Patent Application: US-40620995-A

Abstract:
the present invention is directed to improved pharmaceutical compositions employing paclitaxel that are formulated to increase stability and solubility . these improved formulations are useful in long - term , multi - day continuous infusion protocols , and have the advantage of reducing the number of infusion system breaks during the entire period of drug administration . also disclosed are kits for use in preparing paclitaxel for long - term infusion and enhanced solubility .

Description:
the present invention discloses novel formulations of paclitaxel that increase its stability and maintain solubility for extended periods of time in solution . the paclitaxel extended stability injection of the present invention is a modified formulation of the commercial product taxol ® ( mead johnson oncology , div . bristol - myers squibb ) designed to increase the utility time of paclitaxel in infusion solutions before the drug begins to precipitate ( see , for example , formulas i and ii in table i ). paclitaxel is very insoluble in aqueous media . ( flora et al ., 1992 ). consequently , the commercial injection is formulated as a concentrate at 6 mg / ml in a solvent mixture composed of cremophor ® el surfactant 527 mg / ml and dehydrated alcohol , usp , 49 . 7 % ( v / v ). ( mead johnson oncology , 1993 ). for administration the dose is admixed in 5 % dextrose injection , usp , or 0 . 9 % sodium chloride injection , usp , to a concentration between 0 . 3 and 1 . 2 mg / ml . the official labeling ( mead johnson oncology , 1993 ) cites a maximum stability time of 27 hours from preparation . this is brief but adequate for one - day infusion . a solution stability study of the current commercial formulation was conducted ( formula iv , table i ), and showed that while paclitaxel is chemically stable , it begins to crystalize out of solution after 3 to 5 days , rendering it unsuitable for continued parenteral administration . to allow for preparation time ( usually about 4 hours ) and adequate safety for the potentially erratic precipitation phenomenon , a maximum infusion time of 48 hours is being used based on these data . consequently , the inventor developed modified formulations of paclitaxel designed to keep paclitaxel dispersed for a minimum of seven days . the approach included increasing the solvent content relative to the drug in the vial , and combining this with admixing high concentrations of paclitaxel ( and associated solvent ) in infusion solutions for slow infusion . the paclitaxel thus remains dispersed in solution for long periods of time . a study of each formula in 5 % dextrose injection , usp , showed considerable extension of the time to precipitation . for example , formulas i & amp ; ii exhibited precipitation after two weeks while formula iii has remained in solution for greater than one year . presented in table i are representative paclitaxel formulations of the present invention ( formulas i , ii , iii , and the commercially available formulation ( formula iv )). it is recognized that the present invention is not limited to these formulas , which are representative of the combinations of solvent and surfactant percentages , and paclitaxel concentrations for extended paclitaxel stability in infusion solutions . table i______________________________________representative formulation compositions of the productconcentrates and after dilution for administration concentrate diluted______________________________________formula i ( extended stability formulation ) paclitaxel 3 mg / ml , 1 mg / ml 10 ml / vialsurfactant 2 . 5 ml ( 25 %) 0 . 833 ml ( 8 . 33 %) alcohol dehydrated 7 . 5 ml ( 75 %) 2 . 5 ml ( 25 %) formula ii ( extended stability formulation with preservative ) paclitaxel 3 mg / ml , 1 mg / ml 10 ml / vialsurfactant 2 . 5 ml ( 25 %) 0 . 833 ml ( 8 . 33 %) alcohol dehydrated 7 . 23 ml ( 72 . 3 %) 2 . 41 ml ( 24 . 1 %) benzyl alcohol 0 . 27 ml ( 2 . 7 %) 0 . 09 ml ( 0 . 9 %) formula iii ( modified extended stability formulation ) paclitaxel 3 mg / ml 1 mg / mlsurfactant 5 . 0 ml ( 50 %) 16 . 67 ml ( 16 . 67 %) alcohol dehydrated 5 . 0 ml ( 50 %) 16 . 67 ml ( 16 . 67 %) vial content 10 ml ( 30 mg ) formula iv ( commercial formulation from bristol myers ) paclitaxel 6 mg / ml , 1 mg / ml 5 ml / vialcremophor el ® 2 . 5 ml ( 50 %) 8 . 33 ml ( 8 . 33 %) alcohol dehydrated 2 . 5 ml ( 50 %) 8 . 33 ml ( 8 . 33 %) ______________________________________ . sup . a diluted in 5 % dextrose injection , usp , or 0 . 9 % sodium chloride injection , usp , to a standard concentration suitable for administration . formula i keeps the relative amount of surfactant the same as the current commercial product , which may help with concerns relating to toxicity . a stability study of formula i at 1 mg / ml in 5 % dextrose injection , usp , and 0 . 9 % sodium chloride injection , usp , was conducted over 31 days at several temperatures . the paclitaxel was chemically stable as long as it remained in solution . no occurrence of precipitation ( including subvisual particles ) was found within 14 days in d5w and about 10 days in sodium chloride . an extended stability formula of paclitaxel could be a product marketed for slow multi - day continuous infusion . the problems encountered in the art with drug precipitation in infusion pumps during infusion within the recommended 27 hours could potentially be alleviated . it is envisioned that other drugs might benefit from this approach including docetaxel ( taxotere ), and other taxoids , cyclosporine , teniposide , miconazole , and other water - insoluble drugs to increase their stability for multi - day use . the following examples are included to demonstrate preferred embodiments of the invention . it should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventor to function well in the practice of the invention , and thus can be considered to constitute preferred modes for its practice . however , those of skill in the art should , in light of the present disclosure , appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention . physical stability testing of extended stability formulations has been evaluated for the effects of changing alcohol concentration on precipitation times in infusion solutions . infusion solutions were prepared in 5 % dextrose injection , usp , at a paclitaxel concentration of about 1 mg / ml to be used for multiple day continuous infusion . alcohol concentrations in the final infusion solutions were varied from about 15 % to about 50 % to simulate variations in potential extended stability paclitaxel formulations . the current commercial product is labeled for 27 hour stability . it has been found that the drug molecule is chemically stable in solution , but is subject to early precipitation . crystalline precipitation began in three to five days in some samples and within seven days in most samples . it was determined that the safe stability period in solution was a total of about 52 hours -- 4 hours for preparation and transportation to the use site and 48 hours for administration . it has been found that the time to precipitate formation is variable even with the increased alcohol content . other factors apart from the alcohol content may affect the time to precipitation . such factors may include the inherent particle content ( size , shape , number ) that is inevitable in infusion solutions and drug products . also , the nature of the inner surface of the container and the container material may play a role , with containers having rough spots creating a place for earlier precipitation to begin . all of these other factors are beyond the control of the clinician , which makes the stabilizing effect of an increased alcohol content all the more important . the present study evaluated in triplicate paclitaxel 1 mg / ml in 5 % dextrose injection , usp , with alcohol concentrations ranging from about 15 % to about 50 % ( table ii ). in the 15 to 20 % range , the time to precipitation varied from about 9 to 14 days in most samples . this is comparable to the 10 to 14 days previously found , and substantially better than the 3 to 5 days for the commercial product . within the 15 to 20 % group , however , the time to precipitation was variable and not linearly related to alcohol content . it is surmised that the approximate 1 % alcohol concentration increments studied do not demonstrate a consistent change in paclitaxel solubility within the group . in both this study and the previous studies , paclitaxel solution having alcohol in the 15 to 20 % range have not precipitated before 9 days , a time greater than the current commercial preparation . the 25 % alcohol samples showed increased stability ( see table ii ). the earliest microprecipitation appeared after 14 days in one sample with gross precipitation in 21 days . additionally , the 30 and 50 % alcohol - containing solutions are remarkably more stable . after storage of 60 days , no precipitation , not even microcrystals , have appeared in any sample . while these samples show a much greater stability , the &# 34 ; break point &# 34 ; or step function was achieved at an alcohol concentration of about ≧ 30 %. table ii______________________________________precipitation times of paclitaxel 1 mg / ml in 5 % dextrose injection with varying alcohol concentrations . sup . aalcohol % precipitation time days . sup . b______________________________________15 1416 1217 1018 1219 9 . sup . c20 9 . sup . c25 . sup . 14 . sup . d30 & gt ; 60 . sup . e50 & gt ; 60 . sup . e______________________________________ . sup . a cremophor ® el concentration held constant at 8 . 3 %, the same a the current commercial product diluted to 1 mg / ml . . sup . b earliest precipitation among triplicate samples . . sup . c one sample precipitated at 9 days , 2 samples at 14 days or more . . sup . d one sample did not precipitated after 60 days . . sup . e all three samples were still in solution after 60 days . the food and drug administration is insistent that any infusion solution designed to be administered over periods exceeding 24 hours should be able to pass the usp antimicrobial agent effectiveness test ( uspxxii , & lt ; 51 & gt ;, p 1478 ) whether or not antibacterial preservatives are actually present . this arises from concerns about the potential for microbial growth over time if the solutions are inadvertently contaminated during preparation , and is intended to comply with fda regulations relating to solution sterility for infusion . for administration of the formulas , the dose is diluted to concentration of about 0 . 8 to 1 . 0 mg / ml in 5 % dextrose injection , usp , or 0 . 9 % sodium chloride injection , usp . a 1 . 0 mg / ml concentration is made by diluting with twice the volume of paclitaxel extended stability injection . a suitable intravenous infusion pump is used to assure uniform and constant delivery of this highly - concentrated solution over the required time interval . the fluid volume delivered is much reduced compared to the conventional formulation . for this testing , each of the three formulations were diluted with 5 % dextrose injection , usp , to a final paclitaxel concentration of about 1 mg / ml . at this concentration , the formulation may be used in continuous infusion therapy over multiple days utilizing an infusion pump . formula i is the original proposed extended stability paclitaxel formulation . formula ii is a modification that includes the antimicrobial preservative benzyl alcohol at a concentration that will yield about a 0 . 9 % concentration when diluted in the d5w . for the purposes of this invention , the preservative concentration is nominally at about 0 . 9 %, however it is recognized that any concentration that gives the requisite antimicrobial activity is within the scope of this invention . thus , the concentration of preservative may range from between about 0 . 4 % to about 1 . 8 %, with the preferred concentration at about 0 . 9 %. finally , the current commercial formulation of paclitaxel ( taxol ®, bristol myers ) was also evaluated at 1 mg / ml . the actual testing was performed by an independent contractor . tables iii and iv show that both formula i and ii , with and without added preservative , pass the antimicrobial test . it is of importance to note that the commercial product could not be tested due to drug precipitation . these studies indicate that the extended stability paclitaxel formulation , even without antimicrobial preservative , will be suitable for continuous infusion . table iii__________________________________________________________________________formula i was used in these studies__________________________________________________________________________antimicrobial preservatives effectiveness testmethod : usp xxii , pp . 1478 - 1479 ( anon , 1989 ) on test : 08 / 30 / 1994 off test : 05 / 04 / 1994results : pass__________________________________________________________________________organismtime a . niger c . albicans e . coli p . aeruginosa s . aureus__________________________________________________________________________inoculum1 , 000 , 000 420 , 000 340 , 000 300 , 000 450 , 000per mlorganisms / ml organisms / ml organisms / ml organisms / ml organisms / mlproduct0 hr . 600 , 000 680 , 000 320 , 000 118 , 000 880 , 000organisms / ml organisms / ml organisms / ml organisms / ml organisms / mlweek 11 , 900 less than 10 less than 10 less than 10 less than 10organisms / ml organisms / ml organisms / ml organisms / ml organisms / ml none detected none detected none detected none detectedweek 2100 less than 10 less than 10 less than 10 less than 10organisms / ml organisms / ml organisms / ml organisms / ml organisms / ml none detected none detected none detected none detectedweek 3130 less than 10 less than 10 less than 10 less than 10organisms / ml organisms / ml organisms / ml organisms / ml organisms / ml none detected none detected none detected none detectedweek 420 less than 10 less than 10 less than 10 leas than 10organisms / ml organisms / ml organisms / ml organisms / ml organisms / ml none detected none detected none detected none detected__________________________________________________________________________ table iv__________________________________________________________________________formula ii was used in these studies__________________________________________________________________________antimicrobial effectiveness testmethod : usp xxii , pp . 1478 - 1479on test : 03 / 30 / 1994 off test : 05 / 04 / 1994results : pass__________________________________________________________________________organismtime a . niger c . albicans e . coli p . aeruginosa s . aureus__________________________________________________________________________inoculum1 , 000 , 000 420 , 000 340 , 000 300 , 000 450 , 000per mlorganisms / ml organisms / ml organisms / ml organisms / ml organisms / mlproduct0 hr . 600 , 000 490 , 000 74 , 000 11 , 200 500 , 000organisms / ml organisms / ml organisms / ml organisms / ml organisms / mlweek 180 less than 10 less than 10 less than 10 less than 10organisms / ml organisms / ml organisms / ml organisms / ml organisms / ml none detected none detected none detected none detectedweek 250 less than 10 less than 10 less than 10 less than 10organisms / ml organisms / ml organisms / ml organisms / ml organisms / ml none detected none detected none detected none detectedweek 3less than 10 less than 10 less than 10 less than 10 less than 10organisms / ml organisms / ml organisms / ml organisms / ml organisms / mlnone detected none detected none detected none detected none detectedweek 4less than 10 less than 10 less than 10 less than 10 less than 10organisms / ml organisms / ml organisms / ml organisms / ml organisms / mlnone detected none detected none detected none detected none detected__________________________________________________________________________ paclitaxel injection ( mead johnson oncology , princeton , n . j .) was supplied by the manufacturer . the infusion solutions , 5 % dextrose injection ( mcgaw , irvine , calif .) and 0 . 9 % sodium chloride injection ( mcgaw , irvine , calif . ), were obtained commercially . paclitaxel reference standard ( bristol - myers squibb , princeton , n . j .) was used without further purification . the acetonitrile was hplc grade . the water used was also hplc grade and was prepared immediately before use . paclitaxel concentrations were determined using a stability - indicating hplc assay method based on the method of waugh et al . with modifications to achieve satisfactory chromatography in the inventor &# 39 ; s laboratory . the liquid chromatograph consisted of a multisolvent delivery pump ( waters chromatography , milford , mass . ), a programmable multiple - wavelength ultraviolet light detector ( waters ), a wisp autosampler ,( waters ) and a hplc analytical column ( vydac , hesperia , calif .) ( 250 × 4 . 6 mm , 5 μm particle size ). the system was controlled and integrated by a personal computer ( nec , boxborough , mass .). the mobile phase consisted of 53 % acetonitrile in water . the flow rate was 1 . 5 ml / min and detection was performed at 254 nm . the retention time for paclitaxel was 6 . 09 minutes ( fig1 a ). sample aliquots were filtered through 5 μm filter needle . samples of paclitaxel 1 mg / ml were diluted by a factor of 10 with the respective infusion solution prior to analysis . the hplc analytical method was validated to be stability - indicating by accelerated paclitaxel decomposition . the ph value of a freshly prepared paclitaxel 0 . 1 mg / ml solution was adjusted to 11 . 14 with 0 . 1n sodium hydroxide stock solution . after 1 hr at room temperature , 78 % intact paclitaxel remained ( fig . lb ). a major decomposition peak appeared at 9 . 02 minutes and several small peaks were observed from 2 . 0 to 4 . 18 minutes . the decomposition peaks do not interfere with the parent peak . for a nominal 0 . 1 mg / ml solution of paclitaxel , the mean ± s . d . precision of the assay , determined from 10 replicate injections , was 99 . 3 ± 0 . 75 μg / ml . precision expressed as percent relative standard deviation was 0 . 76 %. calibration curves were constructed from a linear plot of peak area versus concentration ( 0 , 025 to 0 . 15 mg / ml ). the correlation coefficient of the standard curve was greater than 0 . 9999 . the intra - day and inter - day coefficients of variation were 1 . 4 % and 2 . 0 %, respectively . triplicate test solutions of paclitaxel 0 . 1 and 1 mg / ml were prepared both in 5 % dextrose injection and 0 . 9 % sodium chloride injection in 150 - ml polyolefin minibags and stored statically at 32 °, 22 °, and 4 ° c . aliquots were removed from each bag initially and after 1 , 3 , 5 , and 7 days and stored in 2 - ml sterile vials at - 70 ° c . grossly precipitated solutions were assayed after 31 days of storage . duplicate hplc determinations were performed on the aliquots from each test solution . physical compatibility was evaluated by visual examination and turbidimetric quantification . ten - ml samples of each paclitaxel test solution was transferred into colorless 15 - ml borosilicate glass screw - cap culture tubes with polypropylene caps . the tubes and caps were triple - washed in high - performance liquid chromatography - grade water and rinsed exteriorly with ethanol . to minimize the effects of scratches and imperfections in the glass , a thin layer of silicone oil was applied to the exterior of the culture tubes . visual examination of the samples was performed with the unaided eye in normal laboratory fluorescent light . samples with no obvious visual incompatibility were further examined using a tyndall beam ( high - intensity monodirectional light source )( dolan - jenner , woburn , mass .). the test tubes were illuminated from below and viewed at a 90 ° angle against a dark background to enhance the visibility of small particles . turbidimetric assessments of the normally hazy paclitaxel solutions were made using a color - correcting turbidimeter ( hatch , loveland , colo .). the turbidimeter was calibrated in the manner described previously ( trissel et al ., 1992 ). triplicate determinations were made for each sample ; the turbidimeter was allowed to return to zero between determinations . incompatibility has been defined as an increase in turbidity of 0 . 5 nephelometric turbidity unit ( ntu ) or more ( trissel et al ., 1993 ). for drug solutions that are normally hazy , such as paclitaxel , a decrease in expected haze may also be evidence of incompatibility ( trissel et al ., 1993 ). visual inspections and turbidimetric assessments were performed initially and after 1 , 3 , 5 , 7 , 14 , and 31 days of storage at each temperature protected from light . when viewed using the tyndall beam , all samples were initially free of particulate matter but had paclitaxel &# 39 ; s normal haze . turbidity quantification did not result in any change during the study except for samples with noticeable precipitation . tables v and vi cite the appearance of visually observable precipitation in the samples . large amounts of white flocculent precipitate appeared after 31 days of storage in many of the samples and after 14 days in a few samples . precipitation that could be easily seen in the infusion bags with the unaided eye is noted in tables v and vi . however , crystalline and needle - like precipitation , only visible using the tyndall beam , began much earlier . two samples had small amounts of crystalline precipitate within five days of storage . most samples had crystalline precipitation within a week . all samples remained compatible in both infusion solutions for at least three days at all three temperatures in these static solutions . it is possible that agitation of the solutions or other factors could reduce the time to precipitate appearance . the chemical stability of paclitaxel 0 . 1 and 1 mg / ml in 5 % dextrose injection and 0 . 9 % sodium chloride injection are reported in tables vii and viii , respectively . paclitaxel remained chemically stable throughout the study as long a it remained dispersed in the infusion solutions . all assays were above 90 % of the initial concentration and most were near 100 %. no decomposition products appeared on the hplc chromatograms . however , losses of around 30 to 50 % occurred in samples with gross precipitation . as indicated by the results , paclitaxel at 0 . 1 and 1 mg / ml in 5 % dextrose injection and 0 . 9 % sodium chloride injection is chemically stable and physically compatible for three days at 4 °, 22 °, and 32 ° c . precipitation may occur after three days and is the primary limitation on solution utility . table v__________________________________________________________________________visual observations of paclitaxel test solution , in 5 % dextroseinjection . concentration temp . storage time ( days )( mg / ml ) ° c . 0 5 7 14 31__________________________________________________________________________0 . 1 4 --. sup . 1 -- -- -- numerous tiny crystals 22 -- -- tiny large amount of large amount of crystals crystals , needles , crystals , needles , and needles white precipitate white precipitate . sup . 2 32 -- -- tiny crystals , needles , large amount of crystals white precipitate crystals , needles , white precipitate1 4 -- tiny tiny crystals , needles , large amount of crystals crystals white precipitate crystals , needles , white precipitate 22 -- -- tiny crystals , needles , large amount of crystals white precipitate crystals , needles , white flocculent precipitate . sup . 2 32 -- -- tiny crystals , needles , large amount of crystals white precipitate crystals , needles , white flocculent precipitate . sup . 2__________________________________________________________________________ all observations were made using high intensity light enhancement unless stated otherwise . the earliest observed precipitation among triplicate test solutions is reported . all samples were particulatefree at days 1 an 3 . . sup . 1 light blue hazy solution free of particulate matter . . sup . 2 visible in the infusion solution bag in normal diffuse room light . table vi__________________________________________________________________________visual observations of paclitaxel test solutions in 0 . 9 % sodium chlorideinjection . concentration temp . storage time ( days )( mg / ml ) ° c . 0 5 7 14 31__________________________________________________________________________0 . 1 4 --. sup . 1 tiny tiny crystals large amount of large amount of crystals crystals crystals 22 -- -- tiny crystals large amount of large amount of crystals crystals , white precipitate 32 -- -- tiny crystals large amount of large amount of crystals , white crystals , white precipitate flocculent precipitate . sup . 21 4 -- -- tiny crystals large amount of large amount of crystals , white crystals , precipitate needles , white flocculent precipitate . sup . 2 22 -- -- tiny crystals crystals , large amount of needles , white crystals , precipitate needles , white flocculent precipitate . sup . 2 32 -- -- tiny crystals tiny crystals large amount of crystals , needles , white flocculent precipitate . sup . 2__________________________________________________________________________ all observations were made using high intensity light enhancement unless stated otherwise . the earliest observed precipitation among triplicate test solutions is reported . all samples were particulatefree at days 1 an 3 . . sup . 1 light blue hazy solution free of particulate matter . . sup . 2 visible in the infusion solution bag in normal diffuse room light . table vii______________________________________percentage of initial concentration remaining of paclitaxel 0 . 1 and1 mg / ml . sup . a in 5 % dextrose injection , usp . actual initialtemperature sample conc . storage time ( days )(° c .) code ( μg / ml ) 1 3 5 7______________________________________paclitaxel 0 . 1 mg / ml 4 1 102 . 1 99 . 6 100 . 1 100 . 0 100 . 0 100 . 8 100 . 6 100 . 6 101 . 7 100 . 3 2 101 . 3 99 . 6 100 . 2 99 . 8 99 . 9 102 . 1 100 . 8 100 . 4 100 . 3 100 . 0 3 101 . 1 100 . 3 100 . 0 99 . 6 100 . 5 101 . 4 101 . 4 101 . 1 101 . 4 101 . 422 4 100 . 1 99 . 8 99 . 3 99 . 1 100 . 1 100 . 8 100 . 4 99 . 1 99 . 8 101 . 1 5 100 . 3 100 . 6 100 . 8 101 . 1 99 . 6 99 . 4 100 . 5 101 . 7 100 . 9 100 . 6 6 100 . 5 99 . 1 99 . 1 99 . 4 99 . 3 102 . 2 99 . 1 100 . 4 99 . 2 99 . 9 7 106 . 6 98 . 9 98 . 9 98 . 7 100 . 4 106 . 8 100 . 9 99 . 3 99 . 2 99 . 7 8 104 . 4 100 . 6 100 . 2 100 . 3 99 . 4 106 . 3 100 . 7 100 . 5 100 . 1 101 . 2 9 106 . 0 98 . 4 99 . 1 99 . 8 99 . 5 105 . 4 99 . 5 100 . 4 99 . 7 100 . 0paclitaxel 1 mg / ml 4 1 95 . 5 98 . 6 98 . 9 99 . 1 99 . 3 96 . 9 99 . 7 99 . 1 99 . 2 99 . 0 2 94 . 2 101 . 4 99 . 9 99 . 0 99 . 9 94 . 4 100 . 4 99 . 9 99 . 0 100 . 0 3 95 . 9 100 . 6 100 . 3 100 . 1 99 . 7 95 . 9 101 . 2 101 . 0 100 . 2 99 . 722 4 96 . 0 99 . 2 100 . 3 99 . 8 99 . 2 96 . 2 99 . 3 100 . 3 99 . 8 98 . 4 5 98 . 3 97 . 8 100 . 1 98 . 1 100 . 1 98 . 6 98 . 4 99 . 4 98 . 2 100 . 3 6 100 . 9 98 . 3 99 . 1 99 . 2 99 . 7 100 . 9 99 . 3 100 . 0 99 . 8 99 . 132 7 101 . 3 98 . 9 99 . 7 100 . 0 100 . 8 101 . 0 99 . 6 98 . 8 99 . 5 100 . 7 8 99 . 7 100 . 4 100 . 0 100 . 1 99 . 4 99 . 4 100 . 2 100 . 4 101 . 2 98 . 6 9 98 . 5 100 . 6 99 . 4 100 . 3 100 . 0 99 . 3 100 . 3 100 . 1 100 . 5 100 . 6______________________________________ . sup . a nominal concentration . table viii______________________________________percentage of initial concentration remaining of paclitaxel 0 . 1 and1 mg / ml . sup . a in 0 . 9 % sodium chloride injection , usp . initialtemperature sample conc . storage time ( days )(° c .) code ( μg / ml ) 1 3 5 7______________________________________paclitaxel 1 101 . 3 99 . 5 100 . 0 99 . 8 98 . 7 101 . 0 99 . 5 99 . 5 99 . 8 99 . 6 4 2 110 . 3 99 . 2 100 . 6 100 . 0 99 . 9 100 . 0 100 . 7 101 . 8 100 . 3 101 . 1 3 100 . 4 99 . 6 100 . 2 99 . 7 100 . 1 100 . 4 99 . 4 98 . 9 98 . 5 100 . 122 4 100 . 8 100 . 2 100 . 3 100 . 6 99 . 9 100 . 0 99 . 8 100 . 7 100 . 6 100 . 6 5 102 . 3 99 . 6 99 . 3 99 . 1 99 . 6 103 . 0 100 . 6 99 . 8 99 . 5 100 . 1 6 103 . 2 100 . 1 100 . 0 98 . 9 99 . 4 102 . 9 100 . 0 100 . 6 99 . 6 99 . 832 7 102 . 0 101 . 0 100 . 9 100 . 1 101 . 5 102 . 1 100 . 4 101 . 3 101 . 7 99 . 5 8 104 . 4 100 . 1 100 . 7 99 . 4 100 . 2 104 . 8 100 . 7 100 . 1 100 . 1 100 . 0 9 102 . 1 99 . 5 99 . 8 99 . 5 98 . 0 101 . 6 100 . 8 98 . 2 98 . 2 99 . 0 4 1 99 . 7 101 . 3 99 ,. 8 99 . 1 98 . 7 100 . 2 101 . 3 99 . 6 97 . 9 98 . 2 2 99 . 5 97 . 5 98 . 8 98 . 4 97 . 1 99 . 5 96 . 7 98 . 7 96 . 4 94 . 7 3 98 . 5 97 . 8 99 . 0 96 . 0 97 . 3 98 . 2 97 . 9 98 . 6 95 . 8 96 . 222 4 95 . 5 97 . 9 99 . 2 101 . 3 100 . 6 94 . 8 100 . 0 98 . 8 98 . 2 98 . 0 5 97 . 1 97 . 5 97 . 1 98 . 7 98 . 7 97 . 0 97 . 8 99 . 0 97 . 4 98 . 8 6 96 . 1 99 . 5 99 . 0 99 . 4 98 . 8 96 . 3 98 . 1 98 . 6 98 . 432 7 97 . 3 99 . 9 100 . 4 99 . 2 99 . 9 97 . 0 100 . 3 101 . 0 99 . 3 100 . 3 8 98 . 2 99 . 7 99 . 8 100 . 1 100 . 1 97 . 5 99 . 3 99 . 4 100 . 2 100 . 4 5 9 98 . 0 100 . 3 100 . 2 100 . 6 100 . 9 97 . 7 99 . 7 100 . 4 101 . 1 100 . 5______________________________________ the paclitaxel extended stability concentrate for infusion would require dilution to a concentration of about 1 mg / ml in 5 % dextrose injection , usp , or 0 . 9 % sodium chloride injection , usp . a suitable intravenous infusion pump would be used to assure uniform and constant delivery over extended periods . all of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure . while the compositions and methods of this invention have been described in terms of preferred embodiments , it will be apparent to those of skill in the art that variations may be applied to the composition , methods and in the steps or in the sequence of steps of the method described herein without departing from the concept , spirit and scope of the invention . more specifically , it will be apparent that certain agents that are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved . all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit , scope and concept of the invention as defined by the appended claims . the following references , to the extent that they provide exemplary procedural or other details supplementary to those set forth herein , are specifically incorporated herein by reference . alkan - onyuksel , h ., ramakrishnan , s ., chai , h - b , and pezzuto , j . m ., pharm . res . vol 11 , pp 206 - 212 ( 1994 ). anon . the united states pharmacopeia 22 and the 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