This material may be protected by Copyright
`
`law Title 17 US Code
`
`EJFP Science
`Vplume 12
`2006
`Isclv 6
`P 129134
`© 2006 The European Journal of Flzspital Pharmacy Science
`Pll rights reserved 17817595 €20
`
`vwwhporg
`
`Longterm physical and chemical stability of a generic paclitaxel
`infusion under simulated storage and clinical use conditions
`
`Asha Kattige PhD
`
`ABSTRACT
`Study objectives The physical and chemical stability of paclitaxel
`
`infusion prepared from a generic concentrate was investigated in
`
`Freeflex polyolefin bags containing 09 sodium chloride or5 glucose under refrigerated storage and in use conditions 25°C to
`facilitate an outpatient chemotherapy dose banding scheme and to avoid wastage when chemotherapy
`is delayed for clinical reasons
`infusions were sampled at predetermined time intervals and analysed for physical stability pH sub visual particu
`Methods Paclitaxel
`loss visual appearance
`and chemical stability assay using a validated stability indicating high performance
`weight
`chromatography method
`infusion was chemically stable with variation in assay values within ± 5 until
`Results Paclitaxel
`prolonged storage at 5°C and 25°C The stability of paclitaxel
`03 mgmL 075 mgmL and 12 mgmL at 5°C in 5 glucose was 2816 and 12 days respectively Physical
`
`lates
`
`liquid
`
`infusion prepared from generic concentrate at three concentrations
`
`the time the infusion precipitated on
`
`instability was identified
`
`as the limiting factor influencing the stability of the infusion
`Conclusion The stability of paclitaxel
`infusion was limited by physical stability and this was dependent on paclitaxel concentration in the
`infusion diluent used and the storage temperature
`
`KEYWORDS
`
`paclitaxel Freeflex stability
`
`infusions compatibility
`
`INTRODUCTION
`
`Paclitaxel
`
`agent was discovered
`a potent chemotherapeutic
`during a largescale screening programme conducted
`by the
`National Cancer Institute in the 1960s and was initially extracted
`and isolated from the bark of Western Yew Taxus brevifolia 1
`has been indicated in the treatment
`Since its discovery paclitaxel
`of a variety of cancers such as advanced ovarian and breast
`lung cancer and AIDS related Kaposis
`cancer non small cell
`sarcoma 24 In 1979 Schiff and coworkers 5 rekindled
`
`interest in the development of paclitaxel by demonstrating its novel
`is due to
`mechanism of action The antitumour activity of paclitaxel
`its ability to promote polymerisation of tubulin which results in the
`formation of stable dysfunctional microtubules and causes
`
`cell
`
`Contact for correspondence Dr Asha Kattige
`Patheon UK Ltd
`
`Kingfisher Drive
`
`Covingham Swindon
`Wiltshire SN3 5BZ UK
`Tel +44 1225 384038
`
`Fax ±441225 826114
`
`akattigeyahoocouk
`
`1
`
`Department of Pharmacy and Pharmacology University
`
`of Bath Bath UK
`
`death due to disruption of the normal tubule dynamics required for
`
`cell division and vital
`
`interphase processes 6
`
`During formulation development
`
`a primary consideration essen
`
`tial for developing a stable intravenous formulation involves select
`
`to the aqueous solubility of paclitaxel
`
`is its
`
`ing a formulation vehicle in which the drug has adequate solubility
`The major impediment
`extreme lipophilicity 79 which presents difficulties
`in developing
`this problem co sol
`stable parenteral formulations To circumvent
`vents are frequently used in the formulation 10 and commercial
`injection is therefore formulated in a 5050
`ly available paclitaxel
`solvent mixture of Cremophor EL and dehydrated ethanol 11
`However Cremophor EL causes severe hypersensitivity reactions
`in patients and premedication with steroids antihistamines and H2
`receptor antagonists is required 1215 Furthermore this formula
`tion vehicle is incompatible with some plastics and is known to
`each diethylhexylphthalate plasticizers from polyvinyl chloride
`PVC infusion bags and administration sets 1618 It
`recommended that paclitaxel
`infusion be prepared and stored in
`
`is therefore
`
`glass polypropylene or polyolefin containers
`
`In clinical practice paclitaxel
`
`is administered after diluting the drug
`
`concentrate for injection with 09 sodium chloride or 5 dex
`a final concentration of 0312 mgmL 1920
`For an infusion to be safe and therapeutically effective adequate
`
`trose to achieve
`
`Received 26 December 2005 Revised manuscript
`2006 Accepted2 December 2006
`
`received 27 November
`
`use conditions is
`and chemical stability under clinical
`physical
`required to facilitate accurate and reproducible dosing of the drug
`
`European Association of Hospital Pharmacists
`
`H PSelorbee
`
`Volume 12 20066 wwwejhporg 129
`
`Abraxis EX2041
`Actavis LLC v Abraxis Bioscience LLC
`1PR201701101 1PR201701103 1PR201701104
`
`

`

`Fhysicocherrical
`Asha Kattige
`
`stability
`
`of
`
`itad under simulated
`
`storage and dinical
`
`use conditions
`
`The Emopean Joumal of Ibspital Pharmacy Science
`
`However
`infusion after dilution is adequate only for shortterm storage
`
`stability of commercially available paclitaxel
`
`physical
`
`ical
`
`for
`
`infusion exhibited phys
`Published reports indicated that paclitaxel
`instability due to precipitate formation on storage 21 and the
`extent of precipitation was greater for infusions containing more
`than 06 mgmL paclitaxel 22 Moreover
`longterm stability is
`required for the development of dose banding strategies 23 and
`the avoidance of wastage on occasions when treatment
`delayed after the infusion has been prepared
`
`is
`
`In this study a generic paclitaxel
`
`injection Mayne Pharma which
`was pH balanced using anhydrous citric acid to a pH range of 5
`7 to improve stability of the formulation 24 was investigated The
`main objective of this work was to determine the physical
`and
`at concentrations 03
`mgmL 075 mgmL and 12 mgmL in 09 sodium chloride or
`5 glucose under storage at 5°C and 25°C in polyolefin infusion
`
`chemical
`
`stability
`
`of paclitaxel
`
`infusion
`
`bags In addition a limited number of infusions prepared using the
`innovator product Taxol were included for comparison
`
`MATERIALS AND METHODS
`
`Paclitaxel 6 mgmL batch numbers B N036850 P036869
`P026862 was supplied by Mayne Pharma PL Freeflex infusion
`bags containing 250 mL 09 sodium chloride batch number
`SL 7201 08 S1720606 and 5 glucose batch number SD
`
`7206 01 were purchased from Fresenius Kabi
`Ltd Taxol
`6 mgmL injection batch number 5B00028 was obtained
`from BristolMyers Squibb Ltd All other chemicals and reagents
`used were either analytical
`grade or high performance
`chromatography H PLC grade as appropriate
`
`liquid
`
`Preparation of drug infusion
`
`Figure 1 H PLC chromatogram of paclitaxel 60 tgmL
`
`Paclitaxel
`
`infusion was prepared under EU class A conditions
`following GMP procedures
`by aseptic addition of paclitaxel
`to the infusion bag containing 09 sodium
`6 mgmL concentrate
`chloride or5 glucose to achieve the required nominal concentra
`tion of 01 mgmL 03 mgmL 075 mgmL and 12 mgmL These
`concentrations were seeded to represent paclitaxel doses normally
`used in clinical practice After adding the drug concentrate the infu
`
`sion bag was gently agitated to promote adequate mixing Triplicate
`
`combination were
`of each
`concentrationdiluent
`bags
`infusion
`placed in Hue polythene overwraps to protect from light and incu
`refrigerator 5°C or an incubator
`bated
`in a pharmaceutical
`25°C to simulate storage and clinical use conditions Immediately
`after preparation t = 0 and at appropriate time intervals see results
`section samples were withdrawn equilibrated to room temperature
`
`and analysed for physical stability visible and sub visual particulates
`pH
`
`weight loss and chemical stability assay
`
`Determination of chemical stability
`
`Paclitaxel was analysed using a validated
`stability indicating
`reverse phase HPLC method The HPLC system consisted
`of a quaternary gradient pump Jasco PU2089 plus an in
`line degasser autosampler Jasco AS 2057 plus photodi
`ode array detector Jasco MD 2010 plus
`
`HPLC METHOD AND VALIDATION
`HPLC parameters
`Mobile phase composition 50 of 20mM ammonium acetate
`pH 5 40 Acetonitrile and 10 Methanol
`Column C8 Phenomenex 5 im 250 x 46 mm
`Flow rate 15 mLmin
`Injection volume 20 IL
`Detection 227 nm 002 AUFS
`
`008
`
`mAU
`
`paclitaxol standard 1476 DATA 22700 nm
`
`0075
`00
`008
`00
`005
`00
`004 c
`
`0 0
`0035
`0U
`00275
`00c
`001
`001
`000
`
`001
`
`1
`
`10
`
`1
`
`1
`
`12
`
`13
`
`RT min
`15
`
`14
`
`130 EJHP Seiete
`
`Volume12
`
`20066 wwwejhporg
`
`European Association
`
`of Hospital Pharmacists
`
`

`

`Calibration plot
`A typical chromatogram obtained by injecting a solution of pacli
`taxel 60 tgmL is shown in Figure 1 A sixpoint calibration plot
`of paclitaxel over the range 15 to 90 ig mL was constructed with
`triplicate injections at each concentration The data was subjected
`to linear least square regression analysis and the plot was found to
`be linear over the range tested with a regression coefficient of
`09997 Inter day and intra day precision was 16 and 14
`
`respectively
`
`Stability indicating ability ofLCassay
`A study was performed to determine whether paclitaxel could be
`and confirm that
`the
`resolved from any degradation products
`assay was stability indicating In addition spectral purity of paclitax
`el peak was assessed using Chrompass software Table 1 reveals
`
`control
`
`by alkaline acidic or
`the effect of forcibly degrading paclitaxel
`oxidative conditions or by heating at 55°C Paclitaxel 60 vgmL
`stored in the refrigerator was used as a control sample for com
`parison purposes The peak retention time of paclitaxel
`sample was approximately 114 minutes with a drug concentration
`of 6165 vgmL On exposure to oxidative degradation elevated
`temperature of 55°C or acid hydrolysis paclitaxel
`retention time
`was approximately 114 minutes in each case with a drug concen
`tration of 5789 vgmL 6109 vgmL and 3053 vgmL respec
`a cloudy gel was observed in paclitaxel solution
`tively However
`subjected to alkaline hydrolysis The dispersion was filtered using a
`02 im filter and the filtrate analysed for drug content by H PLC
`Results indicated absence of drug peak implying that the paclitax
`
`el had completely precipitated under alkaline conditions and had
`been removed by the filtration process Under other stress condi
`tions there was a distinct separation between the drug and degra
`dation product peak In all cases the spectral purity of the paclitax
`el peak by photodiodearray detector was greater than 98
`
`Determination of physical stability
`Sub visualparticulates
`Sub visual particle counts of infusions at 10 vm and 25 vm par
`ticulate diameters were conducted at predetermined time inter
`
`Table 1 Effect of oxidative
`
`acid
`
`degradation alkaline
`hydrolysis
`55°C
`
`temperature
`
`on paclitaxel
`
`hydrolysis and elevated
`LC assay and on
`
`peak purity of the
`
`Treatment
`
`Control
`
`Oxidative des radat ion
`
`Alkaline h drol
`
`sis
`
`Exeosed to 55°C
`
`Acid hydrolysis
`
`Retention time
`minutes
`
`1137
`
`1136
`
`1135
`
`1136
`
`paclitaxel
`
`peak
`
`Quantity
`gmL
`6165
`
`5789
`
`Peak purity0
`
`10053
`9855
`
`6109
`2906
`
`9867
`9809
`
`Fhysicocherrical
`
`stability
`
`of
`
`paclitad
`
`under simulated
`
`storage and dinical
`
`use conditicns
`Psha Kattige
`
`The European Journal of Ibspital Fhamlacy Science
`
`vak using a calibrated particle counter Model LS 200 Particle
`Measuring Systems A fixed volume of sample was withdrawn
`using a computer controlled syringe sampler and passed through
`Liquilaz sensor at a controlled flow rate and any particles present
`
`in solution counted
`
`Visualappearance
`This was assessed against both Hack
`and white backgrounds
`under standard laboratory lighting and the infusions were exam
`
`ined for any change in colour clarity or for the presence of partic
`ulate matter Any form of turbidity visible particles or fibres was
`classed as precipitation
`
`pH measurement
`A combinational glass electrode and a Hanna pH302 meter
`Hanna Instruments Scientific Laboratory Supplies Ltd was initial
`ly calibrated using standard reference solutions of pH 4 and pH 7
`and was used to measure the pH of infusions at specific time inter
`vak for the duration of the study Addition of paclitaxel
`formulation
`excipients ethanol and Cremophor EL to the reference solutions
`did not influence the accuracy of pH measured
`
`Weight change
`The infusion
`bags were weighed before and after sampling on a
`calibrated analytical balance AND AD 1131 and the
`increase or decrease on incubation calculated
`
`weight
`
`el
`
`RESULTS
`Stability of paclitaxel 03 mgmL 075 mgmL and 12 mgmL
`infusion in Freeflex infusion bags
`It was envisaged that
`the stability results obtained would enable an
`appropriate shelf life to be assigned for various pre filled paclitax
`infusions used in dose banding schemes The chemical stability
`infusion at concentrations 03 mgmL
`data for generic paclitaxel
`075 mgmL and 12 mgmL in 09 sodium chloride or5 glu
`cose and stored at 5°C or 25°C in Freeflex infusion bags for vary
`ing periods of time are shown in Table 2 The infusion was consid
`ered to be chemically stable if variations in drug concentration did
`not exceed ± 5 of the initial concentration The initial concentra
`tion of paclitaxel at time zero was assigned 100 and subsequent
`assay values were expressed as a percentage of the initial concen
`tration In each case data reported are the means and relative
`standard devotion for 3 infusions
`
`Paclitaxel
`
`infusion was examined visually at predetermined time
`
`intervals
`
`for the presence of particulates or turbidity indicating
`
`paclitaxel precipitation and any change in the colour of the infu
`sion Results indicated that the infusion exhibited precipitation on
`prolonged storage at 5°C and 25°C and this was the stability lim
`iting factor of the infusion Visual observation indicated that
`
`the
`
`European Association of Hospital Pharmacists
`
`EJFIPSow Volume 12 20066 wwwejhporg
`
`131
`
`

`

`Fhysicocherrical
`Asha Kattige
`
`stability
`
`of
`
`itad under simulated
`
`storage and dinical
`
`use conditions
`
`The Emopean Joumal of Ibspital Pharmacy Science
`
`extent of precipitation increased on storage and resulted in turbid
`ity for paclitaxel 03 mgmL infusion and the formation of white
`aggregated precipitate for the more concentrated paclitaxel 12
`mgmL infusion
`
`the applied limits ± 5 In addition there was no evidence of any
`
`degradation products in the LC chromatograms The maximum
`shelf life was therefore assigned to the maximum sampling time at
`
`which the infusions in triplicate remained visibly clear with no evi
`dence of precipitation
`
`The data in Table 2 indicate that
`tendency to precipitation was
`related to both concentration of the infusion and to storage tem
`perature with reduced physical stability at
`
`the higher paclitaxel
`
`Data for physical stability other than visual appearance are sum
`marised in Table 3 This table shows that up to the sample times
`concentrations and at room temperature storage Prior to precip
`corresponding to the assigned shelf life there were no significant
`itation the LC assay values obtained for all
`changes in pH or weight for any of the infusions studied Most of
`infusions of paclitaxel Mayne at concentrations of 03 mgmL 075 mgmL and 12 mgmL in 09
`Table 2 Chemical
`chloride or 5
`glucose at 5°C or 25°C
`sodium
`
`infusions were within
`
`stability for
`
`Mean Assay RSD n = 3as
`initial concentration remaining for each infusion concentration
`storage temperature combination
`075 mgmL
`5°C
`
`25°C
`
`12 mgmL
`5°C
`
`25°C
`
`1009906
`994808
`
`992306
`974205
`
`1022907
`991609
`
`1006211
`998711
`
`9834088
`
`1012812
`1003906
`
`1004815
`1001513
`
`9913 01
`9Z7 02
`
`995 06
`982207
`
`Diluent
`
`Storage
`
`time d
`
`G5
`NS
`G5
`NS
`G5
`NS
`G5
`NS
`G5
`NS
`G5
`NS
`G5
`NS
`G5
`NS
`G5
`NS
`G5
`NS
`G5
`NS
`G5
`NS
`G5
`NS
`G5
`NS
`G5
`NS
`
`2
`
`2
`
`3
`
`3
`
`4
`
`4
`
`6
`
`6
`
`8
`
`8
`
`9
`
`9
`
`10
`
`10
`
`12
`
`12
`
`14
`
`14
`
`16
`
`16
`
`18
`
`18
`
`20
`
`20
`
`23
`
`23
`
`25
`
`25
`
`28
`
`28
`
`Visible precipitation in infusion
`
`03 mgmL
`
`5°C
`
`25°C
`997509
`982109
`
`1017308
`992806
`
`1006405
`999216
`
`1006505
`989807
`
`991703
`978904
`1011302
`988402
`989709
`
`1006420
`9855077
`
`1005703
`1002904
`
`1014303
`1008706
`
`1015808
`1007804
`
`1014919
`1010403
`1027104
`1023307
`1030310
`1028604
`996103
`993408
`
`989007
`969906
`1006608
`977419
`982808
`96910
`1018305
`998108
`996606
`986207
`1001312
`994113
`1007502
`993705
`1011606
`992806
`G5 = 5 glucose NS = 09 sodium chloride
`
`132 EJIIPScieme
`
`Volume 12 20066 wwwejhporg
`
`European Association
`
`of Hospital Pharmacists
`
`

`

`the sub visual particulate counts for particle sizes >10 vm diame
`ter obtained at
`the time corresponding
`to the assigned shelf life
`would be considered high for an intravenous infusion However
`would not be appropriate to apply pharmacopoeia l
`infusion for which the marketing authorisation requires administra
`tion via a 022 trri
`
`it
`
`limits to an
`
`in line filter
`
`DISCUSSION
`
`The shelf life of paclitaxel
`
`taxel
`
`infusions was limited by physical stability
`in terms of visible precipitation of drug from the infusion Chemical
`stability was maintained until and probably beyond the time at
`which precipitation was observed Particulate
`formation in pacli
`infusion could be due to drug degradation seeding by par
`ticulate matter in the diluent components being leached from the
`infusion bag into the solution forming an insoluble precipitate or
`more probably from diluting the paclitaxel
`concentrate with the
`infusion fluid to produce an unstable formulation Additional stud
`the precipitate was in each
`
`ies not reported here confirmed that
`
`case paclitaxel
`
`Sub visual particulate monitoring data are not fully reported here
`
`but typically an increase in the sub visual particulate count at 10
`vm was observed in the sample taken prior to the day on which
`visible precipitation was first evident This technique may be a
`
`Fhysicocherrical
`
`stability
`
`of
`
`paclitad
`
`under simulated
`
`storage and dinical
`
`use conditions
`Asha Kattige
`
`The European Journal of Ibspital Riannacy Science
`
`useful predictor of physical stability
`
`if only at a qualitative level
`
`the stability of paclitaxel
`
`01
`
`injection was maintained for at
`
`bility
`
`Previously Xu et al 25 reported that
`mgmL and 1 mgmL in 5 dextrose or 09 sodium chloride
`least 3 days at 4 22 or 32°C
`However
`further storage at these temperatures resulted in precip
`itation which as with this study was the primary factor limiting sta
`In this study the results presented in Tables 2 and 3 indicate
`infusion at concentrations 03 mgmL 075 mgmL
`that paclitaxel
`and 12 mgmL stored at 5°C were physically and chemically
`stable for up to 2820 and 12 days in 5 glucose and 2820 and
`12 days in 09 sodium chloride respectively Stability of the infu
`sions decreased at 25°C and at concentrations 03 mgmL 075
`mgmL and 12 mgmL infusions were stable for 8 4 and 4 days
`in 5 glucose and 6 6 and 4 days in 09 sodium chloride
`
`respectively There was a negligible change in pH and the variation
`over 28 day study period was less than 06 pH units in all cases
`Moisture diffusion across the infusion bag was minimal with less
`than 1 weight
`loss in all containers Moisture loss from the bag
`would not therefore exert any significant effect on the paclitaxel
`
`assay value following either
`25°C storage
`
`refrigerated or room temperature
`
`The findings of this study confirm that
`
`the shelf life of paclitaxel
`
`infu
`
`Table 3 Summary of physical
`chloride under storage
`
`paclitaxel Mayne
`stability data for
`at 5°C or 25°C
`
`infusion of various
`
`concentrations diluted
`
`in 5 glucose or 09 sodium
`
`Diluent
`
`Storage
`Temp
`°C
`
`5
`
`5
`
`Paclitaxel
`Conc
`mgmL
`
`Assigned
`Shelf life
`days
`
`28
`
`28
`
`8
`
`Sub visual
`
`Particulates
`countmLb
`25 Itm
`10 Itm
`044
`
`120
`
`75
`
`49
`
`pH
`
`range`
`
`Weight loss
`my
`
`<06
`
`<02
`
`<06
`
`5 glucose
`09 sodium chloride
`5 glucose
`09 sodium chloride
`5 glucose
`09 sodium chloride
`5 glucose
`09 sodium chloride
`5 glucose
`09 sodium chloride
`5 glucose
`09 sodium chloride
`
`25
`
`25
`
`5
`
`5
`
`25
`
`25
`
`5
`
`5
`
`25
`
`25
`
`03
`03
`03
`03
`
`075
`
`075
`
`075
`
`075
`
`12
`
`12
`
`12
`
`12
`
`022
`050
`022
`
`0
`
`111
`
`0
`
`011
`033
`044
`
`022
`
`033
`
`107
`
`99
`
`194
`50
`
`52
`
`78
`
`118
`
`83
`
`76
`
`4135
`4034
`4138
`3839
`3936
`3935
`3937
`3935
`4037
`3835
`4039
`3835
`
`6
`
`20
`
`20
`
`4
`
`6
`
`12
`
`12
`
`4
`
`4
`
`<02
`
`<01
`
`<02
`
`<02
`
`<01
`
`<02
`
`<05
`
`<01
`
`<03
`
`Reported data are means for 3 infusions n = 3
`Assigned to the longest storage time for which infusions were within assay specification and did not show precipitation see Table 2
`above
`b Values obtained at
`the sample time corresponding
`to assigned shelflife as defined in footnote
`Range of values obtained over period from time = 0 to the assigned shelflife defined in footnote
`
`above
`
`European Association of Hospital Pharmacists
`
`111 PSew Volume 12 20066 wwwejhporg 133
`
`

`

`Fhysicocherrical
`Asha Kattige
`
`stability
`
`of
`
`itad under simulated
`
`storage and dinical
`
`use conditions
`
`The Emopean Joumal of Ibspital Pharmacy Science
`
`sion was dependant on infusion concentration with the lowest
`concentration 03 mgmL infusion exhibiting stability for greater
`time periods compared to higher concentration 12 mgmL infu
`infusion stored at 5°C
`sion Stability was greater
`for paclitaxel
`compared to 25°C
`
`Infusions prepared from the innovator paclitaxel product Taxol at
`a concentration of 12 mgmL were included for comparison The
`results are not reported here but this study was not able to sub
`stantiate the stability claimed in the Taxol data sheet 26 of 7 days
`at 5°C and 25°C when diluted in 5 glucose and 14 days at
`5°C and 25°C when diluted in 09 sodium chloride infusion
`Although the data sheet does not relate the claimed stability to any
`the concentration
`range of
`
`particular paclitaxel
`
`concentration
`
`diluted paclitaxel
`
`is
`
`infusions specified elsewhere in the data sheet
`0312 mgmL and clearly care must be exercised when applying
`manufacturers data to the higher end of the concentration range
`should be
`Although recommendations
`that paclitaxel
`administered via a 022 trn in line filter provide some protection
`this should not be seen as a
`to the patient from physical
`
`infusion
`
`instability
`
`reason to extend the shelf life to unreasonable limits Furthermore
`precipitation of paclitaxel during infusion could Hock the filter or
`result in a reduced dose of the drug reaching the patient
`
`generic product stored at 5°C More importantly in all cases
`physical stablity of the infusion was identified as the limiting factor
`
`influencing the stability of the infusion Maintaining physical stability
`
`of the infusion on prolonged storage under pharmaceutical and
`
`remains a significant challenge and further
`clinical conditions still
`comprehensive investigation is required to understand the under
`in the infusion The practice of
`lying causes of physical
`
`instability
`
`room temperature storage of aseptically prepared infusions which
`appears to be gaining popularity in some hospitals cannot be sup
`ported for paclitaxel
`
`Dose banding is gaining increasing popularity and is widely used
`in the UK as it
`is cost effective enables efficient use of nursing time
`
`and improves the quality of patient services without compromising
`the quality of care 23 However adequate stability data to permit
`batch manufacturing of cytotoxic infusion is
`required before a
`decision to dose band can be made 23 Given the increased
`popularity of the 90 mgm2 weekly regimen in the UK the 03
`mgmL paclitaxel
`concentration would be appropriate for most
`and the 28 day shelf life under
`refrigerated storage is
`patients
`adequate to facilitate an outpatient chemotherapy dose banding
`scheme
`
`In conclusion
`
`the maximum stability period of 28 days was
`infusion 03 mgmL prepared from the
`observed for paclitaxel
`
`The author was supported
`by an unrestricted post doctoral
`fellowship from Mayne Pharma plc
`
`ACKNOWLEDGEMENT
`
`EFERENCES
`1 Wani M Taylore HL Wall ME Coggon R McPhail AT The isolation and structure
`J Am
`of taxol a novel antileukemic and antitumor agent
`Chem Soc1971 93 232537
`LA Donehower RC TaxolA novel
`2 Rowinsky EK Cazenave
`lnst 1990 82124759
`antimicrotubule
`J Natl Cancer
`agent
`3 Donehower RC Rowinsky EK Grochow LB Longenecke SM Ettinger DS
`with advanced cancer Cancer Treat Rep 1987 71
`Phase I trial of taxol
`in patients
`
`from Taxus brevifolia
`
`investigational
`
`11717
`
`assembly in vitro by taxol
`
`4 Huizing MT Misser VH Pieters RC ten Bokkel Huinink WW Veenhof CH
`Vermorken JB Pinedo HM Beijnen JH Taxanes a new class of antitumor agents
`Invest 1995 13 381404
`Cancer
`5 Schiff P Fant J Horwitz SB Promotion of microtubule
`Nature 1979 277 6657
`6 Singla A Garg A Aggarwal D Paclitaxel and its formulations Int J Pharm 2002
`23517992
`Z Lee J Lee SC Acharya G Chang C Park K Hydrotropic
`solubilization of pacli
`taxel Analysis of chemical structures for hydrotropic property Pharm Res 2003
`20102230
`8 Mathew AE Mejillano MR Nath JP Nimes RH Stella VI Synthesis and evalua
`tion of some water insoluble prodrugs and derivatives of Taxol with antitumor
`activity J Med Chem 1992 35145
`9 Panchagnula R Pharmaceutical aspects of paclitaxel
`Int J Pharm 1998172 115
`10 Jonkmande Vries JD Flora KP Bult A Pharmaceutical development
`of investi
`usea review Drug Dev Ind Pharm
`gational anticancer agents for parenteral
`1996 2247594
`11 BristolMyers Squibb Oncology BMS Taxol Paclitaxel Package Insert Mead
`Johnson Oncology BristolMyers Squibb Company Princeton NJ 2003
`12 Rowinsky E Donehower RC Taxol twenty years later
`the story unfolds
`lnst 1991 83 177881
`Cancer
`13 Weiss RB Donehower RC Wiernik PH hnuma T GraIla RI Trump DL Baker
`JR Van Echo DA Von Hoff DD and Leyland Jones B Hypersensitivity reactions
`
`J Natl
`
`tein in vitro conditions
`
`J Clin Onco11990 812638
`from Taxol
`14 Dorr RT Pharmacology
`and toxicology of Cremophor EL diluent Ann
`Pharmacother 1994 28 5114
`15 Mazzo DJ NguyenHuu I I Pagniez S and Denis P Compatibility of docetaxel
`and paclitaxel
`in intravenous solutions with polyvinyl chloride infusion materials
`Am J HealthSyst Pharm 1997 54 5669
`16 Allwood M Martin H The extraction
`of diethylhexylphthalate DEHP from
`of intravenous infusion containers and adminis
`polyvinyl chloride components
`injection Int J Pharm 1996127 6571
`tration sets by paclitaxel
`17 Pfeifer R Hale KN Precipitation of paclitaxel during infusion pump Am J Hosp
`Pharm 1993 50 251821
`18 Song D Hsu L F Au LS Binding of taxol to plastic and glass containers and pro
`J Pharm Sci 1996 85 2931
`19 Waugh W Trissel LA Stella VI Stability compatibility
`and plasticizer extraction of
`taxol NSC 125973 injection diluted in infusion solutions and stored in various
`containers Am J Hosp Pharm 1991 4815204
`20 Krammer 1 Heuser A Paclitaxel pharmaceutical
`Eur Hosp Pharm 19951 3741
`21 Straubinger RM Biopharmaceutics
`formulation activity and
`In Suffness MEd Taxol Science and Applications CRC
`pharmacokinetics
`Press New York 1995 pp 23754
`22 Adams JD Flora KP Goldspiel BR Taxol
`a history of pharmaceutical develop
`lnst 1993151417
`J Natl Cancer
`ment and current pharmaceutical
`concerns
`23 Plumridge RI and Sewell CI Dose banding of
`cytotoxic drugs A new concept
`in cancer chemotherapy Am J HealthSyst Pharm 2001 5817604
`24 Mayne Pharma European Patent 1993 EP 1 500 393 Al
`in 5 dextrose injection or
`25 Xu 0 Trissel LA Martinez IF Stability of paclitaxel
`09 sodium chloride injection at 4 22 or 32 DGC Am J Hosp Pharm 1994
`51305860
`26 Anon SPC for Taxol 6mgm1 Concentrate wwwemcmedicinesorguk
`Accessed 15 December 2005
`
`and pharmacological
`
`issues
`
`of paclitaxelTaxol
`
`134 UHF ScierAE
`
`Volume12 20066 wwwejhporg
`
`European Association
`
`of Hospital Pharmacists
`
`