CA1159368A - Antitumor compositions - Google Patents
Antitumor compositionsInfo
- Publication number
- CA1159368A CA1159368A CA000407044A CA407044A CA1159368A CA 1159368 A CA1159368 A CA 1159368A CA 000407044 A CA000407044 A CA 000407044A CA 407044 A CA407044 A CA 407044A CA 1159368 A CA1159368 A CA 1159368A
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- water
- acridinylamino
- anisidide
- solution
- gluconolactone
- Prior art date
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Abstract
Abstract The invention concerns a crystalline monogluconate salt of the antitumor agent 4'-(9-acridinylamino)-methanesulfon-m-anisidide and compositions comprising mixtures of such salt with an organic acid selected from gluconic acid, glucono-lactone or mixtures thereof. The novel salt and compositions are characterized in having unexpectedly high water-solubility.
Description
Background o the Invention 1. Field of the Invention .
The novel acid addition salt a:nd compositions of the present invention possess the advantageous antitumor properties of the known free base compound and in addition have unexpectedly high water-solubility, thus allowing preparation of useful clinical dosage forms for intravenous administration.
The novel acid addition salt a:nd compositions of the present invention possess the advantageous antitumor properties of the known free base compound and in addition have unexpectedly high water-solubility, thus allowing preparation of useful clinical dosage forms for intravenous administration.
2 Descri tion of the Prior Art :1~
The acridine derivative m-~MSA [4'-9-acridinylamino) methanesulfon-m-anisidide] has been reported by Cain, et al, in Europ. J. Cancer 10:539-549 (1974) to possess ~ignificant _ antitumor activity in animal tumor sys~ems, Since then, this compound has been subjected to clinical evaluation with very promising initial results.
~ en an antitumor agent such as m-AMSA is employed for human clinical use, it is recogniæed that solub.ility of the agent is often the controlling factor in determining route of administration and dosage forms, For instance, a water-soluble substance can be generally administered intra-vanously whereas a water-insoluble material is limited to other ~orms of parenteral administration such as intra-muscular and subcutaneous. A therapeutic agent having wateL
solubility also facilitates preparation of oral and non-intravenous parenteral dosage forms for human administration, ~hus, it i5 decidedly advantageous i~ a therapeutic agent iY water-soluble, particularly when one considers that the most direct route ~or achieviny therapeutic blood levels o~ a drug within the human body is by intravenous administration.
The ~.ree base form o~ m~MSA has very limited solubility in water and thu~ cannot be used as a dosage form for inkravenous administration~ ~ttempts ha~e ~een made to
The acridine derivative m-~MSA [4'-9-acridinylamino) methanesulfon-m-anisidide] has been reported by Cain, et al, in Europ. J. Cancer 10:539-549 (1974) to possess ~ignificant _ antitumor activity in animal tumor sys~ems, Since then, this compound has been subjected to clinical evaluation with very promising initial results.
~ en an antitumor agent such as m-AMSA is employed for human clinical use, it is recogniæed that solub.ility of the agent is often the controlling factor in determining route of administration and dosage forms, For instance, a water-soluble substance can be generally administered intra-vanously whereas a water-insoluble material is limited to other ~orms of parenteral administration such as intra-muscular and subcutaneous. A therapeutic agent having wateL
solubility also facilitates preparation of oral and non-intravenous parenteral dosage forms for human administration, ~hus, it i5 decidedly advantageous i~ a therapeutic agent iY water-soluble, particularly when one considers that the most direct route ~or achieviny therapeutic blood levels o~ a drug within the human body is by intravenous administration.
The ~.ree base form o~ m~MSA has very limited solubility in water and thu~ cannot be used as a dosage form for inkravenous administration~ ~ttempts ha~e ~een made to
3~
prepare acid addition salts to overcome thls solubility problem, but the reported monohydrochloride and monomethane~
sulfonate salts also proved insufficiently water-soluble for clinical useO The formulation presently in clinical use consists of two sterile liquids combined just prior to use.
A solution of m-AMSA in anhydrous N,N-dimethylacetamide is contained in an ampule. A separate vial contains an aqueous lactic acid solution for use as a diluent. When mixed the resulting m-AMSA solution is administered by i.v. infusion.
While the present clinical formulation provides an intravenous dosage form, it suffers from several dis-advantages. In addition to the obvious dificulties in preparing and administering the dosage form, it contains dimethylacetamide as a vehicle. Dimethylacetamide has been reported to show various toxic symp~oms in animals and may thus prove to be unacceptable or undesirable as a pharma-ceutical vehicle.
It is accordingly an object of the present invention to provide water-soluble, stable, therapeutically acceptable forms of m-AMS~ which can be administered lntra-venously (as well as by other routPs) and which do not: con-tain or require dimethylacetamide as a pharmaceutical vehicle, This object as well as other eatures and advantages o~ the invention will be readily apparent to those skilled iIl the art from the disclosure set out below, Summary o~ the Invention _.
In one aspect the present invention provides a novel water-solublQ acid addition salt o~ m-AMSA which upon reconstitution wi.th sterile water or a sterile aqueous ~e~icle can be administered intravenously and which does not have the disadvantages associated with the known intra~
3~
venous forms of this agent. More particularly, there is provided the crystalline monogluconate salt of m-AMSA.
In another aspect the invention provides a stable, solid,-water-soluble composition for reconsti~ution with water or an aqueous vehicle as a s~able solution of m-AMSA, said composition comprising a mixture of about one mole of m-AMSA monogluconate salt per one to three moles of an organic acid (or precursor thereof) selected from gluconic acid, gluconolactone or mixtures thereof.
Also provided are processes for preparing the above-describ~d salt and composition.
Description of the Drawings FIG. 1 shows the infrared absorption spectrum of the crystalline gluconate salt when pelleted in potassium bromide.
FIG. 2 shows the infrared absorption spectrum of a typical water-soluble composition when pelleted in potassium bromide.
Detailed Descri~ion Many conventional pharmaceutically acceptab].e acid addition salts o~ m-AMSA are only slightly soluble in water and are thus unsuited for intravenous administration to human patients. This is evident from literature references to the hydrochloride and methanesulfonate salts as well a~ from solubility tests carried out by the present lnventors on salt~ such as -the levulinate, citrate and lactobionate, In investigating solubility propexties of m-AMSA
acid addition salts, we have unexpectedly found that one particular crystalline salt o~ m-AMSA po~sesses significan~ly high water-solubility at room temperature to provide an acoeptable intravenous dosage form, Thus, the novel mono 3~
gluconate salt of m-AMSA provided by the present invention has an aqueous solubility at room temperature of about 25 mg/ml. This gluconate salt has also been found to have acceptable sta~ility, both as a crys~alline solid and as an aqueous solution upon reconstitution, Preparation of the crystalline gluconate salt of m-AMSA is carried out by the steps of (1) forming a solution of m-~MSA and an organic acid (or precursor thereof) selected from the group consisting of gluconic acid (D-gluconic acid), gluconolactone (D-gluconic acid ~-lactone) and mixtures thereof in an inert aqueous polar organic solvent, the molar ratio of organic acid to m-AMSA
being ~rom about 1:1 to about 2:1;
and (2) crystallizing the desired gluconate salt from the so-produced solution.
The particular inert polar organic solvent used to solubilize thè m-~qSA base is not critical and examples of suitable solvents will be readily apparent to those skilled in the art. Preferred sol~ents are polar alcohols and ketones such as methanol, ethanol, n-propanol, isopropanol, acetone, n-butanol, 2-butanone, n-pentanol, n-hexanol, diethylene glycol, methyl isobutyl ketone, 3-pentanone, etc.
A particularly convenient solvent is ethanol, The so:Lvent system should contain a small percentage of water (e.g~
~0.5~) which may either be added to the organic solvent or pre~erably supplied in the form of aqueous gluconic acid or gluconolactone solution, The term "organic acid" as used herein and in the claims re~ers to gluconic acid ~ se or a precursor thereof which hydroly2es in aqueous solution to form gluconiG acid, e.g. gluconolactone. Gluconic acid is dif~icult to produce in a well-defined crystalline form and thus commercial gluconic acid i~ supplied as a 50% aqueous solution. Gluconolactone, on 5~
the other hand, is a well-defined crystalline material which may be easily hydrolyzed in aqueous solu~ion to gluconic acid. Because of the availability of crystalline glucono-lactone, it is preferred to use gluconolactone as the source of gluconic acid in preparing the gluconate salt, The gluconolactone may be added to an aqueous solution o~ the polar organic solven~ to generate the gluconic acid or may ~e added to the organic solvent in the form of an aqueous solution.
The temperature at which solution is effected is not critical and may range from the freezing point to the boiling point of the solvent system. Most advantageously temperatures of around room temperature or above are used.
It has been found that solubility is maximized if the mix-ture is brought to reflux ~emperature.
The gluconic acid or gluconolactone may be employed in molar ratios of about 1 to 2 moles per mole of m-AMSA
base. Best quality product, however, has resulted from using equimolar quantities of the m~AMSA and organic acid.
After forming a solution of m-AMSA and acid, it is preferred to carry out a ~iltration step before allowing crystallization to proceed, Standard crystallization techniques may then be used to obtain the desired gluconate salt. Seed crystals of the gluconate salt may be added to the reaction mixture to induce and/or enhance crystallization.
After recovery the crystalline salt is washed (e,g, with ethanol) and dried by conventional procedures, Recrystalli-zation (e,g~ from ethanol) may be used to obtain product in a highly puri~ied ~orm~
In another aspect the present invention provides a stable, solid, water-soluble composition suitable upon reconstitution with water or o~her aqueous vehicle as a stable solu~ion o m-AMSA, said composikion comprising a mixture o~ about one mole of m~AMSA monogluconate salt per ~ 6 one to three m~les of an organic acid (or precursor thereof) selected from the group consisting of gluconic acid, glucono-lactone and mixtures thereof.
Thus the present invention provides a process for producing a stable, solid, water-soluble composition for re-constitution with water or aqueous vehicle as a stable solution of ~'-(9-acridinylamino)-methanesulfon-m-anisidide which com-prises the steps of (1) forming an aqueous solution of 4'-(9-acridinylamino~methanesulfon-m-anisidide and an organic acid selected from the group consisting of gluconic acid, glucono-lactone and mixtures thereof, the molar ratio of the organic acid to 4'-(9 acridinylamino)-methanesulfon-m anisidide being from about 2:1 to about 4:1; and (2) lyophilizing the so produced aqueous solutionO
The above-described composition may be employed in the form of either a dry-fill or lyophilized product, but is preferably a lyophilized mixture. The composition may be con-veniently and rapidly reconstituted with sterile water or a sterile aqueous vehicle to provide at least a 5 mg/ml true solution of m-AMSA having excellent stability.
- 6a - ~5~3~8 Preparation of the water-soluble composition may be conveniently accomplished by a conventiona' lyophilization procedure. Thus, an aqueous olution of m-AMSA and an excess of gluconic acid or a source of gluconic acid (i.e. an organic acid which hydrolyzes in water ~o form gluconic acid) is formed, and the solution is then subjected to a standard lyophilization process to obtain the desi:red solid composi~ion.
The gluconic acid (or equivalen~) is used in a molar ratio of about 2-4 moles (most preferably about 2.5 moles) per mole of m-AMSA base. Since as noted above commercial gluconic acid i5 not available in a well-defined crystalline form, it is preferred to use crystalline glucono-lactone as the organic acid. The gluconolactone xapidly hydrolyzes in water to form gluconic acid. During lyo-philization gluconic acid is at least partially converted to gluconolactone. The lyophilized product, therefore, -comprises a mixture of the monogluconate salt of m-AMSA
with from about one to three moles of excess gluconic acid, said acid being partly in the gluconic acid form and partly in the gluconolactone form.
After forming the aqueous solution of m-AMSA and acid, the reaction mixture is preferably iltered before lyophilization, Lyophilization may be carried out in conventional laboratory or industrial lyophilizers. Pre-ferred lyophilization parameters are as follows:
prefreez_n~ at -55~C.;
freezing at ~50C. for 2 hours;
sublimation at -40C. for about 68 hours at a pressure of about 4 x 10 2 torr;
dryin~ at +30C. for abou~ 48 hours.
The crystalline gluconate salk and water~soluble composition provided by the present invention exhibit sub-stantially the same antitumor proper~ies as the prior art m-AMSA forms. Because of their high water-solubility, however, they may be used to prepare clinical dosage forms for intravenous administration which do not contain an undesirable pharmaceutical vehicle such as dimethylacetamide.
The salt and composition, moreover, can be used to prepare a single vial dry-fill or lyophilized product for reconskitution with sterile water or a sterile aqueous vehicle. A pre- ~~
ferred vehicle for reconstitution of the gluconate salt is aqueous gluconic acid, The m~AMSA salt and composition of the present invention may be used to prepare oral or non-intravenous parenteral dosage ~orms as well as the preferred intravenous injectable product. The salt and composition have acceptable stability, both in solid form and in aqueous solution, and have suf~icient water-solubility to permit administration of an effective dose o~ m-AMSA in a relatively small volume of parenteral soLution ~thus allowing for bolus i.v. injections).
In the treatment o~ mammalian tumor~ the salt and composit.ion o~ the present invention may be administered either orally or paxenterally, but pre~erably parenterally, in dosages (adjuæted for ~mount o~ m AMSA base) and according to regimens pre~iously disclosed in the literature, The following examples are ~i~en in illuskraki,on o~, bu~ no~ in limitation o, the preæent invention.
. .
3~3 Example 1 Preoaration of m-AMSA Monoqluconate Salt Delta gluconolactone (0,89 g,; 0~005 mole) was dissolved in 0.5 ml. of water. m-~MSA base (1,95 g,; 0.005 mole) and 100 ml. of ethanol were added, and the mixture was then refluxed for a short time, iOe. about 5-10 minutes.
The resulting solution was allowed to stand ovexnight whereupon crystalline material separated from solution.
The product was recrystallized from 100 mlO of ethanol to give 1.10 g. of crystalline m-AMSA monogluconate salt.
Pro erties of luconate salt:
~ g _ _ m-~MSA content by U,V. = 62O6% (theoretical conkent i5 66.6~);
gluconic acid content by U,V. = 36,9%;
gluconolactone content by U.V. = 1.1%.
Solubility in water: 30 mg/ml. at S0 60C.;
25 mg/ml. at room temperature.
When dissolved in water at a concentration of 7.1 ~g/ml., the gluconate salt exhibits ultraviolet absorption peaks at 208 nm (O.D. = 0.527), 247.5 nm (O.D. = 0.567), 263 nm (O.D. - 0.425) and 412 nm (O.D. =
0.121).
FIG. 1 shows the infrared absorption spectrum of the ~luconate salt when pelleted in potassium bromide.
3~
g Example 2 Preparation of m-AMSA Water-Soluble Composition (for preparation of 75 mg. m-AMSA activity vials) Formula Per Vial Per Liter Batch m AMSA base 75 mg. 5 g.
gluconolactone (gluconic acid ~-lactone) 93~46 mg. 6.23 g.
water for injection q.s. to 15 ml, q.s. to 1 liter Manufacturing Instructions (for 1 liter batch) .L) Preparation of a 10% solution of gluconolactone-- weigh 10 g, of gluconolactone - with agitation, add the lactone into a glass container containing 80 ml. water for injection.
Maintain agitation until complete solution is obtained, - q.s. to 100 ml. with water for injection - stir 5 min.
This solution is to be used after 24 hours of standing at room temperature, Z) Weigh out 5 g~ of m-AMSA base, 3) Into a suitable glass container containing 600 ml. of water for injection, add with agitation 25 ml. of the 10% gluconolacto~e solution,
prepare acid addition salts to overcome thls solubility problem, but the reported monohydrochloride and monomethane~
sulfonate salts also proved insufficiently water-soluble for clinical useO The formulation presently in clinical use consists of two sterile liquids combined just prior to use.
A solution of m-AMSA in anhydrous N,N-dimethylacetamide is contained in an ampule. A separate vial contains an aqueous lactic acid solution for use as a diluent. When mixed the resulting m-AMSA solution is administered by i.v. infusion.
While the present clinical formulation provides an intravenous dosage form, it suffers from several dis-advantages. In addition to the obvious dificulties in preparing and administering the dosage form, it contains dimethylacetamide as a vehicle. Dimethylacetamide has been reported to show various toxic symp~oms in animals and may thus prove to be unacceptable or undesirable as a pharma-ceutical vehicle.
It is accordingly an object of the present invention to provide water-soluble, stable, therapeutically acceptable forms of m-AMS~ which can be administered lntra-venously (as well as by other routPs) and which do not: con-tain or require dimethylacetamide as a pharmaceutical vehicle, This object as well as other eatures and advantages o~ the invention will be readily apparent to those skilled iIl the art from the disclosure set out below, Summary o~ the Invention _.
In one aspect the present invention provides a novel water-solublQ acid addition salt o~ m-AMSA which upon reconstitution wi.th sterile water or a sterile aqueous ~e~icle can be administered intravenously and which does not have the disadvantages associated with the known intra~
3~
venous forms of this agent. More particularly, there is provided the crystalline monogluconate salt of m-AMSA.
In another aspect the invention provides a stable, solid,-water-soluble composition for reconsti~ution with water or an aqueous vehicle as a s~able solution of m-AMSA, said composition comprising a mixture of about one mole of m-AMSA monogluconate salt per one to three moles of an organic acid (or precursor thereof) selected from gluconic acid, gluconolactone or mixtures thereof.
Also provided are processes for preparing the above-describ~d salt and composition.
Description of the Drawings FIG. 1 shows the infrared absorption spectrum of the crystalline gluconate salt when pelleted in potassium bromide.
FIG. 2 shows the infrared absorption spectrum of a typical water-soluble composition when pelleted in potassium bromide.
Detailed Descri~ion Many conventional pharmaceutically acceptab].e acid addition salts o~ m-AMSA are only slightly soluble in water and are thus unsuited for intravenous administration to human patients. This is evident from literature references to the hydrochloride and methanesulfonate salts as well a~ from solubility tests carried out by the present lnventors on salt~ such as -the levulinate, citrate and lactobionate, In investigating solubility propexties of m-AMSA
acid addition salts, we have unexpectedly found that one particular crystalline salt o~ m-AMSA po~sesses significan~ly high water-solubility at room temperature to provide an acoeptable intravenous dosage form, Thus, the novel mono 3~
gluconate salt of m-AMSA provided by the present invention has an aqueous solubility at room temperature of about 25 mg/ml. This gluconate salt has also been found to have acceptable sta~ility, both as a crys~alline solid and as an aqueous solution upon reconstitution, Preparation of the crystalline gluconate salt of m-AMSA is carried out by the steps of (1) forming a solution of m-~MSA and an organic acid (or precursor thereof) selected from the group consisting of gluconic acid (D-gluconic acid), gluconolactone (D-gluconic acid ~-lactone) and mixtures thereof in an inert aqueous polar organic solvent, the molar ratio of organic acid to m-AMSA
being ~rom about 1:1 to about 2:1;
and (2) crystallizing the desired gluconate salt from the so-produced solution.
The particular inert polar organic solvent used to solubilize thè m-~qSA base is not critical and examples of suitable solvents will be readily apparent to those skilled in the art. Preferred sol~ents are polar alcohols and ketones such as methanol, ethanol, n-propanol, isopropanol, acetone, n-butanol, 2-butanone, n-pentanol, n-hexanol, diethylene glycol, methyl isobutyl ketone, 3-pentanone, etc.
A particularly convenient solvent is ethanol, The so:Lvent system should contain a small percentage of water (e.g~
~0.5~) which may either be added to the organic solvent or pre~erably supplied in the form of aqueous gluconic acid or gluconolactone solution, The term "organic acid" as used herein and in the claims re~ers to gluconic acid ~ se or a precursor thereof which hydroly2es in aqueous solution to form gluconiG acid, e.g. gluconolactone. Gluconic acid is dif~icult to produce in a well-defined crystalline form and thus commercial gluconic acid i~ supplied as a 50% aqueous solution. Gluconolactone, on 5~
the other hand, is a well-defined crystalline material which may be easily hydrolyzed in aqueous solu~ion to gluconic acid. Because of the availability of crystalline glucono-lactone, it is preferred to use gluconolactone as the source of gluconic acid in preparing the gluconate salt, The gluconolactone may be added to an aqueous solution o~ the polar organic solven~ to generate the gluconic acid or may ~e added to the organic solvent in the form of an aqueous solution.
The temperature at which solution is effected is not critical and may range from the freezing point to the boiling point of the solvent system. Most advantageously temperatures of around room temperature or above are used.
It has been found that solubility is maximized if the mix-ture is brought to reflux ~emperature.
The gluconic acid or gluconolactone may be employed in molar ratios of about 1 to 2 moles per mole of m-AMSA
base. Best quality product, however, has resulted from using equimolar quantities of the m~AMSA and organic acid.
After forming a solution of m-AMSA and acid, it is preferred to carry out a ~iltration step before allowing crystallization to proceed, Standard crystallization techniques may then be used to obtain the desired gluconate salt. Seed crystals of the gluconate salt may be added to the reaction mixture to induce and/or enhance crystallization.
After recovery the crystalline salt is washed (e,g, with ethanol) and dried by conventional procedures, Recrystalli-zation (e,g~ from ethanol) may be used to obtain product in a highly puri~ied ~orm~
In another aspect the present invention provides a stable, solid, water-soluble composition suitable upon reconstitution with water or o~her aqueous vehicle as a stable solu~ion o m-AMSA, said composikion comprising a mixture o~ about one mole of m~AMSA monogluconate salt per ~ 6 one to three m~les of an organic acid (or precursor thereof) selected from the group consisting of gluconic acid, glucono-lactone and mixtures thereof.
Thus the present invention provides a process for producing a stable, solid, water-soluble composition for re-constitution with water or aqueous vehicle as a stable solution of ~'-(9-acridinylamino)-methanesulfon-m-anisidide which com-prises the steps of (1) forming an aqueous solution of 4'-(9-acridinylamino~methanesulfon-m-anisidide and an organic acid selected from the group consisting of gluconic acid, glucono-lactone and mixtures thereof, the molar ratio of the organic acid to 4'-(9 acridinylamino)-methanesulfon-m anisidide being from about 2:1 to about 4:1; and (2) lyophilizing the so produced aqueous solutionO
The above-described composition may be employed in the form of either a dry-fill or lyophilized product, but is preferably a lyophilized mixture. The composition may be con-veniently and rapidly reconstituted with sterile water or a sterile aqueous vehicle to provide at least a 5 mg/ml true solution of m-AMSA having excellent stability.
- 6a - ~5~3~8 Preparation of the water-soluble composition may be conveniently accomplished by a conventiona' lyophilization procedure. Thus, an aqueous olution of m-AMSA and an excess of gluconic acid or a source of gluconic acid (i.e. an organic acid which hydrolyzes in water ~o form gluconic acid) is formed, and the solution is then subjected to a standard lyophilization process to obtain the desi:red solid composi~ion.
The gluconic acid (or equivalen~) is used in a molar ratio of about 2-4 moles (most preferably about 2.5 moles) per mole of m-AMSA base. Since as noted above commercial gluconic acid i5 not available in a well-defined crystalline form, it is preferred to use crystalline glucono-lactone as the organic acid. The gluconolactone xapidly hydrolyzes in water to form gluconic acid. During lyo-philization gluconic acid is at least partially converted to gluconolactone. The lyophilized product, therefore, -comprises a mixture of the monogluconate salt of m-AMSA
with from about one to three moles of excess gluconic acid, said acid being partly in the gluconic acid form and partly in the gluconolactone form.
After forming the aqueous solution of m-AMSA and acid, the reaction mixture is preferably iltered before lyophilization, Lyophilization may be carried out in conventional laboratory or industrial lyophilizers. Pre-ferred lyophilization parameters are as follows:
prefreez_n~ at -55~C.;
freezing at ~50C. for 2 hours;
sublimation at -40C. for about 68 hours at a pressure of about 4 x 10 2 torr;
dryin~ at +30C. for abou~ 48 hours.
The crystalline gluconate salk and water~soluble composition provided by the present invention exhibit sub-stantially the same antitumor proper~ies as the prior art m-AMSA forms. Because of their high water-solubility, however, they may be used to prepare clinical dosage forms for intravenous administration which do not contain an undesirable pharmaceutical vehicle such as dimethylacetamide.
The salt and composition, moreover, can be used to prepare a single vial dry-fill or lyophilized product for reconskitution with sterile water or a sterile aqueous vehicle. A pre- ~~
ferred vehicle for reconstitution of the gluconate salt is aqueous gluconic acid, The m~AMSA salt and composition of the present invention may be used to prepare oral or non-intravenous parenteral dosage ~orms as well as the preferred intravenous injectable product. The salt and composition have acceptable stability, both in solid form and in aqueous solution, and have suf~icient water-solubility to permit administration of an effective dose o~ m-AMSA in a relatively small volume of parenteral soLution ~thus allowing for bolus i.v. injections).
In the treatment o~ mammalian tumor~ the salt and composit.ion o~ the present invention may be administered either orally or paxenterally, but pre~erably parenterally, in dosages (adjuæted for ~mount o~ m AMSA base) and according to regimens pre~iously disclosed in the literature, The following examples are ~i~en in illuskraki,on o~, bu~ no~ in limitation o, the preæent invention.
. .
3~3 Example 1 Preoaration of m-AMSA Monoqluconate Salt Delta gluconolactone (0,89 g,; 0~005 mole) was dissolved in 0.5 ml. of water. m-~MSA base (1,95 g,; 0.005 mole) and 100 ml. of ethanol were added, and the mixture was then refluxed for a short time, iOe. about 5-10 minutes.
The resulting solution was allowed to stand ovexnight whereupon crystalline material separated from solution.
The product was recrystallized from 100 mlO of ethanol to give 1.10 g. of crystalline m-AMSA monogluconate salt.
Pro erties of luconate salt:
~ g _ _ m-~MSA content by U,V. = 62O6% (theoretical conkent i5 66.6~);
gluconic acid content by U,V. = 36,9%;
gluconolactone content by U.V. = 1.1%.
Solubility in water: 30 mg/ml. at S0 60C.;
25 mg/ml. at room temperature.
When dissolved in water at a concentration of 7.1 ~g/ml., the gluconate salt exhibits ultraviolet absorption peaks at 208 nm (O.D. = 0.527), 247.5 nm (O.D. = 0.567), 263 nm (O.D. - 0.425) and 412 nm (O.D. =
0.121).
FIG. 1 shows the infrared absorption spectrum of the ~luconate salt when pelleted in potassium bromide.
3~
g Example 2 Preparation of m-AMSA Water-Soluble Composition (for preparation of 75 mg. m-AMSA activity vials) Formula Per Vial Per Liter Batch m AMSA base 75 mg. 5 g.
gluconolactone (gluconic acid ~-lactone) 93~46 mg. 6.23 g.
water for injection q.s. to 15 ml, q.s. to 1 liter Manufacturing Instructions (for 1 liter batch) .L) Preparation of a 10% solution of gluconolactone-- weigh 10 g, of gluconolactone - with agitation, add the lactone into a glass container containing 80 ml. water for injection.
Maintain agitation until complete solution is obtained, - q.s. to 100 ml. with water for injection - stir 5 min.
This solution is to be used after 24 hours of standing at room temperature, Z) Weigh out 5 g~ of m-AMSA base, 3) Into a suitable glass container containing 600 ml. of water for injection, add with agitation 25 ml. of the 10% gluconolacto~e solution,
4) ~ith strony agitation add slowly the 5 gv of m~AMSA
base to the gla~s container. Maintain agitation ~or 30 min.
base to the gla~s container. Maintain agitation ~or 30 min.
5) Wi~h agltation add 20 ml. o~ the 10~ gluconolactone solution ~o ~he reaction mixture, Agitate ~or 30 min.
6) Slowly add the remainder of the 10% gluconolaotone solution (17~3 ml.) to the reaction mixture, Maintain agitation until complete solution is obtained.
.
3`~3
.
3`~3
7) ~.S. to 1 liter with water for injection.
8) Using nitrogen pressure pass the solution through a 0.22~ filter.
9) Fill the solution into 30-38 ml, flint glass vials (15 ml. solution per vial). Partially insert red butyl lyophilization stoppers.
0) Subject vials to freeze drying at fol:iowing parameters:
prefreezing at -55C.;
freezing at 50C. for 2 hours;
sublimation at -40C. for about 68 hours at a pressure of about 4 x 10 2 torr;
drying at +30C. for about 48 hours.
11) Stopper the vials under vacuum or nitrogen atmosphere and seal.
12) To reconstitute, use 20 ml. water for injection per vial.
Pro erties of L o hilized Composition:
P Y P
Reconstitution time with 20 ml. water = 4-5 min.
pH of solution: 3.65 Analysis of lyophilized product:
of 0,172 g. total composition, ~72 mg, m-AMSA, ~93 mg. total gluconic acid (potentiometry) of which ~40 mg. is ~-gluconolactone (gas chromato-graphy). Impurities are below detection limits.
% H2O(K.F,) = 0-8 Aqueous stability o~ reconstituted product satis~actory ak 24 hours. Loss of potency barely perceptible and no impurities were noted.
When dissolved in water at a concentration of 12.17 ~g~ml., the lyophilized composition ex-hibits ultraviolet absorption peaks at 209 nm (O.D. = 0.607), 247.5 nm (O.D. = 0.607), 266 nm (O.D. = 0.534~, 413 nm (O.D. = 0.145) and 435 nm (O.D. = 0.143).
FIG. 2 shows the inrared absoxption spectrum of the lyophilized composition when pelleted in potassium bromide.
' `; ~' :.
. .
0) Subject vials to freeze drying at fol:iowing parameters:
prefreezing at -55C.;
freezing at 50C. for 2 hours;
sublimation at -40C. for about 68 hours at a pressure of about 4 x 10 2 torr;
drying at +30C. for about 48 hours.
11) Stopper the vials under vacuum or nitrogen atmosphere and seal.
12) To reconstitute, use 20 ml. water for injection per vial.
Pro erties of L o hilized Composition:
P Y P
Reconstitution time with 20 ml. water = 4-5 min.
pH of solution: 3.65 Analysis of lyophilized product:
of 0,172 g. total composition, ~72 mg, m-AMSA, ~93 mg. total gluconic acid (potentiometry) of which ~40 mg. is ~-gluconolactone (gas chromato-graphy). Impurities are below detection limits.
% H2O(K.F,) = 0-8 Aqueous stability o~ reconstituted product satis~actory ak 24 hours. Loss of potency barely perceptible and no impurities were noted.
When dissolved in water at a concentration of 12.17 ~g~ml., the lyophilized composition ex-hibits ultraviolet absorption peaks at 209 nm (O.D. = 0.607), 247.5 nm (O.D. = 0.607), 266 nm (O.D. = 0.534~, 413 nm (O.D. = 0.145) and 435 nm (O.D. = 0.143).
FIG. 2 shows the inrared absoxption spectrum of the lyophilized composition when pelleted in potassium bromide.
' `; ~' :.
. .
Claims (8)
1. A process for producing a stable, solid, water-soluble composition for reconstitution with water or aqueous vehicle as a stable solution of 4'-(9-acridinylamino)-methane-sulfon-m-anisidide which comprises the steps of (1) forming an aqueous solution of 4'-(9-acridinylamino)-methanesulfon-m-anisidide and an organic acid selected from the group consisting of gluconic acid, gluconolactone and mixtures thereof, the molar ratio of the organic acid to 4'-(9-acridinylamino)-methane-sulfon-m-anisidide being from about 2:1 to about 4:1;
and (2) lyophilizing the so-produced aqueous solution.
and (2) lyophilizing the so-produced aqueous solution.
2. The process according to Claim 1 wherein the organic acid is gluconolactone.
3. The process according to Claim 1 wherein the molar ratio of organic acid to 4'-(9-acridinylamino)-methanesulfon-m-anisidide is about 2.5:1.
4. The process according to Claim 1 wherein the aqueous solution of step (1) is filtered prior to lyophilization.
5. A stable, solid, water-soluble composition for reconsti-tution with water or aqueous vehicle as a stable solution of 4'-(9-acridinylamino)-methanesulfon-m-anisidide, said composi-tion being produced by the steps of (1) forming an aqueous solution of 4'-(9-acridinylamino)-methanesulfon-m-anisidide and an organic acid selected from the group consisting of gluconic acid, gluconolactone and mixtures thereof, the molar ratio of the organic acid to 4'-(9-acridinylamino)-methane-sulfon-m-anisidide being from about 2:1 to about 4:1;
and (2) lyophilizing the so-produced aqueous solution.
and (2) lyophilizing the so-produced aqueous solution.
6. The composition according to Claim 5 wherein about 2.5 moles of organic acid are used per mole of 4'-(9-acridinylamino)-methanesulfon-m-anisidide.
7. The composition according to Claim 5 or Claim 6 where-in the organic acid used is gluconolactone.
8. The composition according to Claim 5 wherein the aqueous solution of step (1) is formed by reacting about 5 g.
4'-(9-acridinylamino)-methanesulfon-m-anisidide and 6.23 g.
gluconolactone per liter of solution.
4'-(9-acridinylamino)-methanesulfon-m-anisidide and 6.23 g.
gluconolactone per liter of solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000407044A CA1159368A (en) | 1980-01-24 | 1982-07-09 | Antitumor compositions |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11480980A | 1980-01-24 | 1980-01-24 | |
| US114,809 | 1980-01-24 | ||
| CA000369109A CA1252103A (en) | 1980-01-24 | 1981-01-22 | Crystalline gluconate salt of 4'-(9-acridinylamino)- methanesulfo-m-anisidide |
| CA000407044A CA1159368A (en) | 1980-01-24 | 1982-07-09 | Antitumor compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1159368A true CA1159368A (en) | 1983-12-27 |
Family
ID=27166949
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000407044A Expired CA1159368A (en) | 1980-01-24 | 1982-07-09 | Antitumor compositions |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1159368A (en) |
-
1982
- 1982-07-09 CA CA000407044A patent/CA1159368A/en not_active Expired
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