Patent Application: US-52295195-A

Abstract:
7 - ethyl - 10 - hydroxy camptothecin , an active metabolite of the camptothecin analog cpt - 11 which is used as an anticancer drug , is poorly soluble in water . because of its poor water solubility , hecpt has not been directly administered by parenteral or oral routes in human patients for the purpose of inhibiting the growth of cancer cells . there is also unpredictable interpatient variability in the metabolic production of hecpt from cpt - 11 which limits the utility of cpt - 11 . this invention overcomes these limitations by teaching novel pharmaceutically acceptable lactone stable hecpt formulations for the direct administration of lactone stable hecpt formulations orally or parenterally to patients with various forms of cancer .

Description:
in its preferred embodiments , this invention involves preparation and administration of novel lactone stable hecpt formulations as described below . the following examples illustrate selected modes for carrying out the claimed invention and are not to be construed as limiting the specification and claims in any way . the foregoing description of the formulation invention has been directed to particular preferred embodiments in accordance with the requirements of the patent statutes and for purposes of explanation and illustration . those skilled in the art will recognize that many modifications and changes may be made without departing from the scope and the spirit of the invention . for injection or infusion into aqueous body fluids , a formulation containing about 0 . 1 to about 2 . 5 mg of hecpt dissolved in 500 to 10 , 000 parts by weight of dimethylisosorbide based on the total weight of the formulation , about 1 to 1 , 000 parts by weight of a pharmaceutically acceptable acid , about 20 to 7 , 000 parts by weight of a pharmaceutically acceptable alcohol , about 20 to about 8 , 000 parts by weight a polyethylene glycol , and about 20 to about 8 , 000 parts of a non - ionic surfactant . suitable alcohols include ethyl alcohol and benzyl alcohol . suitable polyether glycols for this formulation include polyethylene glycol 300 , polyethylene glycol 400 and propylene glycol . suitable non - ionic surfactants include polysorbate - 80 . in a preferred embodiment , the formulation of hecpt is supplied as an intravenous injectable in a unit dose sealed vial comprising a sterile , nonaqueous solution of drug in a vehicle comprising dimethylisosorbide , ethyl alcohol with or without benzyl alcohol , citric acid , polyethylene glycol 300 , and polysorbate ( tween 80 ) in acidified medium with a ph of 3 to 4 at a final concentration of 0 . 1 to 1 . 0 mg of hecpt per 1 ml of formulation . a second formulation comprises from about 0 . 1 mg to about 2 . 5 mg of hecpt dissolved in a formulation containing 20 to 7 , 000 parts by weight of a pharmaceutically acceptable alcohol and about 20 to 8 , 000 parts by weight of formulation of a non - ionic surfactant . suitable alcohols include dehydrated ethyl alcohol usp with or without benzyl alcohol . suitable non - ionic surfactants include the polyoxyethylated oils , such as polyoxyethylated vegetable oils , such as castor oil , peanut oil , and olive oil . in a preferred embodiment 0 . 1 mg to 1 . 0 mg hecpt per ml of formulation consists of 500 to 10 , 000 parts by weight of dimethylisosorbide , 20 to 8 , 000 parts by weight of cremaphor el ( polyoxyethylated castor oil ) , 20 to 7 , 000 parts by weight of ethyl alcohol and 1 to 1 , 000 parts by weight of total solution weight of citric acid . an oral formulation of hecpt in soft gelatin capsules ( comprised of gelatin / glycerin / sorbitol / purifiers / purified water ) containing hecpt in a final concentration of 0 . 1 to 1 . 0 mg per ml in a formulation containing 500 to 10 , 000 parts of dimethylisosorbide by weight of total solution , citric acid 1 to 1 , 000 parts by weight , glycerin 1 to 1 , 000 parts by weight , and polyethylene glycol 300 or polyethylene glycol 400 20 to 8 , 000 parts by weight , ethyl alcohol 20 to 7 , 000 parts by weight , sodium acetate 0 . 1 to 250 parts by weight , pluronic f - 127 poloxamer 0 . 1 to 800 parts by weight , and taurocholic acid 10 to 2 , 500 parts by weight of total solution weight . the soft gelatin capsules may also be composed of any of a number of compounds used for this purpose including , for example , a mixture of gelatin , glycerin , sorbitol , purified water , and parabens . for injection or infusion into aqueous body fluids , a formulation comprises from about 0 . 1 to about 5 . 0 mg of hecpt dissolved in 500 to 10 , 000 parts by weight of total solution weight of dimethylacetamide ( dma ), about 1 to about 1 , 000 parts by weight of a pharmaceutically acceptable acid , about 20 to about 7 , 000 parts by weight of an alcohol , about 20 to about 8 , 000 parts by weight of a polyether glycol including polyethylene glycol , and about 20 to about 8 , 000 parts of a non - ionic surfactant . suitable pharmaceutically acceptable acids include citric acid , hydrochloric acid and phosphoric acid alone or in any combination . suitable alcohols include dehydrated ethyl alcohol , benzyl alcohol . suitable polyether glycols , which can be used individually or in any combination include polyethylene glycol 200 , polyethylene glycol 300 , polyethylene glycol 400 and propylene glycol . suitable non - ionic surfactants include polysorbate - 80 . in a preferred embodiment , the formulation of hecpt is supplied as an intravenous injectable in a sealed unit dose vial comprising a sterile , nonaqueous solution of drug in a vehicle comprising ethyl alcohol , benzyl alcohol , citric acid , polyethylene glycol 300 , and polysorbate ( tween 80 ) in an acidified medium with a ph of 3 to 4 containing hecpt at a final concentration of 0 . 2 mg per ml . a second formulation contains about 0 . 1 mg to about 5 . 0 mg of hecpt dissolved in 500 to about 10 , 000 parts by weight of dimethylacetamide , 1 to 1 , 000 parts by weight of citric acid , 20 to 7 , 000 parts by weight of an alcohol and about 20 to 8 , 000 parts by weight of a non - ionic surfactant . suitable alcohols include dehydrated ethyl alcohol usp or dehydrated ethyl alcohol and benzyl alcohol . suitable non - ionic surfactants include the polyoxyethylated oils , such as polyoxyethylated vegetable oils , such as castor oil , peanut oil , and olive oil . in a preferred embodiment 0 . 1 to 5 mg hecpt is formulated in 500 to 10 , 000 parts by weight of dimethylacetamide ( dma ), 20 to 8 , 000 parts by weight of cremaphor el ( polyoxyethylated castor oil ), 20 to 7 , 000 parts by weight dehydrated ethyl alcohol usp , and 50 to 750 parts by weight of citric acid to adjust the final ph between 3 to 4 . an oral formulation of hecpt in soft gelatin capsules ( comprised of gelatin / glycerin / sorbitol / purifiers / purified water ) containing 0 . 1 to 15 mg of hecpt dissolved or suspended in 500 to 10 , 000 parts of dimethylacetamide , citric acid 1 to 1 , 000 parts by weight , glycerin 1 to 1 , 000 parts by weight , and polyethylene glycol 300 or polyethylene glycol 400 20 to 8 , 000 parts by weight , dehydrated ethyl alcohol 20 to 7 , 000 parts by weight , sodium acetate 0 . 1 to 250 parts by weight , pluronic f - 127 poloxamer 0 . 1 to 800 parts by weight , and taurocholic acid 10 to 2 , 500 parts by weight . the soft gelatin capsules may also be composed of any of a number of compounds used for this purpose including , for example , a mixture of gelatin , glycerin , sorbitol , purified water , and parabens . to allow a prolonged parenteral infusion of hecpt to patients with cancer for clinical infusions , the drug may diluted in 5 % dextrose in water ( d5w ) to a final concentration of 0 . 001 mg / ml to about 0 . 01 mg / ml of hecpt prior to injection or infusion . maintaining an acidic ph ( 3 to 4 ) in the formulation is particularly important to reduce the slow conversion of hecpt lactone to the e - ring - hydrolyzed carboxylate form , which occurs at physiological ph . at equilibrium under physiologic ph , the ratio of the open - ring carboxylate form to lactone form increases . hydrolysis of the hecpt lactone e - ring will be substantially reduced if the drug is kept in an acidic environment . some of the unpredictable toxicity seen in earlier clinical trials using sodium camptothecin may have been due to the formation of greater amounts of the lactone form of camptothecin , which is 10 - fold more toxic than sodium camptothecin in mice . the lactone form of camptothecin , as in hecpt , is less water soluble than the carboxylate e - ring form . when early clinical trials were first conducted with camptothecin formulated using naoh , the significance of maintaining the closed lactone e ring for uniform efficacy in treating patients with cancer was poorly understood . the early reported unpredictable clinical toxicities associated with camptothecin administration may have been exacerbated by the naoh formulation which promotes the formation of the carboxylate form , and by the relative lack of understanding of the significance of the lactone form of camptothecin as it relates to antitumor activity . this example was designed to test the solubility of camptothecin , which is used as a reference compound for 7 - ethyl - 10 - hydroxy camptothecin in different solvents . for this example , bnpi - 1028 is camptothecin . the solubility of camptothecin was tested in water , ethanol , benzyl alcohol , propylene glycol , peg 300 , dmi and dma . for this example , the maximum amount of camptothecin that would dissolve in 1 ml of the indicated solvent at 4 ° c . or at 25 ° c . was measured . for example , referring to table 4 , 0 . 928 mg camptothecin dissolved in 1 ml of dmi at 25 ° c ., 5 . 0 mg camptothecin was dissolved in 1 ml of dma at 25 ° c ., while only 0 . 051 mg camptothecin dissolved in 1 ml of ethanol ( 200 proof ) 25 ° c . see table 4 below . see table 4 . the numbers in the parentheses are greater than highest calibration standard . they are considered acceptable because of the linear response of the method . this example confirmed the poorly water soluble nature of camptothecin and demonstrated that camptothecin is relatively insoluble in water and polar solvents ( i . e . ethanol , propylene glycol ). this example also showed that camptothecin was much more soluble in non - polar solvents such as benzyl alcohol , dimethyl isosorbide and dimethylacetamide . from this data , it can be concluded that maximum dissolution of camptothecin depends on the temperature ( 4 ° c . versus 25 ° c .) and solvent . as is evident , camptothecin dissolves better in dmi and dma than in ethanol or water . also , camptothecin is much more soluble in dma than in dmi . table 4______________________________________solubility of camptothecin in dma or dmi in different solvents target 4 ° c . actual 25 ° c . actual concentration concentration concentrationsolvent ( μg / ml ) ( μg / ml ) ( μg / ml ) ______________________________________milli - q water 2620 0 . 7 0 . 2ethanol ( 200 proof ) 2620 41 51benzyl alcohol 2710 ( 2663 ) 1674propylene glycol 3150 236 281peg 300 2660 650 ( 706 ) dimethylisosorbide 2460 510 928n , n - dimethyl 10000 5500 5000acetamide______________________________________ this example was designed to determine the range in parts by weight for a variety of different components added to an initial solution of hecpt and dma . table 5 is a compilation of these ranges . various combinations of the components are presented in tables 6 , 7 , and 8 . table 5______________________________________solubility of sn38 ( 0 . 1 mg / ml to 10 mg / ml ) in dma with additional components ( range in parts by weight ) range in parts tablecomponent by weight number______________________________________dimethylacetamide ( dma ) 500 - 10 , 000 6 , 7 , 8total acid 1 - 3 , 500 6 , 7 , 8citric acid 1 - 1 , 000 6 , 7 , 8taurocholic acid 10 - 2 , 500 8peg 300 , peg 400 20 - 8 , 000 7 , 8glycerin 1 - 1 , 000 8benzyl alcohol 20 - 4 , 000 6dehydrated ethyl alcohol usp 20 - 7 , 000 6 , 7 , 8 ( ethanol ) polysorbate - 80 20 - 8 , 000 6cremaphor el 20 - 8 , 000 7 ( polyoxyethylated castor oil ) propylene glycol 20 - 8 , 000poloxamer ( poloxamer 127 ) 0 . 1 - 800 8sodium acetate 0 . 1 - 250 8______________________________________ this example presents one preferred parenteral formulation of hecpt and dma in combination with a variety of different components . for each formulation approximately 2 . 5 mg of hecpt was dissolved in 1000 parts of a pure form of dma at 25 ° c . dissolution was achieved with gentle agitation until a clear solution resulted within about 2 hours . approximately one hundred ( 100 ) parts of a mineral acid is added to this solution of hecpt and dma to obtain a final ph of between 2 and 6 . a more preferred ph range is between 3 and 4 . examples of mineral acids are pure hydrochloric acid ( 0 . 1n ) and phosphoric acid . these are examples only and not intended to be the only mineral acids used in this invention . range of hecpt in dma is 0 . 1 mg to 0 . 25 mg hecpt per ml of formulation . this example presents another preferred parenteral formulation of hecpt and dma in combination with a variety of different components . for each formulation approximately 2 . 5 mg of hecpt was dissolved in 1000 parts of a pure form of dma at 25 ° c . dissolution was achieved with gentle agitation until a clear solution resulted within about two hours . about five hundred ( 500 ) parts of a carboxylic acid is added to this solution of hecpt and dma . examples of carboxylic acids are tartaric acid , citric acid , succinic , fumaric , maleic acid , gluconic acid , ascorbic acid , taurocholic acid , and taurocholic acid in an admixture with citric acid . these are examples only and not intended to be the only carboxylic acids for this invention . examples of different combinational parenteral formulations are presented in table 6 below . this parenteral formulation includes between about 0 . 1 to about 0 . 25 mg per ml of hecpt per ml of formulation , ethanol ( about 20 to about 7 , 000 parts by weight ), benzyl alcohol ( about 500 to about 5 , 000 parts by weight ), citric acid ( about 1 to about 1 , 000 parts by weight ), polyethylene glycol 300 ( peg 300 : about 20 to about 8 , 000 parts by weight ), dma ( also called dmac : about 500 to about 10 , 000 parts by weight ) and tween 80 ( polysorbate - 80 , a non - ionic surfactant : about 20 to about 8 , 000 parts by weight ). table 6__________________________________________________________________________modified oral or parenteral formlation version 1 ( with dmac ) ethanol benzyl alcohol citric acid peg 300 dmac tween 80formulation nominal exact nominal exact nominal exact nominal exact nominal exact nominal exactnumber ( ml ) ( ml ) ( ml ) ( ml ) ( g ) ( g ) ( g ) ( g ) ( ml ) ( ml ) ( g ) ( g ) __________________________________________________________________________ 4 - dmac 6 . 337 6 . 337 -- -- 1 . 0000 1 . 0077 50 . 0000 49 . 9909 10 . 684 10 . 684 10 . 0000 10 . 0097 9 - dmac 1 . 901 1 . 901 -- -- 1 . 5000 1 . 5085 15 . 0000 15 . 0179 32 . 051 32 . 051 30 . 0000 29 . 992910 - dmac 20 . 279 20 . 279 3 . 444 3 . 444 4 . 0000 3 . 9962 40 . 0000 40 . 2157 8 . 547 8 . 547 8 . 0000 8 . 0297__________________________________________________________________________ this example presents yet another preferred parenteral formulation of hecpt and dma in combination with a variety of different components . for each formulation approximately 2 . 5 mg of hecpt was dissolved in 1000 parts of a pure form of dma at 25 ° c . dissolution was achieved with gentle agitation until a clear solution resulted within about two hours . about five hundred ( 500 ) parts of a carboxylic acid is added to this solution of hecpt and dma . examples of carboxylic acids are tartaric acid , citric acid , succinic , fumaric , maleic acid , gluconic acid , ascorbic acid , taurocholic acid , and taurocholic acid in an admixture with citric acid . these are examples of carboxylic acids only and not intended to be the only carboxylic acids for this invention . examples of different combinational parenteral formulations are presented in table 7 below . this parenteral formulation contains hecpt between about 0 . 1 to about 0 . 25 mg per ml , ethanol ( about 20 to about 7 , 000 parts by weight ), citric acid ( about 1 to 1 , 000 parts by weight ), dma ( also called dmac : about 500 to about 10 , 000 parts by weight ) and cremaphor el ( 20 - 8 , 000 parts by weight ). table 7__________________________________________________________________________modified oral or parenteral formulation version 2 ( with dmac ) cremaphor el ethanol citric acid dmacformulation nominal exact nominal exact nominal exact nominal exactnumber ( g ) ( g ) ( ml ) ( ml ) ( g ) ( g ) ( ml ) ( ml ) __________________________________________________________________________1 40 . 0000 39 . 9927 25 . 349 25 . 349 4 . 0000 4 . 0000 42 . 735 42 . 7352 100 . 0000 100 . 0010 6 . 337 6 . 337 5 . 0000 5 . 0008 10 . 684 10 . 6843 10 . 0000 10 . 0100 6 . 337 6 . 337 5 . 0000 5 . 0012 106 . 838 106 . 8389 4 . 0000 4 . 0458 50 . 697 50 . 697 2 . 0000 2 . 0010 42 . 735 42 . 735__________________________________________________________________________ this example a preferred oral formulation of hecpt and dma in combination with a variety of different components . for each formulation approximately 2 . 5 mg of hecpt was dissolved in 1000 parts of a pure form of dma at 25 ° c . dissolution was achieved with gentle agitation until a clear solution resulted within about two hours . about five hundred ( 500 ) parts by weight of a carboxylic acid is added to this solution of hecpt and dma . examples of carboxylic acids are tartaric acid , citric acid , succinic , fumaric , maleic acid , gluconic acid , ascorbic acid , taurocholic acid , and taurocholic acid in an admixture with citric acid . these are examples of carboxylic acids only and not intended to be the only carboxylic acids for this invention . examples of different combinational oral formulations are presented in table 8 below . this oral formulation contains about 0 . 1 to about 0 . 25 mg per ml of hecpt , citric acid ( about 1 to about 1 , 000 parts by weight ), glycerin ( about 1 to about 1 , 000 parts by weight ), peg 300 ( about 20 to about 8 , 000 parts by weight ), ethanol ( about 20 to about 7 , 000 parts by weight ), dma (: about 500 to about 10 , 000 parts by weight ), a surfactant ( polaxomer 127 : about 0 . 1 to about 800 parts by weight ), sodium acetate ( about 0 . 1 to about 250 parts by weight ), and taurocholic acid ( about 10 to about 2 , 500 parts by weight ). table 8__________________________________________________________________________oral formulations - version 2 ( with dmac and polaxomer 127 ) citric acid glycerine peg 300 ethanolformulation nominal exact nominal exact nominal exact nominal exactnumber ( g ) ( g ) ( g ) ( g ) ( g ) ( g ) ( ml ) ( ml ) __________________________________________________________________________ 1 * 10 . 0000 10 . 0000 6 . 0000 6 . 0269 45 . 0000 45 . 0118 10 . 111 10 . 111 2 0 . 2000 0 . 2001 -- -- 36 . 0000 36 . 5757 10 . 849 10 . 849 3 0 . 4000 0 . 4001 -- -- 40 . 0000 40 . 0169 18 . 276 18 . 276 4 0 . 1000 0 . 1000 -- -- 18 . 0000 18 . 0109 10 . 488 10 . 488 5 * 6 . 0000 6 . 0012 -- -- 15 . 0000 15 . 0052 5 . 725 5 . 725 6 0 . 1500 0 . 1503 3 . 6000 3 . 6014 15 . 0000 15 . 2513 5 . 475 5 . 475 7 0 . 2000 0 . 2023 4 . 8000 4 . 8090 20 . 0000 20 . 0186 20 . 659 20 . 659 8 * 10 . 0000 10 . 0029 6 . 0000 6 . 0084 45 . 0000 45 . 0218 10 . 111 10 . 111 9 8 . 0000 8 . 0002 -- -- 20 . 0000 20 . 0190 10 . 139 10 . 13910 8 . 0000 8 . 0096 4 . 8000 4 . 8458 36 . 0000 36 . 0201 16 . 793 16 . 79311 0 . 1000 0 . 1001 -- -- 18 . 0000 18 . 0001 10 . 488 10 . 48812 0 . 1000 0 . 1000 2 . 4000 2 . 4169 18 . 0000 18 . 0392 7 . 534 7 . 53413 2 . 5000 2 . 5003 1 . 5000 1 . 5247 6 . 2500 6 . 4536 9 . 846 9 . 84614 0 . 2000 0 . 2022 -- -- 36 . 0000 36 . 0383 10 . 849 10 . 84915 2 . 5000 2 . 5017 -- -- 11 . 2500 11 . 2540 10 . 579 10 . 57916 * 6 . 0000 6 . 0001 -- -- 15 . 0000 15 . 0010 5 . 725 5 . 725__________________________________________________________________________dmac polaxomer 127 na acetate taurocholic a . formulation nominal exact nominal exact nominal exact nominal exactnumber ( ml ) ( ml ) ( g ) ( g ) ( g ) ( g ) ( g ) ( g ) __________________________________________________________________________ 1 * 5 . 342 5 . 342 5 . 0000 5 . 0021 0 . 8000 0 . 8055 -- -- 2 42 . 735 42 . 735 0 . 2000 0 . 2025 0 . 6400 0 . 6404 -- -- 3 8 . 547 8 . 547 8 . 0000 8 . 0011 1 . 2800 1 . 2796 -- -- 4 2 . 137 2 . 137 2 . 0000 2 . 0016 -- -- 11 . 0000 11 . 0139 5 * 3 . 205 3 . 205 0 . 1500 0 . 1501 -- -- 16 . 5000 16 . 6039 6 3 . 205 3 . 205 0 . 1500 0 . 1532 0 . 4800 0 . 4802 16 . 5000 16 . 8519 7 42 . 735 42 . 735 0 . 2000 0 . 1995 -- -- -- -- 8 * 5 . 342 5 . 342 5 . 0000 5 . 0019 0 . 8000 0 . 8002 -- -- 9 42 . 735 42 . 735 4 . 0000 4 . 0015 -- -- -- -- 10 4 . 274 4 . 274 0 . 2000 0 . 2012 -- -- -- -- 11 2 . 137 2 . 137 2 . 0000 2 . 0069 -- -- 11 . 0000 11 . 114312 21 . 368 21 . 368 2 . 0000 2 . 0705 -- -- 11 . 0000 11 . 062413 13 . 355 13 . 355 1 . 2500 1 . 2512 0 . 2000 0 . 2003 6 . 8750 6 . 940214 42 . 735 42 . 735 0 . 2000 0 . 2072 0 . 6400 0 . 6401 -- -- 15 13 . 355 13 . 355 0 . 0630 0 . 0628 0 . 2000 0 . 2005 6 . 8750 6 . 887216 * 3 . 205 3 . 205 0 . 1500 0 . 1508 -- -- 16 . 5000 16 . 4333__________________________________________________________________________ * prepared with citric acidmonohydrate , all others prepared with citric acidannhydrous . this example was designed to determine the range in parts by weight for a variety of different components added to an initial solution of hecpt and dmi . table 9 is a compilation of these ranges . various combinations of the components are presented in tables 10 , 11 , and 12 . table 9______________________________________solubility of sn38 ( 0 . 1 mg / ml to 1 . 0 mg / ml ) in dmi with additional components ( range in parts by weight ) range in parts tablecomponent by weight number______________________________________dimethylisosorbide ( dmi ) 500 - 10 , 000 10 , 11 , 12total acid 1 - 3 , 500 10 , 11 , 12citric acid 1 - 1 , 000 10 , 11 , 12taurocholic acid 10 - 2 , 500 12polyethylene glycol ( peg 300 20 - 8 , 000 10 , 12or peg 400 ) propylene glycol 20 - 8 , 000glycerin 1 - 1 , 000 12benzyl alcohol 20 - 4 , 000 10dehydgated ethyl alcohol usp 20 - 7 , 000 10 , 11 , 12 ( ethanol ) polysorbate ( tween 80 ) 20 - 8 , 000 10cremaphor el 20 - 8 , 000 11 ( polyoxyethylated castor oil ) ionic surfactant ( polaxomer 127 ) 0 . 1 - 800 12sodium acetate 0 . 1 - 250 12______________________________________ this example presents one preferred parenteral formulation of hecpt and dmi in combination with a variety of different components . for each formulation approximately 0 . 1 to 0 . 25 mg of hecpt was dissolved in 1000 parts of a pure form of dmi at 25 ° c . dissolution was achieved with gentle agitation until a clear solution resulted within about two hours . about one hundred ( 100 ) parts by weight of a mineral acid is added to this solution of hecpt and dmi to obtain a final ph of between 2 and 6 . a more preferred ph range is between 3 and 4 . examples of mineral acids are pure hydrochloric acid ( 0 . 1n ) and phosphoric acid . these are examples only and not intended to be the only mineral acids used in this invention . the concentration range of hecpt in this formulation is about 0 . 1 mg to about 0 . 25 mg hecpt per ml . this example presents another preferred parenteral formulation of hecpt and dmi in combination with a variety of different components . for each formulation approximately 2 . 5 mg of hecpt was dissolved in 1000 parts of a pure form of dmi at 25 ° c . dissolution was achieved with gentle agitation until a clear solution resulted within about two hours . about five hundred ( 500 ) parts by weight of a carboxylic acid is added to this solution of hecpt and dmi . examples of carboxylic acids are tartaric acid , citric acid , succinic , fumaric , maleic acid , gluconic acid , ascorbic acid , taurocholic acid , and taurocholic acid in an admixture with citric acid . these are examples only and not intended to be the only carboxylic acids for this invention . examples of different combinational parenteral formulations are presented in table 10 below . this parenteral formulation includes 0 . 1 to about 0 . 25 mg of hecpt per ml of formulation , ethanol ( about 20 to about 7 , 000 parts by weight ), benzyl alcohol ( about 20 to about 4 , 000 parts by weight ), citric acid ( about 1 to about 1 , 000 parts by weight ), polyethylene glycol 300 ( about 20 to about 8 , 000 parts by weight ), dmi ( about 500 to about 1 , 000 parts by weight ) and polysorbate - 80 ( tween 80 , a non - ionic surfactant : about 20 to about 8 , 000 parts by weight ). table 10__________________________________________________________________________parenteral or oral formulation version 1 ( with dmi ) ethanol benzyl alcohol citric acid peg 300 dmi tween 80formulation nominal exact nominal exact nominal exact nominal exact nominal exact nominal exactnumber ( ml ) ( ml ) ( ml ) ( ml ) ( g ) ( g ) ( ml ) ( ml ) ( ml ) ( ml ) ( g ) ( g ) __________________________________________________________________________ 1 2 . 281 2 . 281 1 . 55 1 . 55 0 . 3600 0 . 3601 28 . 75 32 . 4 3 . 13 3 . 13 33 . 3 33 . 3 ml 2 8 . 745 8 . 745 -- -- 0 . 3450 0 . 3457 27 . 55 27 . 5 30 . 00 30 . 0 3 . 4500 3 . 4644 3 19 . 011 19 . 011 3 . 23 3 . 3 3 . 7500 3 . 7520 33 . 27 33 . 3 6 . 52 6 . 522 7 . 5000 7 . 6955 4 7 . 605 7 . 605 -- -- 1 . 2000 1 . 2024 53 . 24 53 . 2 10 . 44 10 . 435 12 . 0000 11 . 1000 5 7 . 605 7 . 605 1 . 29 1 . 3 0 . 3000 0 . 3001 13 . 31 13 . 3 26 . 09 26 30 . 0000 29 . 9663 6 8 . 745 8 . 745 -- -- 0 . 3450 0 . 3455 27 . 55 27 . 5 30 . 00 30 3 . 4500 3 . 5841 7 8 . 745 8 . 745 -- -- 1 . 7250 1 . 7250 27 . 55 27 . 5 3 . 00 3 . 0 34 . 5000 34 . 4804 8 2 . 281 2 . 281 1 . 55 1 . 55 0 . 3600 0 . 3605 28 . 70 28 . 7 3 . 13 3 . 13 36 . 0000 36 . 2250 9 1 . 901 1 . 901 -- -- 1 . 5000 1 . 4999 13 . 31 13 . 3 26 . 09 26 30 . 0000 30 . 091710 19 . 011 19 . 011 3 . 23 3 . 3 3 . 7500 3 . 7501 33 . 27 33 . 3 6 . 52 6 . 522 7 . 5000 7 . 553011 1 . 901 1 . 901 -- -- 1 . 5000 1 . 5011 13 . 31 13 . 3 26 . 09 26 30 . 0000 30 . 021512 2 . 281 2 . 281 1 . 55 1 . 55 1 . 8000 1 . 7017 28 . 75 28 . 7 31 . 30 31 . 3 3 . 6000 3 . 6106__________________________________________________________________________ this example presents yet another preferred parenteral formulation of hecpt and dmi in combination with a variety of different components . for each formulation approximately 0 . 25 mg of hecpt was dissolved in 1000 parts of a pure form of dmi at 25 ° c . dissolution was achieved with gentle agitation until a clear solution resulted within about two hours . about five hundred ( 500 ) parts of a carboxylic acid is added to this solution of hecpt and dmi . examples of carboxylic acids are tartaric acid , citric acid , succinic , fumaric , maleic acid , gluconic acid , ascorbic acid , taurocholic acid , and taurocholic acid in an admixture with citric acid . these are examples of carboxylic acids only and not intended to be the only carboxylic acids for this invention . examples of different combinational parenteral formulations are presented in table 11 below . this parenteral formulation includes 0 . 1 to about 0 . 25 mg per ml of hecpt , ethanol ( 20 to 7 , 000 parts by weight ), citric acid ( about 1 to about 1 , 000 parts by weight ), dmi ( about 500 to about 10 , 000 parts by weight ) and cremaphor el ( about 20 to about 8 , 000 parts by weight ). table 11__________________________________________________________________________parenteral or oral formulation version 2 ( with dmi ) cremaphor el ethanol citric acid dmiformulation nominal exact nominal exact nominal exact nominal exactnumber ( g ) ( g ) ( ml ) ( ml ) ( g ) ( g ) ( ml ) ( ml ) __________________________________________________________________________ 1 40 . 0000 39 . 9939 25 . 349 25 . 350 4 . 0000 4 . 0007 34 . 783 34 . 783 2 100 . 0000 100 . 0850 6 . 337 6 . 337 5 . 0000 5 . 0013 8 . 696 8 . 7 3 10 . 0000 9 . 9343 6 . 337 6 . 337 5 . 0000 5 . 0001 86 . 957 87 4 4 . 0000 4 . 0099 50 . 697 50 . 7 2 . 0000 2 . 0005 34 . 783 34 . 783 5 30 . 0000 30 . 0684 38 . 023 38 0 . 3000 0 . 3000 26 . 087 26 . 1 6 40 . 0000 39 . 9942 25 . 349 25 . 35 4 . 0000 3 . 9997 34 . 783 34 . 8 7 30 . 0000 30 . 1973 38 . 023 38 0 . 3000 0 . 3234 26 . 087 26 8 6 . 0000 6 . 7330 76 . 046 76 0 . 6000 0 . 6010 5 . 217 5 . 217 9 4 . 0000 4 . 0018 50 . 697 50 . 7 2 . 0000 2 . 0004 34 . 783 34 . 810 40 . 0000 39 . 9882 50 . 697 50 . 7 2 . 0000 2 . 0000 3 . 478 3 . 511 50 . 0000 49 . 9857 3 . 169 3 . 16 0 . 5000 0 . 5019 43 . 478 43 . 512 100 . 0000 100 . 0470 6 . 337 6 . 337 5 . 0000 5 . 0013 8 . 696 8 . 7__________________________________________________________________________ this example is a preferred oral formulation of hecpt and dmi in combination with a variety of different components . for each formulation approximately 0 . 25 mg of hecpt was dissolved in 1000 parts of a pure form of dmi at 25 ° c . dissolution was achieved with gentle agitation until a clear solution resulted within about two hours . about five hundred ( 500 ) parts by weight of a carboxylic acid is added to this solution of hecpt and dmi . examples of carboxylic acids are tartaric acid , citric acid , succinic , fumaric , maleic acid , gluconic acid , ascorbic acid , taurocholic acid , and taurocholic acid in an admixture with citric acid . these are examples of carboxylic acids only and not intended to be the only carboxylic acids for this invention . examples of different combinational oral formulations are presented in table 12 below . this oral formulation includes 0 . 1 to about 0 . 25 mg of hecpt per ml , citric acid ( about 1 to about 1 , 000 parts by weight ), glycerin ( about 1 to about 1 , 000 parts by weight ), polyethylene glycol 300 ( peg 300 : about 20 to about 8 , 000 parts by weight ), ethanol ( about 20 to about 7 , 000 parts by weight ), dmi ( about 500 to about 10 , 000 parts by weight ), a surfactant ( polaxomer 127 : 0 . 1 to about 800 parts by weight ), sodium acetate ( about 0 . 1 to about 250 parts by weight ), and taurocholic acid ( about 10 to about 2 , 500 parts by weight ). table 12__________________________________________________________________________oral formulation - version 1 ( vith dmi and polaxomer 68 ) citric acid glycerine peg 300 ethanolformulation nominal exact nominal exact nominal exact nominal exactnumber ( g ) ( g ) ( g ) ( g ) ( g ) ( g ) ( ml ) ( ml ) __________________________________________________________________________ 1 10 . 0000 10 . 0132 6 . 0000 6 . 0484 45 . 0000 45 . 1421 10 . 111 10 . 111 2 0 . 2000 0 . 2045 -- -- 36 . 0000 36 . 5490 10 . 849 10 . 849 3 0 . 4000 0 . 4019 -- -- 40 . 0000 40 . 0001 18 . 276 18 . 276 4 0 . 1000 0 . 1003 -- -- 18 . 0000 18 . 0706 10 . 488 10 . 488 5 * 6 . 0000 15 . 0036 -- -- 15 . 0000 15 . 0766 5 . 725 14 . 316 6 * 0 . 1500 0 . 3995 3 . 6000 3 . 6017 15 . 0000 15 . 0050 5 . 475 14 . 582 7 0 . 2000 0 . 2005 4 . 8000 4 . 8596 20 . 0000 20 . 1606 20 . 659 20 . 659 8 10 . 0000 10 . 0125 6 . 0000 5 . 9997 45 . 0000 44 . 9950 10 . 111 10 . 111 9 8 . 000 8 . 0083 -- -- 20 . 0000 20 . 0880 10 . 139 10 . 13910 8 . 0000 7 . 9995 4 . 8000 4 . 8743 36 . 0000 35 . 9995 16 . 793 16 . 79311 0 . 1000 0 . 1011 -- -- 18 . 0000 18 . 0057 10 . 488 10 . 48812 * 0 . 1000 0 . 1506 2 . 4000 2 . 4393 18 . 0000 18 . 0398 7 . 534 11 . 30113 * 2 . 5000 6 . 0028 1 . 5000 1 . 5152 6 . 2500 6 . 6421 9 . 846 23 . 63014 0 . 2000 0 . 2001 -- -- 36 . 0000 36 . 0393 10 . 849 10 . 84915 * 2 . 5000 5 . 0038 -- -- 11 . 2500 11 . 5865 10 . 579 21 . 15816 * 6 . 0000 15 . 0002 -- -- 15 . 0000 15 . 0224 5 . 725 14 . 312dmi polaxomer 68 na acetate taurocholic a . formulation nominal exact nominal exact nominal exact nominal exactnumber ( ml ) ( ml ) ( g ) ( g ) ( g ) ( g ) ( g ) ( g ) __________________________________________________________________________ 1 4 . 348 4 . 348 5 . 0000 5 . 0041 0 . 8000 0 . 7968 -- -- 2 34 . 783 34 . 783 0 . 2000 0 . 2106 0 . 6400 0 . 6446 -- -- 3 6 . 957 6 . 957 8 . 0000 8 . 0086 1 . 2800 1 . 2869 -- -- 4 1 . 739 1 . 739 2 . 0000 1 . 9992 -- -- 11 . 0000 11 . 0033 5 * 2 . 609 2 . 609 0 . 1500 0 . 1526 -- -- 16 . 5000 16 . 5011 6 * 2 . 609 2 . 609 0 . 1500 0 . 1522 0 . 4800 0 . 4867 16 . 5000 16 . 5025 7 34 . 783 34 . 783 0 . 2000 0 . 2010 -- -- -- -- 8 4 . 348 4 . 348 5 . 0000 5 . 0025 0 . 8000 0 . 8256 -- -- 9 34 . 783 34 . 783 4 . 0000 4 . 0045 -- -- -- -- 10 3 . 478 3 . 478 0 . 2000 0 . 2074 -- -- -- -- 11 1 . 739 1 . 739 2 . 0000 2 . 0018 -- -- 11 . 0000 11 . 011812 * 17 . 391 17 . 391 2 . 0000 2 . 0039 -- -- 11 . 0000 11 . 004113 * 10 . 870 10 . 870 1 . 2500 1 . 2548 0 . 2000 0 . 2144 6 . 8750 6 . 874114 34 . 783 34 . 783 0 . 2000 0 . 2026 0 . 6400 0 . 6414 -- -- 15 * 10 . 870 10 . 870 0 . 0630 0 . 0616 2 . 0000 0 . 2076 6 . 8750 6 . 876516 * 2 . 609 2 . 609 0 . 1500 0 . 1515 -- -- 16 . 0000 16 . 5052__________________________________________________________________________ * these formulations were prepared by adding the exact amounts of citric acid to ethanol as described . the nominal quantity of this solution was transferred to another volumetric flask and the remaining excipients added . ______________________________________u . s . patents4 , 399 , 276 8 / 1983 miyasaka et al . 4 , 399 , 282 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