of lowering the temperature (■), and the step (II
) is characterized by comprising a step (III) of drying the frozen product obtained in step (3) at a predetermined temperature and reduced pressure, and then drying it at a temperature higher than the temperature and under reduced pressure conditions greater than the reduced pressure. It is something to do.

Effects The production method according to the present invention is a method for providing a freeze-dried preparation that maintains the stability of an anthracycline compound or its salt, and has excellent shape and solubility. This is understood to be unexpected for those skilled in the art. The present invention makes it possible to provide anthracycline compounds or salts thereof in a highly stable state, and is expected to make a significant contribution to the field of pharmaceuticals.

[Detailed Description of the Invention] Summary The substance that is the object of the production method according to the present invention is an anthracycline compound or a pharmaceutically acceptable salt thereof;
A preferred example of the anthracycline compound is 3'
-deamino-3'-(4-morpholinyl)-13-deoxo-10-hydroxy-carminomycin, and 3
'-deamino-3' -(4-morpholinyl)-1
1-Deoxy-13-deoxo-carminomycin is mentioned, and the compound mentioned in particular has not only excellent antitumor properties, but also low cardiotoxicity and a high therapeutic index, making it a highly potent compound with few side effects. It is a promising antitumor agent.

As described above, the method for producing a freeze-dried preparation of an anthracycline compound or a salt thereof according to the present invention includes steps (I) to (III).

Note that the term "lyophilized preparation" as used in the present invention means a preparation that becomes a solution suitable for administration with water for injection or the like upon reconstitution.

Also, "pharmaceutical" or "pharmaceutically" are terms referring to applications in both the human and veterinary fields.

Anthracycline compound or its salt step (I) This step is a step in which an anthracycline compound or its salt is blended with at least an excipient as a stabilizer for this substance and obtained as an aqueous solution, and then This is a step of preparing an aqueous solution for the freezing step and vacuum drying step. Therefore, the substance composition in the aqueous solution obtained in step (I) and the composition of the lyophilized preparation finally obtained according to the present invention are basically the same. In addition,
In the present invention, this step is referred to as "the step of obtaining the anthracycline compound as an aqueous solution" in addition to the case where an aqueous solution is prepared from the anthracycline compound (or its salt) as a solid standard. (or a salt thereof) to obtain a predetermined aqueous solution.

As the excipient in the present invention, any excipient can be used as long as it increases the stability of the anthracycline compound or its salt when added to the substance.

Examples of such excipients include the monosaccharide galac+
-sugar, xylose, glucose, fructose, mannose, trisaccharide lactose, sucrose, cellobiose, maltose, trisaccharide maltotriose,
Examples include raffinose, sugar alcohols inositol, xylitol, sorbitol, and D-mannitol, but particularly preferred are lactose, maltose,
and D-mannitol.

In the present invention, one or more excipients including the above-mentioned preferred examples are used.

The amount of the excipient is 5 to 50 parts by weight, preferably 10 parts by weight, per 1 part by weight of the anthracycline compound or its salt.
~30 parts by weight. In addition, when two or more types of excipients are used, this blending ratio indicates the blending ratio as the total amount thereof.

When anthracycline compounds or their salts are added with excipients, during step (I) or when using lyophilized preparations,
That is, during reconstitution, it is turned into an aqueous solution, and the pH of this aqueous solution changes depending on the type of excipient. In the present invention, in addition to the excipient, a pharmaceutically acceptable pH 2 moderating agent is further added, so that the pH of the aqueous solution is maintained within a certain range, preferably from 3.5 to 6.0, more preferably from 3.5 to 6.0. p
It is desirable to adjust it to a range of H4.5 to 5.5. This pH adjuster can further enhance the stability of the lyophilized preparation.

Pharmaceutically acceptable pH regulators include, for example, acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and citric acid; bases such as sodium hydroxide, potassium hydroxide, and sodium bicarbonate; and buffers such as potassium dihydrogen phosphate. Examples include disodium hydrogen phosphate, sodium dihydrogen phosphate-citric acid, citric acid-sodium citrate, and potassium dihydrogen citrate-sodium hydroxide.

The composition in step (I) thus contains one or more selected from the group consisting of an anthracycline compound or a pharmaceutically acceptable salt thereof and a saccharide as an excipient, and preferably further includes pH adjustment. It contains an acid, a base, or a buffer as an agent. A specific example of this preferred composition is one comprising an anthracycline compound or a pharmaceutically acceptable salt thereof, lactose as an excipient, and sodium hydroxide as a pH adjusting agent.

The pharmaceutically acceptable salt of the anthracycline compound is a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, and salts with hydrochloric acid are particularly preferred.

The composition in step (I) is finally made into an aqueous solution using water for injection or the like in this step.

To bring the composition into an aqueous solution, any conventional operation is possible, but the anthracycline compound or its salt, the excipient, and preferably the pH adjusting agent are stirred into an appropriate amount of water, such as water for injection. Preferably, the solution is dissolved sequentially and then additional water for injection is added to the desired final volume.

The resulting aqueous solution must be rendered sterile by suitable sterilization means, such as ifiltration sterilization, under aseptic conditions.

Step (II) This step is an ideal frozen product preparation step for freezing the aqueous solution obtained in step (I) and subjecting it to the next vacuum drying step.
The aqueous solution obtained in I) is pre-frozen, and this frozen product is
After raising the temperature to the specified temperature while maintaining the frozen state,
The process consists of lowering the temperature again to the above-mentioned pre-freezing temperature.

The conditions for pre-freezing are that the cooling temperature is, for example, -35°C or lower, preferably about -40°C, and the maintenance time is, for example, 1 hour or more, preferably 2 to 3 hours.

The above-mentioned predetermined temperature after raising the temperature from pre-freezing is, for example, -
5 to -25°C, preferably -10° to -20°C,
The maintenance time is, for example, 0.1 to 10 hours, preferably 2 to 6 hours.
It's time. The speed of this temperature increase varies somewhat depending on the combination of the initial temperature and the temperature after the temperature increase, but the time required to reach the temperature after the temperature increase from the initial temperature is, for example, 0°2 to 3 hours. , preferably 0.5 to 2 hours.

As a means for the freezing operation, a commonly used appropriate cooling device may be used.

Step (I[I) This step is a step of drying the frozen product obtained in (■) under reduced pressure to prepare a freeze-dried preparation, which is the final composition of the production method according to the present invention. II)
The method consists of drying the frozen product obtained by drying at a predetermined temperature and reduced pressure, and then drying it at a temperature higher than the predetermined temperature and under reduced pressure conditions larger than the reduced pressure.

The initial reduced pressure conditions are such that the temperature is, for example, 0 to 15°C, preferably about 10°C, and the degree of vacuum is, for example, 0.08 to 0.0°C.
, 2 mbars preferably 0, 1 mbar
The maintenance time is, for example, about 7 to 20 hours, preferably about 12 hours.

The subsequent reduced pressure conditions are such that the temperature is, for example, 15-30'C1, preferably about 20°C, and the degree of vacuum is, for example, 0,045-0.
．． The pressure is about 0.07 mbar, preferably about 0.05 mbar, and the maintenance time is, for example, about 5 to 15 hours, preferably about 8 hours.

As a means for the reduced pressure operation, a commonly used freeze dryer may be used.

Preferred Embodiments Preferred embodiments of the production method according to the present invention, including steps (I) to (In), are as shown below.

It should be noted that the lyophilized formulation according to the invention can be prepared according to the manufacturing method described above - but with all the precautions required in handling hazardous substances such as anthracycline compounds. Thus, for example, the hydrochloride salt of an anthracycline compound, excipients, and pH adjusting agent are sequentially dissolved in an appropriate amount of water for injection with stirring, and then additional water for injection is added to reach the desired final volume. The resulting solution is filtered under aseptic conditions and dispensed into sterile containers (preferably ampoules or vials) of the desired volume.

Next, as pre-freezing, the temperature is maintained at -40°C for 2 to 3 hours, and then the temperature is raised to about -10°C to -20°C over 0.5 to 2 hours, and the temperature is maintained at that temperature for 2 to 6 hours. then one forty
After being recooled to ℃ and maintained at that temperature for 2-3 hours,
12-15 hours at about 10℃, vacuum degree 0, 15 bar, then 8-12 hours at about 20℃, vacuum degree 0.05 bar.
Let dry for an hour.

Seal under sterile conditions following normal procedures. The inner wall of the ampoule or vial is preferably coated with silicone in order to ensure good drainage during use and to maintain good shape and stability of the freeze-dried solid in the vial. When sealing lyophilized preparations under aseptic conditions, it is common to include an inert gas in order to increase stability.

As the inert gas, nitrogen, helium, neon, argon, and carbon dioxide gas are used, preferably nitrogen.

The following examples are detailed explanations of the present invention, but the present invention is not limited thereby.

Example 1 3'-deamino-3'-(4-morpholinyl)-
A lyophilized formulation containing 5 mg of 13-deoxo-10-hydroxy-carminomycin was prepared as follows.

Ishin-HCI Lactose 50.0a+g amount) Water for injection Appropriate ffi (amount required to make 2 ml) The dissolved above prescription solution was filtered through a 0.22μ membrane filter under sterile conditions. Then sterile volume 10
2.0 in a silicone-coated vial of 1.
One portion was dispensed. The vial was placed in a freeze dryer and pre-frozen to a shelf temperature of about -40°C and maintained at that temperature for 2 hours. Then, it takes about 1 hour to cool down to about -15°C.
and maintained at that temperature for 4 hours. Then about -
After being recooled to 40°C and maintained at that temperature for 3 hours,
Shelf temperature 10°C, vacuum degree 0, 1 mbar for 12 hours, then shelf temperature 20°C, vacuum degree 0. A lyophilized formulation was obtained by drying at 0.05 Ilbar for 8 hours.

Examples 2 to 5 In the same manner as in the method described in Example 1, instead of lactose, glucose (Example 2), sucrose (Example 3),
Maltose (Example 4), D-mannitol (Example 5)
) were obtained.

Reference Example Stability tests were conducted on the freeze-dried formulations obtained according to Examples 1 to 5. Table 1 shows the results of HPLC determination of the residual content compared to immediately after freeze-drying after storage at 60° C. for 5 weeks. Note that the HPLC conditions are as follows.

Mobile phase Niacetonitrile: Water - 35: 65 (adjusted to pH 2.0 with phosphoric acid) Mobile phase flow rate: 1. 5 ml/sin Analysis wavelength: 254 na Column packing: YMCAM-312 (ODS) (manufactured by Yamamura Chemical) Note) Control: Freeze-dried formulation at pH 5.0 with no excipients added.

Claims (1)

[Scope of Claims] 1. A step of blending at least one or more excipients into an anthracycline compound or a pharmaceutically acceptable salt thereof and obtaining the same as an aqueous solution (I);
and a step (II) of pre-freezing the aqueous solution obtained in step (I), raising the temperature of this frozen material to a predetermined temperature while maintaining the frozen state, and then cooling it again to the pre-freezing temperature. A step (III) of drying the frozen product obtained in step (II) at a predetermined temperature and reduced pressure, and then drying it at a temperature higher than the temperature and under reduced pressure conditions greater than the reduced pressure. A method for producing a lyophilized preparation of an anthracycline compound or a salt thereof, characterized by: 2. Anthracycline compound is 3'-deamino-3
'-(4-morpholinyl)-13-deoxo-10-hydroxy-carminomycin or 3'-deamino-3
2. The method according to claim 1, wherein the compound is '-(4-morpholinyl)-11-deoxy-13-deoxo-carminomycin. 3. The manufacturing method according to claim 1 or 2, wherein the pharmaceutically acceptable salt thereof is a hydrochloride. 4. The blending ratio of excipients is 5 to 1 part by weight per 1 part by weight of the anthracycline compound or a pharmaceutically acceptable salt thereof.
The manufacturing method according to any one of claims 1 to 3, wherein the amount is 50 parts by weight. 5. One or more excipients: galactose, xylose, glucose, fructose, mannose for monosaccharides; lactose, sucrose, cellobiose, maltose for disaccharides; maltotriose, raffinose for trisaccharides; and for sugar alcohols The manufacturing method according to any one of claims 1 to 4, characterized in that it is selected from the group consisting of inositol, xylitol, sorbitol, and D-mannitol. 6. When the lyophilized preparation is used, the pH of the solution is 3.
．． The manufacturing method according to any one of claims 1 to 5, characterized in that the preparation contains a pH adjuster so that the pH is 5 to 6.0. 7. The anthracycline compound or its salt is 3'-deamino-3'-(4-morpholinyl)-13-deoxo-10-hydroxy-carminomycin hydrochloride, the excipient is lactose, and the pH adjuster is sodium hydroxide. The manufacturing method according to any one of claims 1 to 6.