JP2003321364A - Antineoplastic agent-containing composition solubilized and stabilized with cyclodextrin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an antineoplastic agent composition containing solubilized and stabilized N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide. <P>SOLUTION: The medicament composition comprises an antineoplastic compound N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide and a cyclodextrin. The medicament composition further comprises a physiologically permissible pH regulator and/or a carrier. The method for preparing the medicament composition comprises using N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide and cyclodextrin, and further using a pH regulator and/or a carrier, as occasion demands. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an antitumor agent-containing composition solubilized and stabilized by cyclodextrin and a method for producing the same.

[0002]

PRIOR ART AND PROBLEMS TO BE SOLVED BY THE INVENTION N-
(3-Chloro-7-indolyl) -1,4-benzenedisulphonamide is an antitumor compound that arrests the growth of cancer cells by a new mechanism of action. A group of compounds including this compound is disclosed in JP-A-7-165708. Oral administration is the most commonly used method of administering antitumor agents because it is the easiest to take and the burden on the patient is light. However, an injectable preparation is required when administration to a patient who cannot progress on his own due to the progress of medical conditions or when oral administration is impossible depending on the tumor site.

N- (3-chloro-7-indolyl)-
1,4-benzenedisulphonamide is a poorly water-soluble drug, and is insoluble by itself in the vicinity of pH 5 to 7, which is close to physiological conditions. Therefore, in WO97 / 30706, N- (3-chloro-7-indolyl) -1,4-
Contains benzenedisulphonamide and basic substances,
A pharmaceutical composition having a pH of 7 or more after being dissolved in water is disclosed. However, coloration with time may be observed in an alkaline solution, and a reaction product of N- (3-chloro-7-indolyl) -1,4-benzenedisulphonamide and a basic substance may be observed. There is such a problem.

An object of the present invention is to provide an antitumor agent composition containing solubilized and stabilized N- (3-chloro-7-indolyl) -1.4-benzenedisulphonamide. .

[0005]

The present inventors have found that the above problems can be solved by adding cyclodextrin, and have completed the present invention.

That is, the present invention relates to the antitumor compound N- (3-
Chloro-7-indolyl) -1,4-benzenedisulphonamide and a cyclodextrin-containing pharmaceutical composition, and a pharmacologically acceptable pH adjuster and / or
Alternatively, it provides a pharmaceutical composition containing a carrier. The dosage form of the antitumor agent-containing pharmaceutical composition of the present invention is not particularly limited, and examples thereof include liquid preparations, solid preparations, transdermal preparations, ointments, suppositories, etc., but aqueous preparations or freeze-dried preparations. Is preferable, and particularly, an aqueous injection or a lyophilized injection for dissolution at the time of use is preferable. The present invention also provides a pharmaceutical composition in which the above-mentioned pharmaceutical composition further contains an isotonicity agent, particularly an aqueous injection or a lyophilized injection for dissolution before use. Therefore, the present invention provides N- (3-chloro-7-indolyl)-
There is also provided a method for producing a pharmaceutical composition containing 1,4-benzenedisulphonamide and cyclodextrin, and a method for producing a pharmaceutical composition further containing a pharmacologically acceptable pH adjuster and / or carrier. Further provided is a method for producing a pharmaceutical composition in which the above-mentioned pharmaceutical composition also contains an isotonicity agent, particularly an aqueous injection or a lyophilized injection that is dissolved before use.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION N- (3-chloro-7-indolyl) -1,4-benzenedisulphonamide used in the present invention has the formula (I)

[0008]

[Chemical 1]

It is a compound having a structure represented by the formula (1), showing excellent antitumor activity and low toxicity. This compound can be produced, for example, by the method disclosed in JP-A-7-165708.

In the present invention, the cyclodextrin is, for example, β-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, β substituted with a hydroxyalkyl group or a sulfoalkyl ether group.
Examples thereof include cyclodextrin derivatives, and α-
Cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin are preferred, more preferably hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin. It is a dextrin. These cyclodextrins may be used alone or in combination of two or more.

The content of cyclodextrin in the composition of the present invention is N- (3-chloro-7-indolyl) -1,
With respect to 1 mol of 4-benzenedisulphonamide, it is 0.
A molar ratio of 05 to 10 mol is preferable, and a molar ratio of 0.1 to 5 mol is more preferable.

The composition according to the present invention can be made into various dosage forms for administering a drug, and particularly when it is made into an aqueous solution preparation or a freeze-dried preparation, it exhibits an excellent effect.
More preferably, aqueous injections and lyophilized injections for dissolution before use can be mentioned.

The composition of the present invention may contain a pharmacologically acceptable pH adjuster. The pH adjuster used in the present invention is not particularly limited as long as it can be used for pharmaceutical purposes and is a pharmacologically acceptable substance, but preferably sodium hydroxide, meglumine, carbonate buffer,
Phosphate buffer, citrate buffer, acetate buffer and hydrochloric acid. These pH adjusters may be used alone or in combination of two or more. The content of the pH adjuster in the composition of the present invention is preferably such that the pH of the solution after dissolution in water is 2 to 12, and more preferably 3 to 11.

The composition of the present invention may contain a pharmacologically acceptable carrier. Examples of the carrier include mannitol, lactose, sucrose, trehalose, dextrose and the like, and at least one of them can be used. The content of the carrier in the composition of the present invention is not particularly limited, but is preferably 1 to 30% by weight, more preferably 5 to 20% by weight.

In the present invention, when the composition is in the form of injection, at least one of sodium chloride and dextrose can be used as a tonicity agent.

According to the present invention, by adding cyclodextrin, N- (3-chloro-7-indolyl) -1,4-benzenediene is obtained not only in an alkaline solution but also in the vicinity of pH 5 to 7 which is close to physiological conditions. The solubility of sulfonamide is increased, and a solubilized preparation can be obtained.
In addition, the coloring over time observed in an alkaline solution is
It can be prevented by lowering H or N- (3-chloro-
It is possible to suppress the formation of a reaction product of 7-indolyl) -1,4-benzenedisulphonamide and a basic substance.

The production of the composition according to the present invention is not particularly limited, but for example, in the case of an aqueous solution preparation, N- (3-chloro-7-indolyl) -1,4-benzenedisulphonamide, cyclodextrin, and necessary The pH adjusting agent and / or carrier may be weighed in a predetermined amount according to the above, dissolved by adding purified water, filtered, filled in a vial or the like, and sealed. In the case of a freeze-dried preparation, N- (3-chloro-7-indolyl) -1,4-benzenedisulphonamide, cyclodextrin, and if necessary, a predetermined amount of a pH adjusting agent and / or carrier are weighed out. It can be obtained by adding purified water to dissolve it, filtering it, filling it into a vial, and lyophilizing it in a conventional manner.

[0018]

INDUSTRIAL APPLICABILITY According to the present invention, by adding cyclodextrin, N- (3-chloro-7
-Indolyl) -1,4-benzenedisulphonamide solubility is increased. Further, it becomes possible to secure the excellent photostability and heating stability of the composition containing N- (3-chloro-indolyl) -1,4-benzenesulfonamide.
Experimental examples showing these effects are given below.

Experimental Example 1: Solubility of N- (3-chloro-7-indolyl) -1,4-benzenedisulfonamide in the vicinity of neutrality by addition of cyclodextrin. The solution obtained in Example 1 below was used. Used in the presence of each of various cyclodextrins (α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin or sulfobutylether-β-cyclodextrin). The solubility of -chloro-7-indolyl) -1,4-benzenedisulphonamide was evaluated. The solubility was evaluated by measuring the absorbance at a wavelength of 220 nm with an ultraviolet spectrophotometer. As a control experiment, N- (3-chloro-7-indolyl) -without addition of cyclodextrin was used.
The solubility of 1,4-benzenedisulphonamide was evaluated (measured in the same manner as in Example 1 except that cyclodextrin was not added).

In Table 1, in the presence of the various cyclodextrins obtained in Example 1 (cyclodextrin concentration 10 m
M) and the solubility (concentration) of N- (3-chloro-7-indolyl) -1,4-benzenedisulphonamide (Compound I) in the control experiment.

[0021]

[Table 1]

Further, as cyclodextrin, sulfobutyl ether-β-cyclodextrin (SBE-
βCD) or hydroxypropyl-β-cyclodextrin (HP-βCD), N- (3-chloro-7-indolyl) -1,4-benzenedisulfonamide is added to an aqueous solution of various concentrations of each cyclodextrin. 25
FIG. 1 shows the relationship between the cyclodextrin content of the aqueous solution dissolved at 0 ° C. and the solubility (concentration) of N- (3-chloro-7-indolyl) -1,4-benzenedisulphonamide (Compound I). Indicated.

These experimental results show that the addition of cyclodextrin improves the solubility of N- (3-chloro-7-indolyl) -1,4-benzenedisulfonamide near neutral. ing.

Experimental Example 2: Photostability of N- (3-chloro-7-indolyl) -1,4-benzenedisulphonamide in aqueous solution by addition of cyclodextrin. Solution of the solution obtained in Example 2 below. A photostability test was performed. The photostability test was carried out with N- (3-chloro-7- in the solution of Example 2 and 0.1M sodium hydroxide as a control.
Indolyl) -1,4-benzenedisulfonamide was dissolved at a concentration of 0.5 mg / mL, each was filled in a white ampoule, and a white fluorescent lamp 1000 Lux light irradiation was performed in a thermostat at 25 ° C. and 60% relative humidity. It was carried out for 20 days. The absorbance of this solution at a wavelength of 420 nm was measured with an ultraviolet spectrophotometer. The results are shown in Table 2 together with the pH measurement results.

[0025]

[Table 2]

As shown in Table 2, when the control alkaline solution was irradiated with light, the absorbance at a wavelength of 420 nm increased, and yellow coloring was observed. However, in the case of the solution of Example 2,
The increase in absorbance was slight, and improvement in photostability was observed.

Experimental Example 3: Thermal stability of N- (3-chloro-7-indolyl) -1,4-benzenedisulphonamide in aqueous solution by addition of cyclodextrin. Solution of the solution obtained in Example 2 below. A thermal stability test was conducted. The thermal stability test was carried out with N- (3-chloro-7- in the solution of Example 2 and as a control in 0.1 M sodium hydroxide.
Indolyl) -1,4-benzenedisulfonamide at a concentration of 0.5 mg / mL dissolved in glass vials, and each was placed in an autoclave at 121 ° C. for 20 minutes.
It was carried out by performing high-pressure steam sterilization for 1 minute. The absorbance of this solution at a wavelength of 420 nm was measured with an ultraviolet spectrophotometer. The results are shown in Table 3 together with the pH measurement results.

[0028]

[Table 3]

As shown in Table 3, when the alkaline solution of the control example was heated, the absorbance at a wavelength of 420 nm increased and yellow coloring was observed. However, in the case of the solution of Example 2, the increase in absorbance was slight and the improvement in thermal stability was observed.

Experimental Example 4: Thermal stability of N- (3-chloro-7-indolyl) -1,4-benzenedisulfonamide in the solid state by addition of cyclodextrin. Freeze-drying obtained in Example 3 below. A thermal stability test of the formulation was performed. The thermal stability test was carried out by placing the freeze-dried preparations of the formulations-1 to 4 obtained in Example 3 in a box and storing it in a thermostat at 60 ° C for 1 week. The amount of impurities produced in this freeze-dried preparation was measured by high performance liquid chromatography. The results are shown in Fig. 2.

FIG. 2 shows the impurity N- (3-chloro-).
The relationship between the production amount of the reaction product of 7-indolyl) -1,4-benzenedisulphonamide and meglumine and the content of hydroxypropyl-β-cyclodextrin (HP-βCD) was shown. This result indicates that the amount of produced impurities decreases depending on the content of hydroxypropyl-β-cyclodextrin. Therefore, by adding cyclodextrin, N- (3-chloro-7-indolyl) -1,4
-Indicates that the solid-state thermal stability of benzenedisulfonamide is improved.

[0032]

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

Example 1 In 0.1M phosphate buffer (pH 6.5), α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin. Dextrin was dissolved in 10 mM. N- (3-chloro-7-indolyl) was added to 5 mL of each cyclodextrin solution.
An excess amount of -1,4-benzenedisulphonamide was added, and the mixture was stirred at 25 ° C for one day. After stirring, undissolved N- (3-chloro-7-indolyl) was obtained by filtration with a filter.
-1,4-benzenedisulphonamide was removed and N-
A clear colorless aqueous solution containing (3-chloro-7-indolyl) -1,4-benzenedisulphonamide and cyclodextrin was obtained.

Example 2 100 mg of N- (3-chloro-7-indolyl) -1,4-benzenedisulfonamide is dissolved in a 0.1 M aqueous sodium hydroxide solution. 0.5 mL of this solution was added to 2.26 g of sulfobutyl ether-β-cyclodextrin.
Is added to about 7 mL of dissolved 0.1 M phosphate buffer. After stirring and mixing, the mixture was macerated to 10 mL with 0.1 M phosphate buffer to obtain a colorless clear aqueous solution having a pH of about 6.4.

Example 3 1.9 g of meglumine and a predetermined amount of hydroxypropyl-β-cyclodextrin (HP-βCD) shown in Formulations 2 to 4 in Table 4 are dissolved in about 6 mL of water for injection. The solution is warmed to about 50 ° C and mannitol 2.38 is added thereto.
Add g and dissolve. After visually confirming dissolution, approx. 50 ° C
Make up to about 12.5 mL with water for injection, and then N
0.5 g of-(3-chloro-7-indolyl) -1,4-benzenedisulphonamide (E7070) is added. After charging N- (3-chloro-7-indolyl) -1,
While confirming the dissolution state of 4-benzenedisulfonamide, the pH was adjusted by adding a 2M NaOH solution little by little.
To about 11. After completion of the dissolution, the mixture was cooled to room temperature, made up to 15 mL with water for injection, and mixed with stirring to obtain a clear solution. This solution was filled in a glass vial and freeze-dried to obtain a solid mixture. Further, for comparison, a solid mixture was obtained in the same manner as in Formulations 2 to 4 except that hydroxypropyl-β-cyclodextrin was not added (Formulation 1). These formulations are summarized in Table 4.

[0036]

[Table 4]

[Brief description of drawings]

FIG. 1 shows the content of cyclodextrin in an aqueous solution and N
2 is a graph showing the relationship with the solubility of-(3-chloro-7-indolyl) -1,4-benzenedisulphonamide.

FIG. 2 Hydroxypropyl-β-cyclodextrin content and N- (3-chloro-7-indolyl)-
It is a graph which shows the relationship between the production amount of the reaction product of 1,4-benzenedisulphonamide and meglumine.

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Claims (10)

[Claims] 1. A pharmaceutical composition containing the antitumor compound N- (3-chloro-7-indolyl) -1,4-benzenedisulphonamide and cyclodextrin. 2. The composition according to claim 1, further comprising a pharmacologically acceptable pH adjuster. 3. The composition according to claim 1, further comprising a pharmacologically acceptable carrier. 4. The cyclodextrin is at least one selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin. The composition according to any one of 1 to 3. 5. The pH adjusting agent is at least one selected from sodium hydroxide, meglumine, carbonate buffer, phosphate buffer, citrate buffer, acetate buffer and hydrochloric acid. The composition according to. 6. The composition according to claim 3, wherein the carrier is at least one selected from mannitol, lactose, sucrose, trehalose and dextrose. 7. The composition according to claim 1, which is an aqueous solution formulation or a lyophilized formulation. 8. The composition according to claim 7, wherein the aqueous solution preparation is an aqueous injection, and the freeze-dried preparation is a dissolution-type freeze-dried injection before use. 9. The composition according to claim 8, which contains at least one tonicity agent selected from the group consisting of sodium chloride and dextrose. 10. N- (3-chloro-7-indolyl)
The method for producing the composition according to claim 1, wherein -1,4-benzenedisulphonamide and cyclodextrin are used.