医薬品相互作用研究

Vol.45, No. 3（2021）

13（129）14（14）

医薬品相互作用研究ノート

45（3）13-17（2021）

Suitability…of…5%…glucose…solution…and…Solita®-T…No.…3…for…infusion…of…
tedizolid…phosphate
Satoshi…YOSHIKAWA1,2,…Shinichi…YOSHIKAWA3,…Akira…SATO2,3,…Gen…KUSANO1,…
Tsukasa…MATSUMOTO2,3
Department…of…Pharmacy,…Iwaki…City…Medical…Center
Graduate…School…of…Life…Science…and…Technology,…Iryo…Sosei…University
3…
Faculty…of…Pharmacy,…Iryo…Sosei…University
1…

2…

（Received…June…1,…2021;…Revised…June…26,…2021;…Accepted…July…8,…2021）

Abstract
Tedizolid… phosphate… is… a… next-generation… oxazolidinone… drug… with… activity… against… methicillin-resistant… Staphylococcus
aureus… and… vancomycin-resistant… Enterococcus… spp.… The… injectable… form… of… tedizolid… is… lyophilized,… and… while… the… choice…
of… diluent… for… infusion,… which… depends… on… drug… properties… and… the… patient’s… condition,… is… crucial… for… drug… stability…
and… patient… safety,… there… are… no… reports… on… tedizolid… stability… in… infusion… solutions… other… than… physiological… saline,…
which… is… recommended… by… the… manufacturer.… Therefore,… we… investigated… the… stability… of… tedizolid… in… various… infusion…
solutions,… including… Solita®-T… No.… 3… and… 5%… and… 50%… glucose… solutions… in… comparison… with… physiological… saline,… using…
high-performance… liquid… chromatography.… Tedizolid… was… not… insolubilized… in… any… of… the… solutions… tested.… We… observed…
no… significant… changes… in… tedizolid… concentration… up… to… 48… h… after… dilution… with… physiological… saline,… 5%… glucose,… and…
Solita®-T…No.…3…infusion…solution;…however,…a…significant…decrease…in…tedizolid…concentration…was…observed…after…dilution…in…
50%…glucose,…with…a…residual…concentration…at…48…h…after…dilution…of…<20%.…Further…analysis…revealed…that…this…was…mainly…
due…to…the…low…pH…of…the…50%…glucose…solution.…Based…on…our…findings,…5%…glucose…solution…and…Solita®-T…No.…3…infusion…
solution…are…suitable…for…tedizolid…infusion…in…clinical…practice.
Keyword:…Tedizolid…phosphate;…methicillin-resistant…Staphylococcus aureus;…vancomycin-resistant…Enterococcus…spp.

1. Introduction

tissue… infection… samples… are… increasing,… and… there… is…

resistant…gram-positive…pathogens,…such… as… methicillin-increase… owing… to… its… strong… transmission… ability 4）.…

Nosocomial… infections… caused… by… antimicrobial-

resistant… Staphylococcus aureus（… M R S A ）… a n d…
vancomycin-resistant… Enterococcus… spp.,… have… become…

concern…that…the…number…of…MRSA…infections…will…further…

Currently… clinically… used… anti-MRSA… drugs… include…
glycopeptide,… aminoglycoside,… cyclic… lipodepsipeptide,…

a… worldwide… threat.… In… Europe… and… the… United… States,…

and…oxazolidinone…antibacterial…drugs.

（HA-）MRSA… and… community-acquired…（ CA-）MRSA…

subunit… and… thus… inhibit… the… formation… of… the… 70S…

nosocomial… infections… caused… by… healthcare-associated…

are… on… the… rise,… and… the… number… of… related… deaths… is…
increasing

1,… 2）.… In… Japan,… nosocomial… and… community-

Oxazolidinone…antibacterials…bind…to…the…50S…ribosomal…

initiation… complex,… thereby… inhibiting… bacterial… protein…
synthesis… and… growth.… Recently,… tedizolid… phosphate…

acquired… infections… caused… by… various… multidrug-…was…approved…
（formerly…torezolid,…trade…name…Sivextro®）

problem,… and… MRSA… reportedly… accounts… for… many… of…

class… after… linezolid… to… be… available… in… clinical… practice.…

resistant… bacteria… have… become… a… significant… clinical…

the…new…infections…caused…by…drug-resistant…bacteria3）.…
The… isolation… rates… of… HA-MRSA… from… pneumonia… and…
bacteremia…samples…and…of…CA-MRSA…from…skin…and…soft…

for… clinical… use,… becoming… the… second… agent… of… this…
Tedizolid…can…be…administered…via…the…oral…and…parenteral…
routes,…e.g.,…via…intravenous…drip…infusion,…and…tedizolid…

administration…can…be…switched…from…the…intravenous…to…

…16…Kusehara,…Uchigoumimayamachi,…Iwaki,…Fukushima…973-8555,…Japan…5-5-1…Iino,…Chuo-dai,…Iwaki,…Fukushima…970-8551,…Japan
Satoshi…YOSHIKAWA E-mail：…df2003@isu.ac.jp TEL：0246-26-3151 Fax：0246-26-9863
1

2,3

15（15）14（130）

医薬品相互作用研究

Vol.45, No. 3（2021）

oral… route… without… dose… modification,… even… in… patients…

purchased… from… Nacalai… Tesque…（ Kyoto,… Japan）.…

function5）.

from… MSD… Corp.…（Sivextro®,… Tokyo,… Japan）.… Dimethyl…

with… high… drug… bioavailability… and… impaired… renal…
The… choice… of… diluent… for… infusion… may… be… crucial,…

depending… on… the… patient’s… condition.… The… injectable…

Tedizolid… phosphate… for… clinical… use… was… purchased…

sulfoxide…（ DMSO）…and… acetonitrile… were… obtained…

from…Wako…Pure…Chemicals…Co.…（Osaka,…Japan）.…Thin-

form…of…tedizolid…is…lyophilized,… and…the…package…insert…

layer… chromatography…（ TLC）…plates… precoated… with…

chloride… solution）…as… a… diluent5）.… It… has… been… reported…

from… Merck…（ Darmstadt,… Germany）.… Physiological…

recommends…using…physiological…saline…（isotonic…sodium…
that… tedizolid… is… incompatible… with… any… solutions… that…

contain… divalent… cations,… such… as… calcium… chloride,…

silica…gel…（60F-254,…20…cm × 20…cm）…were…purchased…
saline… for… injection… and… 5%… and… 50%… glucose… solutions…

were… purchased… from… Otsuka… Pharmaceutical… Factory…

calcium… gluconate,… and… magnesium… sulfate,… including…

（Tokyo,…Japan）.…Solita®-T…No.…3…（a…glucose,…lactate,…and…

However,…there…are…no…reports…on…whether…other…infusion…

from…Yoshindo…Inc.…（Toyama,…Japan）.…The…compositions…

drug…diluent,…can…be…used.…In…this…study,…we…investigated…

Table…1.…

Ringer’s… lactate… solution… and… Hartmann’s… solution 6）.…
solutions,…such…as…5%…glucose,…which…is…widely…used…as…a…

the…stability…of…tedizolid…in…physiological…saline,…Solita -T…

electrolyte-containing…infusion…solution）…was…purchased…

of… all… solutions… tested… in… this… study… are… presented… in…

®

No.…3,…5%…and…50%…glucose…solution.
…

2.1. Reagents

2.2. Methods

Tedizolid…diluted…in…physiological…saline,…5%…and…50%…

2. Materials and Methods

glucose…solutions,…and…Solita®-T…No.…3…was…sampled…every…

A… standard… sample… of… tedizolid… phosphate… was…

purchased… from… MedChemExpres…（ Princeton,… NJ,…

0,…1,…12,…24,…and…48…hrs,…respectively,…and…the…changes…
in… concentration… were… examined… by… high-performance…
liquid… chromatography…（HPLC）.… All…experiments… were…

Table 1 Compositions of the solutions tested in this study (g/250 ml)

USA）.… p-Nitroaniline… was… purchased… from… BioVision…

（Milpitas,…CA,…USA）,…and…12…molybdo（IV）phosphoric…
acid… n-hydrate…（ phosphomolybdic… acid,… PMA）…was…

conducted…under…room…temperature…conditions…
（25…±…2°C）…
with…an…irradiance…of…500…lx.

Table 1 Compositions of the solutions tested in this study (g/250 ml)
Table 1 Compositions of the solutions tested in this study（g/250 ml）

Solutionssodiumchloridepoyassiumchloride

L-sodiumlactateglucoseOtsuka nomal saline

0.225

-

-

-

Otsuka glucose injection(5%)

-

-

-

12.5

®

Solita T No.3

0.225

0.3725

0.56

10.75

Otsuka glucose injection(50%)

-

-

-

125

2.2.1. Preparation of the sample solutions

Lichrosorb…RP-18…column…（ODS,…5…µm,…4.0 × 120…mm,…

water… at… 50… mg/ml… according… to… the… manufacturer’s…

conditions…were…set…according…to…previous…reports7,8,9）.…

Tedizolid… phosphate… was… dissolved… in… distilled…

instruction…for…injection…（MSD…Corp.）…and…then…diluted…

with… physiological… saline,… 5%… glucose,… 50%… glucose,… or…

Kanto…Chemical…Co.,…Ltd.,…Tokyo,…Japan）.…The…analytical…

In… brief,… the… mobile… phase… was… a… mixture… of… 19.2… mM…

sodium… acetate… buffer…（pH… 7.4）…and… 15%… acetonitrile,…

Solita -T…No.…3…infusion…solution…at…0.8…mg/ml.

the…flow…rate…was…1.0…ml/min,…and…tedizolid…was…detected…

2.2.2. Quantitative analysis of tedizolid in dilution

samples…were…filtered…through…a…0.2-µm…cellulose…acetate…

®

Tedizolid… was… analyzed… by… HPLC… using… a… Hibar…

by… measuring… UV… absorbance… at… 251… nm.… The… HPLC…

filter…（ AGC… Techno… Glass,… Tokyo,… Japan）.… Diluted…

医薬品相互作用研究

sample…solutions…of… tedizolid…（0.45…ml）…were…collected…

over… time,… mixed… with… 0.5… ml… of… DMSO… containing… 0.5…

Vol.45, No. 3（2021）

15（131）16（16）

the… possibility… of… tedizolid… insolubilization… by… dilution,…

each…dilution…was…subjected…to…high-speed…centrifugation…

mg… p-nitroaniline… as… an… internal… standard,… and… then…

（10,000…×…g,…30…min）.…No…precipitates…were…observed…

50%… glucose… solution… was… analyzed… using… the… absolute…

results…suggest…that…tedizolid…is…not…insolubilized…in…the…

subjected… to… HPLC… analysis.… The… sample… diluted… with…

after… centrifugation… for… any… of… the… solutions.… These…

calibration…curve…method.…

solutions…tested.

2.2.3. TLC analysis of tedizolid

analyzed…using…HPLC.…Fig.…1…shows…the…chromatograms…

The…stability…of…tedizolid…in…the…various…solutions…was…

Tedizolid… phosphate… in… different… diluents… was…

partitioned… between… ethyl… acetate… and… water,… and…
tedizolid… was… obtained… from… the… ethyl… acetate… layer.…

The… sample… was… analyzed… by… TLC… using… ethyl… acetate…

of… the… blank… mobile… phase… and… the… mobile… phase… with…

tedizolid…and…the…internal…standard…added.…In…the…blank…

mobile…phase,…there…was…no…interference…peak…between…

tedizolid… and… the… internal… standard.… The… retention…

as… a… developing… solvent.… PMA… was… used… to… visualize…

time… of… tedizolid… was… 3.8… minutes… and… that… of… the…

heated…on…a…plate…heater…at…150°C…for…3…min.

experimental… conditions,… the… calibration… curve… showed…

the… analyte,… and… the… analyte… complexed… with… PMA… was…

2.2.4. Statistical analysis

Data… are… expressed… as… the… mean… ±… SD…（ n… =… 4）.…

Differences… between… groups… were… analyzed… using…

Dunnett’s…test.…P…<…0.05…was…considered…significant.

internal… standard… was… 9.4… minutes.… Under… the… present…

linearity… in… the… range… of… 0.125… mg/ml… to… 1.0… mg/ml,…
with… a… regression… coefficient… of… 0.9997.… A… regression…

coefficient… of… 0.99… or… higher… is… generally… considered…
to… be… evidence… that… the… data… fit… the… regression… line…
well.… No… significant… changes… in… the… concentration… of…
tedizolid… were… observed… up… to… 48… h… after… dilution… with…

3. Results and Discussion

physiological…saline,…5%…glucose…solution,…and…Solita®-T…

in… distilled… water…（50… mg/ml）…and… then… diluted… to… 0.8…

decrease… in… the… concentration… of… tedizolid… in… the…

Lyophilized… tedizolid… phosphate… was… reconstituted…

mg/ml…with…physiological…saline,…Solita -T…No.…3,…or…5%…
®

or… 50%… glucose… solution.… The… solutions… were… visually…

inspected…for…visible…features…and…turbidity.…The…tedizolid…

No.…3…infusion…solution…（Fig.…2）.…However,…a…significant…
50%… glucose… solution… was… observed,… and… the… residual…

concentration…of…tedizolid…in…this…solution…at…48…h…after…

dilution… was… <20%…（ Fig.… 2）.… The… quantitative… HPLC…

solutions…were…colorless…or…slightly…light-yellowish,…and…

analysis… results… were… supported… by… TLC… findings.… The…

at…room…temperature…（25…±…2°C）…for…24…h.…To…examine…

physiological…saline,…5%…glucose…solution,…and…Solita®-T…

no…change…in…appearance…was…observed…during…storage…

Fig. 1. HPLC
Chromatogram of mobile phase.
TLC…spot…of…tedizolid…did…not…
change…for…up…to…48…h…in…

Fig. 1．HPLC Chromatogram of mobile phase.

Fig. 1.

1: TZD, 2: I.S: p-Nitroanilline 0.1 mg/ml.
HPLC Chromatogram of mobile
phase.

1: TZD, 2: I.S: p-Nitroanilline 0.1 mg/ml.

Fig. 2. Stability of tedizolid in various diluents.

17（17）
16（132）

医薬品相互作用研究

Vol.45, No. 3（2021）

120
100

TZD(%)

80
Physiological saline

60

5％ Glucose solution
Solita®-T No.3 infusion
50％ Glucose solution

40
20
0

0

10

20

30

40

50

Time(hr)Fig. 2．Stability of tedizolid in various diluents. Tedizolid diluted with various

Fig. 2. Stability ofsolutions
tedizolidwas
in various
diluents.
dilutedwith various
sampledsampledfor up Tedizolid
to 48 h andsubjected
to HPLCsolutions
analysis.was
Data
arefor up to 48 h andexpressedsubjected toanalysis.
Data= areas HPLCthe mean± SD（n4）.expressed as the mean ± SD (n = 4).

50%… glucose… solution,… and… Solita ®-T… No.… 3… was… 7.28…

No.…3…infusion…solution…but…had…nearly…disappeared…after…

48…h…in…the…50%…glucose…solution…（Fig.…3）.…These…results…

±…0.09,…7.32… ±…0.06,…2.85… ±…0.04,…and…6.71… ±…0.13,…

and…Solita -T…No.…3…infusion…solution…as…well…as…in…saline…

week,… but… there… was… no… significant… change…（ 7.30,…

respectively.… The… pH… was… also… checked… after… one…

suggest… that… tedizolid… is… stable… in… 5%… glucose… solution…
®

but…not…in…50%…glucose…solution.…

7.25,…2.91,6.60）.…To…clarify…the…cause…of…instability…of…

The… pH… of… physiological… saline,… 5%… glucose… solution,…

tedizolid…in…50%…glucose,…the…eff…ect…of…pH…on…its…stability…

was… examined… using… saline… solutions… with… different… pH…
values…prepared…by…adjusting…the…pH…with…hydrochloric…

acid.… After… incubation… of… tedizolid… in… solutions… with…
diff…erent…pH…values…for…48…h,…a…signifi…cant…decrease…in…the…

tedizolid…concentration…was…observed…at…low…pH…（Fig.…4）.…
Fig. 4. Stability of tedizolid in solutions under varying pH conditions.
These…results…suggest…that…the…low…stability…of…tedizolid…in…
50%…glucose…solution…is,…at…least…in…part,…due…to…the…low…

pH… of… the… solution.… However,… the… detailed… mechanism…
responsible… for… the… decomposition… of… tedizolid… in… 50%…

10

*

110

*P < 0.05

TZD(%)

100
90
80
70
60

pH 7.35

pH 4.13

pH 3.20

pH 2.71

Fig. 4．Stability of tedizolid in solutions under varying pH conditions.
Tedizolid
was under
dilutedwith salinewith varying
pH values
and withFig. 4. Stability of tedizolid
in solutions
varying
pH conditions.
Tedizolid
was diluted

Fig. 3．TLC Chromatogram of authentic samples.

immediately
subjectedsubjectedto HPLC to
analysis.
are expressedas the as
saline with varying pH values
and immediately
HPLC Data
analysis.
Data are expressed

1: Control, 2: Physiological saline, 3: 5% Glucose solution, 4:

Solita®-T No. 3 infusion solution, 5: 50% Glucose solution.
the mean ± SD (n = 4).

mean ± SD（n = 4）.

医薬品相互作用研究

glucose…solution…remains…to…be…clarified.

Tedizolid…was… unstable…in… 50%… glucose… solution,…and…

Vol.45, No. 3（2021）

17（133）18（18）

organisms:… methicillin-resistant… enterococci,… Mayo…

Clin.…Proc.,…86（12）,…1230-1243,…2011.

the… residual… rate… of… tedizolid… was… ≤… 90%… immediately…

… 2）…Sievert… DM,… Rudrik… JT,… Patel… JB,… McDonald… LC,…

is… presumed… that… tedizolid… should… not… be… administered…

Staphylococcus aureus…in… the… United… States,… 2002-

The… availability… of… tedizolid… administration… with… a… high…

… 3）…Ministry… of… Health,… Labour… and… Welfare:… Public…

after…dilution…with…50%…glucose…（Fig.…2）.…Therefore,…it…

from… the… same… line… during… total… parenteral… nutrition.…

concentration…of…glucose…via…a…central…vein…is…of…clinical…
importance…but…requires…further…study.

Wilkins… MJ,… Hageman… JC:… Vancomycin-resistant…
2006,…Clin.…Infect.…Dis.,…46（5）,…668-674,…2008.

information…on…all…inpatient…departments…of…nosocomial…
infection…control…surveillance…in…Japan,…2019.

Tedizolid…has…a…high…absolute…bioavailability…and…a…long…

…4）…Tanihara…S,…Suzuki…S:…Estimation…of…the…incidence…of…

once… daily,… does… not… require… dose… adjustment… even… in…

using…health…insurance…claim…data,…Epidemiol.…Infect.,…

half-life.… It…can… be… administered… intravenously…or…orally…

patients…with…renal…dysfunction,…and…its…oral…form…is…stable…

after…crushing,…making…it…convenient…for…clinical…use.

11）

T h e … c r i t e r i a … f o r … j u d g i n g … t h e … s u i t a b i l i t y … o r…

MRSA…patients:…evaluation…of…a…surveillance…system…
144（11）,…2260-2267,…2016.

… 5 ）… F l a n a g a n … S, … F a n g … E, … M u ñ o z … KA, … M i n a s s i a n…
SL,… Prokocimer… PG:… Single-and… multiple-dose…

incompatibility… of… injection… or… infusion… solutions… are…

pharmacokinetics… and… absolute… bioavailability… of…

.…As…

…6）
…Ghazi…I,…Hamada…Y,…Nicolau…DP:…Physical…compatibility…

infusion… solution… showed… any… change… in… appearance…

simulated…Y-site…administration,… Am.…J.…Health-Syst.…

“remain… the… same… in… appearance”… and… “the… ingredient…

is…stable…for…at…least…24…h…（residual…rate…of…≥…90%）”10）neither…the…5%…glucose…solution…nor…the…Solita®-T…No.…3…

after… tedizolid… dilution,… and… the… residual… rate… at… 24… h…

after…dilution…was… ≥ 90%,…it…is…considered…that…dilution…
of… tedizolid… in… 5%… glucose… solution… or… Solita -T… No.… 3…
®

infusion… solution… or… administration… via… a… side… tube… are…

tedizolid,…Pharmacotherapy,…34（9）,…891-900,…2014.

of…tedizolid…phosphate…with…selected…i.v.…drug…during…
Pharm.,…73（21）,…1769-1776,…2016.

…7）…Santini…DA,…Sutherland…CA,…Nicolau…DP:…Development…
of… a… high… performance… liquid… chromatography…

method…for…the…determination…of…tedizolid…in…human…

suitable… in… actual… medical… practice,… as… well… as… dilution…

plasma,…human…serum,…saline…and…mouse…plasma,…J.…

the…infusion…bag…in…this…experiment…was…not…considered…

…8）…Dorn…C,…Schießer…S,…Wulkersdorfer…B,…Hitzenbichler…

concentration…of…tedizolid…diluted…in…physiological…saline.

clindamycin,… flucloxacillin… or… tedizolid… in… plasma:…

with… physiological… saline.… In… addition,… adsorption… to…
to… be…a…problem… because… there… was… no…decrease…in…the…

4. Conclusion

In…this…study,…changes…in…tedizolid…content…in…various…

diluents… at… injection… concentrations… actually… used…
in… clinical… practice… were… evaluated… using… HPLC.… No…

decrease… in… concentration… over… time… was… observed…

after… dilution… with… 5%… glucose… solution… and… Solita -T…
®

No.…3…infusion…or…with…physiological…saline,…the…dilution…

solvent…recommended…in…the…package…insert…of…tedizolid…

phosphate.…This…study…identified…useful…diluents…suitable…

for…tedizolid…administration…in…the…clinic.

5. Competing interests

There…are…no…conflicts…of…interest…to…declare.

6. References… 1）…Rivera… AM,… Boucher… HW:… Current… concepts… in…
antimicrobial…therapy… against… select… gram-positive…

Chromatogr.…Sep.…Tech.,…6,…4,…2015.

F,… Kees… MG,… Zeitlinger… M.:… Determination… of… free…
Pay… attention… to… physiological… conditions… when…
using…ultrafiltration,…Biomed.…Chromatogr.,…34（6）,…

e4820,…2020.

… 9 ）… A n e r a o … A , … D i g h e … V, … J o h n … S , … P r a d h a n … N :…
Enantioseparation… of… tedizolid… phosphate… by… RP-

HPLC,… using-cyclodextrin… as… a… chiral… mobile… phase…

additive,…J.…Appl.…Pharm.…Sci.,…7（10）,…030-036,…2017.

10）…Akase… T,… Nakamura… H:… Chapter… 2:… Introduction…
to… the… coordination… change… theory,… Evidence-

based… understanding… of… compounding… changes… in…
injectable… drugs… and… infusions,… Yodosha,… Tokyo,…

pp.35（single…page）,…2009.

11）…Kennedy… G,… Osborn… J,… Flanagan… S,… Alsayed… N,…

Bertolami…S:…Stability…of…crushed…tedizolid…phosphate…
tablets…for…nasogastric…tube…administration,…Drugs.…R.…

D.,…15,…329-333,…2015.