CA2247329C - Composition containing antitumor agent - Google Patents
Composition containing antitumor agent Download PDFInfo
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- CA2247329C CA2247329C CA002247329A CA2247329A CA2247329C CA 2247329 C CA2247329 C CA 2247329C CA 002247329 A CA002247329 A CA 002247329A CA 2247329 A CA2247329 A CA 2247329A CA 2247329 C CA2247329 C CA 2247329C
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- Prior art keywords
- composition
- indol
- chloro
- sulfamoylbenzenesulfonamide
- basic substance
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- 239000000203 mixture Substances 0.000 title claims abstract description 18
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- SETFNECMODOHTO-UHFFFAOYSA-N indisulam Chemical compound C1=CC(S(=O)(=O)N)=CC=C1S(=O)(=O)NC1=CC=CC2=C1NC=C2Cl SETFNECMODOHTO-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000000126 substance Substances 0.000 claims abstract description 19
- 238000002347 injection Methods 0.000 claims abstract description 18
- 239000007924 injection Substances 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 239000007864 aqueous solution Substances 0.000 claims abstract description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 6
- 229960003194 meglumine Drugs 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 19
- 239000000243 solution Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- WTFWZOSMUGZKNZ-UHFFFAOYSA-N 1H-indol-7-amine Chemical compound NC1=CC=CC2=C1NC=C2 WTFWZOSMUGZKNZ-UHFFFAOYSA-N 0.000 description 1
- HFFXLYHRNRKAPM-UHFFFAOYSA-N 2,4,5-trichloro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC(Cl)=C(Cl)C=2)Cl)=N1 HFFXLYHRNRKAPM-UHFFFAOYSA-N 0.000 description 1
- PUPBEGMQWLQKFS-UHFFFAOYSA-N 4-n-(1h-indol-7-yl)benzene-1,4-disulfonamide Chemical compound C1=CC(S(=O)(=O)N)=CC=C1S(=O)(=O)NC1=CC=CC2=C1NC=C2 PUPBEGMQWLQKFS-UHFFFAOYSA-N 0.000 description 1
- LLFQHNCOIPUFIJ-UHFFFAOYSA-N 4-sulfamoylbenzenesulfonyl chloride Chemical compound NS(=O)(=O)C1=CC=C(S(Cl)(=O)=O)C=C1 LLFQHNCOIPUFIJ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a preparation for injection comprising an antitumor agent which is sparingly soluble in water. Specifically, it provides a composition containing N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide, which contains N-(3-chloro-1H-indol-7-yl)-4- sulfamoylbenzenesulfonamide and a basic substance and will provide an aqueous solution having a pH of 7 or higher when dissolved in water.
Description
~~0/j ~~T CA 02247329 1998-08-25 Description COMPOSITION CONTAINING AN ANTITUMOR AGENT
Field of the Invention The present invention relates to a composition containing N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide which is an antitumor agent.
Prior Art N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide is an antitumor agent, which terminates multiplication of tumor cells by a novel mechanism of action. The excellent effects of the antitumor agent has been demonstrated by experiments on animals. A group of the compounds encompassing the compound of the present invention is disclosed in JP-A-7-165708. On the other hand, various methods for administering an antitumor agent are known, among which oral administration is generally regarded as the easiest to dose and the least troublesome for a patient. However, oral administration cannot always be applied depending on degrees of progression of the disease of a patient or sites of formation of tumors, so that it often becomes inevitable to form an antitumor agent into a preparation for injection.
N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide is a compound which is sparingly soluble in water. The compound is substantially insoluble in water at a pH around the range of 5 to 7 , at which a preparation for injection is commonly used. In general, it is necessary to dissolve a pharmaceutical substance in water for forming a preparation for injection. Therefore, it is very difficult to form the compound of the present invention into a preparation for injection. The inventors of the present invention have intensively studied to obtain an aqueous solution of N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide. As a result of the studies , they have found that an aqueous solution which is safe and stable for a long period and also a preparation for injection thereof can be obtained by the means as described below. The present invention has been accomplished on the basis of this finding.
Disclosure of the Invention The present invention relates to a composition containing N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide, which is characterized in that the composition contains N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide and a basic substance and will provide an aqueous solution having a pH of 7 or higher when dissolved in water.
In other words, the present invention provides a pharmaceutical composition containing N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide in a pharmacologically effective dose and a basic substance and providing an aqueous solution having a pH of 7 or higher when dissolved in water.
Field of the Invention The present invention relates to a composition containing N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide which is an antitumor agent.
Prior Art N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide is an antitumor agent, which terminates multiplication of tumor cells by a novel mechanism of action. The excellent effects of the antitumor agent has been demonstrated by experiments on animals. A group of the compounds encompassing the compound of the present invention is disclosed in JP-A-7-165708. On the other hand, various methods for administering an antitumor agent are known, among which oral administration is generally regarded as the easiest to dose and the least troublesome for a patient. However, oral administration cannot always be applied depending on degrees of progression of the disease of a patient or sites of formation of tumors, so that it often becomes inevitable to form an antitumor agent into a preparation for injection.
N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide is a compound which is sparingly soluble in water. The compound is substantially insoluble in water at a pH around the range of 5 to 7 , at which a preparation for injection is commonly used. In general, it is necessary to dissolve a pharmaceutical substance in water for forming a preparation for injection. Therefore, it is very difficult to form the compound of the present invention into a preparation for injection. The inventors of the present invention have intensively studied to obtain an aqueous solution of N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide. As a result of the studies , they have found that an aqueous solution which is safe and stable for a long period and also a preparation for injection thereof can be obtained by the means as described below. The present invention has been accomplished on the basis of this finding.
Disclosure of the Invention The present invention relates to a composition containing N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide, which is characterized in that the composition contains N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide and a basic substance and will provide an aqueous solution having a pH of 7 or higher when dissolved in water.
In other words, the present invention provides a pharmaceutical composition containing N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide in a pharmacologically effective dose and a basic substance and providing an aqueous solution having a pH of 7 or higher when dissolved in water.
The basic substance is preferably at least one selected from the group consisting of meglumine, sodium carbonate, monoethanolamine and sodium hydroxide.
Furthermore, the present invention also provides a use of N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide and a basic substance for producing an injection of an antitumor agent.
Detailed description of the Invention N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide is a novel sulfonamide derivative having a bicyclic heterocycle, which is a compound exhibiting an excellent antitumor activity based on the mechanism of action and having a low toxicity. The compound (hereinafter sometimes referred to as the present compound) is represented by the following structural formula.
HN
The synthesis of the present compound can be carried out according to the process disclosed in JP-A-7-165708. For example, the present compound can be synthesized as follows.
After dissolving 264 mg (2 mmol) of 7-amino-1H-indole in pyridine, 767 mg (3 mmol) of 4-sulfamoylbenzenesulfonyl chloride is added thereto under stirring at room temperature.
After the mixture is stirred overnight at room temperature, the solvent is evaporated under reduced pressure. Ethyl acetate and 0.2 N hydrochloric acid are added to the resulting residue.
The organic layer is separated, washed with water, and dried over magnesium sulfate, followed by evaporation of the solvent.
The resulting residue is purified by silica gel column chromatography to give 445 mg of N-(1H-indol-7-yl)-4-sulf amoylbenz enesulf onamide .
The product thus obtained is dissolved in a mixed solvent of dichloromethane and dimethylformamide, followed by addition of N-chlorosuccinimide under stirring under nitrogen atmosphere. After 1.5 hours of stirring at room temperature, water is added thereto, and the mixture is concentrated. After adding ethyl acetate and 0.2 N hydrochloric acid to the concentrated solution, the organic layer is separated and washed successively with a saturated aqueous solution of sodium bicarbonate and brine. Then the organic layer is dried over magnesium sulfate, followed by evaporating the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography to give 349 mg of N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide.
In the present invention, a basic substance means a substance of which an aqueous solution is basic when the substance is dissolved in water, and also which can be employed for use in pharmaceuticals. Examples thereof include meglumine, sodium carbonate, monoethanolamine and sodium hydroxide, etc. among which meglumine and sodium carbonate are still preferable. These basic substances may be used singly or as a combination of two or more thereof . The mixing ratio of the basic substance to the present compound is not particularly limited so long as the solution in which the components are dissolved has a pH of 7 or higher. However, the mixing ratio generally is 0.1 to 50 parts by weight of the basic compound to 1 part of the present compound, and more preferably 0.5 to 20 parts by weight. A solution obtained by the composition containing N-(3-chloro-1H-indol-7-yl)-4--sulfamoylbenzenesulfonamide according to the present invention in water or water/a water-soluble organic solvent has a pH of 7 or higher, preferably 8 or higher, more preferably 9 or higher, and still more preferably 10 or higher.
The composition according to the present invention may be formed into various dosage forms for administration, and exerts its excellent effect particularly in a dosage form for injection. Examples of the dosage form include a solution for injection and a freeze-dried preparation. For these dosage forms, conventional substances such as glucose, mannitol, lactose, sodium chloride or the like may be used, and substances such as hydrochloric acid, phosphoric acid or the like may be used for pH adjustment.
According to the present invention, the solubility of the present compound which is extremely difficult to be dissolved in water increases , so that the present compound can be formed into a preparation for injection. This is an object of the present invention.
The production of the composition according to the present invention is not particularly limited. For example, a solution for injection can be prepared as follows. The present compound and a basic substance are each weighed out in a prescribed amount, respectively, followed by addition of distilled water for injection to dissolve the components therein. After filtration, the solution is placed and sealed in an ampule or the like, followed by sterilization. An ampule for injection can be obtained in this manner. Alternatively, a freeze-dried preparation can be prepared, for example, as follows . The present compound and a basic substance are each weighed out in a prescribed amount, respectively, followed by addition of distilled water for injection. A preparation can be obtained in this manner.
The present invention is explained below in more detail by reference to the following examples, but the present invention should not be construed as being limited thereto.
N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide for use in the present invention is also called as N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide according to the IUPAC nomenclature.
Examples Example 1 With 0.1 g of N-(3-chloro-1H-indol-7-yl)-4 sulfamoylbenzenesulfonamide (the present compound), l.Og of meglumine was mixed, followed by addition of 5 ml of distilled water for injection thereto and stirring to give a transparent solution.
The solution had a pH of 11. 4 . This solution was stable even after sterilization for 60 minutes at 115°C.
Example 2 Separate portions of 0 . 1 g of the present compound were weighed out. Sodium carbonate, monoethanolamine, and sodium hydroxide is separately added to each portion in an amount of 1.0 g, respectively, followed by addition of 5 ml of distilled water for injection thereto and stirring to give transparent solutions.
The respective solutions had a pH of 11.4, 11.8, and 12.3, respectively.
Example 3 Separate portions of 0.1 g of the present compound were weighed out . Then , 0 . 7 g of meglumine , 1. 0 g of sodium carbonate , 1.0 g of monoethanolamine, and 0.7 g of sodium hydroxide is separately added to each portion, followed by addition of 5 ml of distilled water for injection thereto and stirring to give transparent solutions. These respective solutions were subjected to sterilizing filtration and placed in a 10-ml glass vial, respectively, and freeze-dried to obtain solid mixtures.
Furthermore, the present invention also provides a use of N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide and a basic substance for producing an injection of an antitumor agent.
Detailed description of the Invention N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide is a novel sulfonamide derivative having a bicyclic heterocycle, which is a compound exhibiting an excellent antitumor activity based on the mechanism of action and having a low toxicity. The compound (hereinafter sometimes referred to as the present compound) is represented by the following structural formula.
HN
The synthesis of the present compound can be carried out according to the process disclosed in JP-A-7-165708. For example, the present compound can be synthesized as follows.
After dissolving 264 mg (2 mmol) of 7-amino-1H-indole in pyridine, 767 mg (3 mmol) of 4-sulfamoylbenzenesulfonyl chloride is added thereto under stirring at room temperature.
After the mixture is stirred overnight at room temperature, the solvent is evaporated under reduced pressure. Ethyl acetate and 0.2 N hydrochloric acid are added to the resulting residue.
The organic layer is separated, washed with water, and dried over magnesium sulfate, followed by evaporation of the solvent.
The resulting residue is purified by silica gel column chromatography to give 445 mg of N-(1H-indol-7-yl)-4-sulf amoylbenz enesulf onamide .
The product thus obtained is dissolved in a mixed solvent of dichloromethane and dimethylformamide, followed by addition of N-chlorosuccinimide under stirring under nitrogen atmosphere. After 1.5 hours of stirring at room temperature, water is added thereto, and the mixture is concentrated. After adding ethyl acetate and 0.2 N hydrochloric acid to the concentrated solution, the organic layer is separated and washed successively with a saturated aqueous solution of sodium bicarbonate and brine. Then the organic layer is dried over magnesium sulfate, followed by evaporating the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography to give 349 mg of N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide.
In the present invention, a basic substance means a substance of which an aqueous solution is basic when the substance is dissolved in water, and also which can be employed for use in pharmaceuticals. Examples thereof include meglumine, sodium carbonate, monoethanolamine and sodium hydroxide, etc. among which meglumine and sodium carbonate are still preferable. These basic substances may be used singly or as a combination of two or more thereof . The mixing ratio of the basic substance to the present compound is not particularly limited so long as the solution in which the components are dissolved has a pH of 7 or higher. However, the mixing ratio generally is 0.1 to 50 parts by weight of the basic compound to 1 part of the present compound, and more preferably 0.5 to 20 parts by weight. A solution obtained by the composition containing N-(3-chloro-1H-indol-7-yl)-4--sulfamoylbenzenesulfonamide according to the present invention in water or water/a water-soluble organic solvent has a pH of 7 or higher, preferably 8 or higher, more preferably 9 or higher, and still more preferably 10 or higher.
The composition according to the present invention may be formed into various dosage forms for administration, and exerts its excellent effect particularly in a dosage form for injection. Examples of the dosage form include a solution for injection and a freeze-dried preparation. For these dosage forms, conventional substances such as glucose, mannitol, lactose, sodium chloride or the like may be used, and substances such as hydrochloric acid, phosphoric acid or the like may be used for pH adjustment.
According to the present invention, the solubility of the present compound which is extremely difficult to be dissolved in water increases , so that the present compound can be formed into a preparation for injection. This is an object of the present invention.
The production of the composition according to the present invention is not particularly limited. For example, a solution for injection can be prepared as follows. The present compound and a basic substance are each weighed out in a prescribed amount, respectively, followed by addition of distilled water for injection to dissolve the components therein. After filtration, the solution is placed and sealed in an ampule or the like, followed by sterilization. An ampule for injection can be obtained in this manner. Alternatively, a freeze-dried preparation can be prepared, for example, as follows . The present compound and a basic substance are each weighed out in a prescribed amount, respectively, followed by addition of distilled water for injection. A preparation can be obtained in this manner.
The present invention is explained below in more detail by reference to the following examples, but the present invention should not be construed as being limited thereto.
N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide for use in the present invention is also called as N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide according to the IUPAC nomenclature.
Examples Example 1 With 0.1 g of N-(3-chloro-1H-indol-7-yl)-4 sulfamoylbenzenesulfonamide (the present compound), l.Og of meglumine was mixed, followed by addition of 5 ml of distilled water for injection thereto and stirring to give a transparent solution.
The solution had a pH of 11. 4 . This solution was stable even after sterilization for 60 minutes at 115°C.
Example 2 Separate portions of 0 . 1 g of the present compound were weighed out. Sodium carbonate, monoethanolamine, and sodium hydroxide is separately added to each portion in an amount of 1.0 g, respectively, followed by addition of 5 ml of distilled water for injection thereto and stirring to give transparent solutions.
The respective solutions had a pH of 11.4, 11.8, and 12.3, respectively.
Example 3 Separate portions of 0.1 g of the present compound were weighed out . Then , 0 . 7 g of meglumine , 1. 0 g of sodium carbonate , 1.0 g of monoethanolamine, and 0.7 g of sodium hydroxide is separately added to each portion, followed by addition of 5 ml of distilled water for injection thereto and stirring to give transparent solutions. These respective solutions were subjected to sterilizing filtration and placed in a 10-ml glass vial, respectively, and freeze-dried to obtain solid mixtures.
Claims (9)
1. A pharmaceutical composition which comprises N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide in a pharmacologically effective dose and a basic substance and will provide an aqueous solution having a pH of 7 or higher when dissolved in water.
2. The composition as claimed in claim 1, wherein the basic substance is at least one selected from the group consisting of meglumine, sodium carbonate, monoethanolamine and sodium hydroxide.
3. The composition as claimed in claim 1 or 2, wherein the basic substance is contained in an amount of 0.1 to 50 parts by weight per part by weight of N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide.
4. The composition as claimed in any one of claims 1 to 3, which further comprises water and is an injection.
5. The composition as claimed in claim 1, wherein the basic substance is pharmacologically acceptable.
6. The composition as claimed in any one of claims 1 to 5, which is an antitumor agent.
7. The composition as claimed in claim 4, which has a pH of 10 or higher.
8. Use of N-(3-chloro-1H-indol-7-yl)-4-sulfamoylbenzenesulfonamide and a basic substance for producing an antitumor agent.
9. The composition as claimed in any one of claims 1 to 3, which is a freeze-dried preparation whose aqueous solution has a pH of 12.3 or lower.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8-37765 | 1996-02-26 | ||
| JP3776596 | 1996-02-26 | ||
| PCT/JP1997/000560 WO1997030706A1 (en) | 1996-02-26 | 1997-02-26 | Composition containing antitumor agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2247329A1 CA2247329A1 (en) | 1997-08-28 |
| CA2247329C true CA2247329C (en) | 2006-07-04 |
Family
ID=36648525
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002247329A Expired - Fee Related CA2247329C (en) | 1996-02-26 | 1997-02-26 | Composition containing antitumor agent |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2247329C (en) |
-
1997
- 1997-02-26 CA CA002247329A patent/CA2247329C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2247329A1 (en) | 1997-08-28 |
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