Int. J. N
carrie impr poten multi acid techn gene of as diffe of A The funct 5 hou (hum ASA comm It rev biom Keyw aspir
the nano nano ratio main of gr nano
* ) For
Nanoelectronic
Aspirin charac Siti Haja Ibrahim2
1Faculty o
2Departm Skudai, J
Abstrac Carbon n ers for dru rove substan
ntial explo iwalled car (68%) and niques and ration of ca spirin (ASA rent concen ASA attache results from tionalized M urs sonicati man body te A from A
mercialized veals that M medical appl
words: Mu rin.
1. Intro Recently significant oemulsions, oparticles an and a diam n types: (i)
raphene she otubes (MW
r Corresponde
cs and Materials
n adsorpt teristics i ar Alias1*, N
2
of Applied Sc ment of Chem Johor, Malay
ct
nanotubes ( ug delivery ntially thei itation of rbon nanotu d sulfuric ac d were ch arboxylic gr A) drug onto
ntration of A ed onto fun
m UV-Vis MWCNTs w ion. From th emperature)
SA-f-MWC d aspirin tab MWCNTs h
lications, thu ultiwalled c
oduction y, new appr
t advance dendrimer nd carbon na meter in the
single-walle eet seamles WCNTs), wh
ence, E-mail:
s 7 (2014) 35-4
tion on mu in simulat Nor Aziah B
cience, Univ mistry, Facult
ysia
(CNTs) hav y applicatio r dispersab carbon nan ubes (MWC cid (98%) i haracterized roups was p o functiona ASA drug so nctionalized
Spectropho with the amo he release s
and 39oC ( CNTs com
blets and fol have the ab
us it can be carbon nano
roaches are s in nan rs, solid lip
anotubes (C e nanoscale ed carbon n ssly rolled hich compr
sitihajar404@
43
ultiwalled ted body f Buang2, Alia
versiti Teknol ty of Science
ve been pro ons. The fu bility and b notubes in CNTs) wer
in the ratio d using va proven by F alized MWC
olutions and d MWCNTs
otometer g ount of 77.6 study of AS (fever temp mposite for
llowed by a bility to imp e used to imp
otubes, fun
emerging i notechnolog pid nanopa CNTs) [1]. C
range. It ca nanotubes (
into a cyli rise multipl
@perlis.uitm.ed
d carbon fluid as Mohd Yu
logi MARA, e, Universiti T
oposed and unctionaliza biocompatib drug adm e functiona o of 3:1 vol arious char T-IR spectr CNTs was d
d at differen s was deter
ave the per 64% (77.64 SA in Simul perature), th the first a controlled prove the p
prove the dr nctionalized
in the field gy such articles, pol CNTs are tu an be classi SWCNTs), indrical tub le layers of
du.my
nanotube
usof2 and M
02600 Arau, Teknologi M
actively ex ation of car bility profil ministration.
alized using lume per vo racterization roscopy. In done by son nt sonication rmined by F rcentage of
mg/ 100 m lated Body he results sh 5 hours d release at
harmacokin rug delivery d, drug load
of drug del as liposom lymeric nan ubular objec
ified by the which con be, and (ii)
f concentric
es and its
Mohd Lokma
, Perlis, Mal Malaysia, 813
xplored as in arbon nanot
le, thus off In this s g concentra olume by s n instrume addition, th nication tec on time. The FT-IR spec f ASA load mg) at 30 00
Fluid (SBF how a fast r compared the followi netics of AS
y system.
ding, drug
livery, main mes, nano anoparticles
cts with a hi eir structure nsist of a sin
multiwalle c cylinders
release
an
laysia 310
nnovative tubes can fering the study, the ated nitric
sonication ents. The he loading chnique at e presence ctroscopy.
ding onto 0 ppm for F) at 37oC release of d to the
ing hours.
SA in the
released,
nly due to ocapsules, , ceramic igh aspect e into two ngle layer ed carbon with the
Siti Hajar Alias, et al. / Aspirin adsorption on multiwalled carbon nanotubes…
36
space of about 0.34 nm between the adjacent layers [2]. CNTs have very interesting physicochemical properties such as ultralight weight, high mechanical strength, high electrical conductivity, high thermal conductivity, metallic or semi-metallic behavior and high surface area. The combinations of these characteristics make CNTs a unique material with the potential for diverse application, including biomedical [3].
Aspirin or also known as acetylsalicylic acid is one of the most commonly NSAIDs used drugs and billions of tablets are produced every year. Aspirin frequently used in the treatment of mild to moderate pain, including migraine and fever [4]. However, due to administration of free drugs, such as limited solubility, poor bio distribution, lack of selectivity, unfavorable pharmacokinetics, and healthy tissue damage, a drug will be difficult to deliver to the targeted cell. A drug delivery system will be used to overcome this problem and it is generally designed to improve the pharmacological and therapeutic profile of a drug molecule [5].
According to Sekhar et al. [6], a drug with poor solubility can be replaced with a drug delivery system where both hydrophilic and hydrophobic environments exist and thereby increase the solubility. A drug may also cause damage to the non-infected tissue.
Therefore, with targeted drug delivery, regulated drug release can eliminate the problem.
Besides that, when a drug is release fast and not retain in the infected human body even before the body could assimilate it, it can cause the patient to use higher doses to make up the bio-availability. However, with targeted drug delivery system, elimination can be avoided by altering the pharmacokinetics of the drug. Other than that, poor bio-distribution is a problem that can affect normal tissues (non target tissues) adversely through unwanted widespread distribution. The particulates from targeted drug delivery systems reduce the rate of distribution and reduce the effect on non-target tissue thereby drastically reducing the side effects. Therefore, CNTs have been proposed as multipurpose innovative carries for drug delivery applications [7].
The pristine CNTs (non-functionalized) are inherently hydrophobic, therefore the main obstacle in the utilization of CNTs in biology and medical chemistry is their poor dispersion in most solvents. To overcome this problem the surface modification of the CNTs (functionalization) with different molecules is achieved by adsorption, electrostatic interaction or covalent bonding of different molecules and chemistries that render them to be hydrophilic. Through such modification, the water solubility of CNTs is improved and their biocompatibility profile completely transformed [4]. Functional groups including carboxylates, can be further modified with therapeutic agents to create CNTs conjugates to endowed with some kind of pharmacological activities. CNTs are able to carry one or more therapeutic moieties with optical or other probes for imaging. Thus, specific recognition systems for targeting, can offer multimodal options in the treatment of where activity is required only at specific sites in the human body [2].
Potential of aspirin drug loaded onto MWCNTs and release characteristics of aspirin loaded MWCNTs composites has not been much investigated. In this work, we have compared the potential of aspirin drug loaded onto functionalized and non-functionalized MWCNTs. The authors also highlight the release characteristics of aspirin drug from MWCNTs in vitro at human body temperature (37oC) and fever temperature (39oC).
Int. J. Nanoelectronics and Materials 7 (2014) 35-43
37 2. Experimental
2.1 Materials
Commercialized MWCNTs were purchased from Sun Nanotech Co. Ltd with 10-30 nm diameters and more than 90% purity. Mixture of nitric acid (65%) and sulfuric acids (96%) were used for acid treatment of MWCNTs. While acetylsalicylic acid (ASA) was purchased from Sigma-Aldrich, lnc and aspirin tablets were purchased from Bayer Corp.
which contains 500 mg of acetylsalicylic acids as one of the active ingredients.
2.2 Functionalization of MWCNTs using Liquid Phase Oxidation Method 200 mg of pristine MWCNTs were treated with 100 ml of aqueous acid solution H2SO4/HNO3 mixtures in the ratio of 3:l by volume per volume. Mixture of MWCNTs and acid solutions were ultrasonically vibrated in water bath ultrasonic Branson 2000. The suspension was separated by centrifuge process and subsequently filtered through nylon membrane filter (pore size: 0.2 pm). The residue was washed with distilled water during filtration until it is at pH 7. Finally, functionalized MWCNTs were heated in an oven for 24 hours at 60oC to remove all remains of water.
2.3 Drug Loading onto Functionalized MWCNTs
The functionalized MWCNTs were suspended in a 50 ml solution of aspirin in sodium hydroxide. This mixture was sonicated at 5 hours sonication time with 30 000 ppm of acetyl salicylic acid and left for 24 hours at room temperature (25oC). Then, the solution was centrifuged for 20 min at 4000 rpm to separate the CNTs. CNTs were subsequently left to dry at ambient temperature.
2.4 Characterizations
Several techniques were used to characterize the non-functionalized and functionalized MWCNTs and ASA-MWCNTs composite (ASA loading onto MWCNTs).
FT-IR was used to determine the functional groups generated on the surface of MWCNTs and detection of aspirin absorbed into the MWCNTs. Characterization of MWCNTs was carried out using Perkin Elmer SpectrumTM 400 FT-IR spectrophotometer. Field Emission Scanning Electron Microscope (FESEM), model JSM-6701F, JEOL Company was used to observe the morphology structure of MWCNTs before and after functionalization of MWCNTs and the morphology of MWCNTs after ASA was loaded onto MWCNTs. Energy Dispersive X-Ray Analysis (EDX), model EX-230**BU, JEOL Company Japan was used to observe the elemental analysis of MWCNTs possibly found on the structure of functionalized MWCNTs.
The amount of ASA loaded onto MWCNTs was determined by using UV-Vis Spectrophotometer. Concentrations of ASA were determined by using Beer's Law with the excitation wavelength for ASA of approximately 290 nm [8] and each sample were recorded at the same wavelength.
Siti Hajar A
38 2.
S using pre similar Na+/K+/C mg of AS ml SBF before SB using UV ASA-f-M
3.
3.
T before an functiona the C=C H2SO4/H associate stretching groups ha
F treatment loosely p functiona surface (F was poss surface [ process a tips were layers of ends of th
Alias, et al. / Asp
.5 In Vitro imulated bo epared simu to the Ca2+/Mg2+/C SA-f-MWC
at 37oC (n BF was tak V-Vis spect MWCNTs co . Results a .1 Functio The FT-IR s nd after th alized MWC C stretching HNO3 mixtu ed with C=O
g, C-O stre ave been in
Fig.
ig. 2(a) sh ts. Non-fun packed bun alization pro Fig. 2(b)). T sibly associ
9]. Hence, as reported e exposed, w f the co-axia
he MWCNT
pirin adsorption
o Released S ody fluid ( ulated body e human Cl-/HCO3-
/H CNTs compo normal hum
ken out at trophotome omposites.
and Discuss onalization spectra (Fig e functiona CNTs, a sin g of carbon
ure, peaks a O stretchin etching and troduced on
. 1: FT-IR sp
hows the m nctionalized ndles of M ocess, the s The rough a iated to the
the MWCN by Kumar which indic al tubes. Th Ts [11].
n on multiwalle
Study SBF, pH=7 y fluid. Sim n plasma HPO42-
/SO42
osites (ASA man body te a predeterm ter to deter
sion of MWCN . 1 (a) & (b alization of ngle peak w n nanotubes
appeared on g vibration d O-H bend
nto the func
pectra of MW (b) after micrograph d MWCNTs MWCNTs a
smooth surf and groovy e functional NTs floss w
et al. [10].
cated that th hus, allowin
ed carbon nanot
7.4) was us mulated bod
a (ppm:
2-). The rele A loading on emperature) mined time
rmine the c
NTs
b)) show th f the MWC was observe s backbone n functiona n of carboxy
ding deform ctionalized M
WCNTs (a) b er functionali h of non-fu
s showed t arrangement
face of the y surface of l groups ch was loosely After the a he breaking ng the gener
tubes…
ed to inves dy fluid (SB
142.0/5 ease of drug nto function ) as well a
interval. T concentratio
e compariso CNTs. From ed at 1636 e. After MW alized MWC
yl groups.
mation peak MWCNTs.
efore functio ization.
functionalize the presenc
t as report MWCNTs the sidewa hemically at
entangled d acid oxidati g of the C-
ration of fu
stigate drug BF) has a c 5.0/2.5/1.5/1
gs was don nalized MW
s 39oC (fev The samples on of aspiri
on of the ab m FT-IR sp
cm-1 which WCNTs we CNTs as ar
With the p ks revealed
onalization, a
ed MWCN e of a smo ted in liter
was transfo ll of acid tr ttached onto due to the f ion, some o C bond alo unctional gro
g release pr composition 147.8/4.2/1 ne by soakin WCNTs) into ver tempera s were ana in released
bsorptions b pectrum on h is associat
ere treated round 1700 presence of d that carbo
and
NTs before ooth surface rature. Afte
ormed to gr reated MWC
o the MWC functionaliz of the MWC ong the grap roups at the
rocess n very .0/0.5 ng 20 o 350 ature) alyzed from
bands non- ted to
with 0 cm-1
C=O oxylic
acid e and er the roovy CNTs CNTs zation CNTs phene open
Fig. 2
befor besid was f was n the im
Ta
Non Fun
Com
band respe 1658 to th respe MWC loadi
(a)
2: Micrograp
EDX res re and after des the pres found in the not found in mpurities su able 1: Elem
MW
n-functionaliz ctionalized M
3.2 Dru mposites
The FT- ds of ASA
ectively. Th 8 cm-1, ll88- he C=O stre
ectively. Fr CNTs com ing was suc )
ph FESEM fo
sults (Table r the acid t sence of car e EDX anal n the functi uch as alum mental percen
WCNTs
zed MWCNT MWCNTs
ug Loading
IR spectra A, ASA-n he significan
-l248 cm-1,1 etch, C-O rom the FT mposites an
ccessful.
or (a) non-fu treatment 1) shows c reatments w rbon and ox
lyses. After onalized M minum from tage of non-f
Ts
g Analysis o
(Fig. 3 (a), nf-MWCNT nt peaks ob 1578-1658 stretch, C-C T-IR spectra nd ASA-nf-
unctionalized
(functionaliz changes in th
with mixtur xygen, a sm
the functio MWCNTs. It the MWCN functionalize
techniqu
Carbon (C 94.63 88.91
of Aspirin L
, (b) and (c Ts compos bserved for cm-1, 964 c C, C=C be a, the appe -MWCNTs
Int. J. Nan
d MWCNTs b zed MWCNT he elementa res. For the
all amount nalization w t shows that NTs [l 2].
ed and functi ue
Weigh C) Ox
Loaded MW
)) show the sites and ASA before cm-1, 893 cm end, aromat earance of composite (b)
noelectronics an
before acid tr Ts).
al composit e non-functi
of impuritie with mixture t functional
ionalized MW
t Elements ( xygen (O2)
5.19 11.09
WCNTs (A
e compariso ASA-f-MW e loading on m-1, 759 cm tic O-H str
the ASA p es have pro
nd Materials 7
treatment, (b)
tion of the M ionalized M
es such as a e of acids, a lization can
WCNTs usin
(%)
Alumin 0
ASA-MWCN
on of the ab WCNTs co onto MWCN m-1 which co retch and o peaks in th oven that
(2014) 35-43
39 ) after acid
MWCNTs MWCNTs, aluminum aluminum eliminate
ng EDX
num (Al) 0.17
NTs)
bsorptions omposites NTs are at orrespond o-benzene, he ASA-f-
the ASA
Siti Hajar A
40 Fig. 3:
F are no di after drug ASA load surface o groovy su
Fig. 4: M
F functiona also be l percentag efficiency With the carboxyli
(a)
Alias, et al. / Asp
FT-IR spect
ig. 4(a) sho ifferences i g loading, a ded is show of the non- urface of M
Micrograph F
ig. 5 show alized MWC loaded onto ge compare y depends o presence o ic group on
pirin adsorption
tra of (a) ASA
ow the micr in the morp as they appe wn in Fig. 4
-functionali MWCNTs (F
FESEM for ( ASA ws that th
CNTs when o the non-f ed to the on the prese of functional n the surface
(b)
(c) (a)
n on multiwalle
A, (b) ASA- co ograph of A phology ob
ear the sam (b). From th ized MWCN Fig. 4(b)).
(a) loading o A onto non-fu
e amount n sonicated functionaliz
functionali ence of the f l group, the e of f-MWC
ed carbon nanot
nf-MWCNT omposites.
ASA loaded served for me. The func he microgra NTs Fig. 2
of ASA onto functionalized
of ASA l and stirred zed MWCN ized MWC functional g e ASA mole CNTs.
(b)
tubes…
Ts composites
d onto funct both struct ctionalized M
aph, it can b 2(a) has be
functionaliz d MWCNTs loading on d with 30 0 NTs with re CNTs. This
group on the ecules may
s, and (c) AS
tionalized M ures before MWCNTs m be observed een altered
ed MWCNT .
nto non-fun 000 ppm of esults show is becaus e surface of effectively
SA-f-MWCN
MWCNTs. T e (Fig. 2(b)
micrograph d that the sm
into rough
Ts, (b) loadin
nctionalized f ASA. ASA w that the l
se drug lo f MWCNTs bonded wit
NTs
There )) and h after mooth h and
ng of
d and A can
lower ading s [13].
th the
comp and 7 stabi rema be di wate MWC
Fig.
Simu ASA (39oC 5 hou ASA from relea ASA
Fig.
3.3 Disp Fig. 6 s posites in w 7 days later
lity after 7 ains stable a ispersed be r dispersib CNTs while
After add 6: Dispersion
time (A 3.4 Dru Fig. 7 an ulated Body A tablets in t C), respectiv urs compare A released f m commerci ased from A A tablets.
A
5: Percentag persion An shows the water at the r. Fig. 6 sho 7 days in w after 7 days.
efore they a ility throug e increasing
dition
n test of ASA A: ASA-f-MW ug Released nd 8 show th y Fluid (SB
the market vely. Fig. 7 ed to the co from ASA-f ialized ASA ASA-f-MW
B
ge of ASA nalysis
dispersed moment of ows that the water compa . According are used in
gh chemica g their bioco
One hou A-nf-MWCN WCNTs com d Analysis
he compari BF) from A at normal h shows the ommercializ f-MWCNTs A tablets a WCNTs com
A
loaded onto
states of A f dispersion e ASA-nf-M ared to the g to Foldva therapeutic al modifica ompatibility
ur
NTs and ASA mposite in wa
son of the p ASA-f-MWC human body fast release zed ASA tab
s composite and after 6 mposite was
B
Int. J. Nan
o f-MWCNT
ASA-nf-MW n and at app MWCNTs co ASA-f-MW ari, et al., [1 c formulatio ation will r
y [2].
One day A-f-MWCNT ater; B: ASA
percentage r CNTs comp
y temperatu e of ASA fro
blets. Howe e was nearl hours onw s lower com
A
noelectronics an
Ts and nf-M
WCNTs an proximately omposites h WCNTs com
4], it is esse ons. This i
educe the
y
Ts composite A-nf-MWCNT
released of posite and fr
re (37oC) an om the ASA ever, after 5
ly the same wards, the mpared to
B
nd Materials 7
MWCNTs.
nd ASA-f-M y one hour, have poor su omposites w
ential that M s because i
cytotoxic e
Seven da e in water ac Ts in water).
ASA in the from comm and fever tem
A-f-MWCN hours, perc e with ASA percentage
the comm A
(2014) 35-43
41 MWCNTs 24 hours uspension which still
MWCNTs increasing effects of
ays
cording to
e prepared mercialized mperature NTs within centage of A released e of ASA mercialized
B
Siti Hajar A
42 Fig. 7:
c A SBF at 39 the drug ASA-f-M 10.23% o 39oC.
Fig.
T shows th commerc control re have the drug eff pharmace mainly tr resulted including been thou
Alias, et al. / Asp
Comparison commerciali As shown in
9oC. Howev release in MWCNTs co
of ASA was
8: Comparis
The fast rele he improv cialized AS elease of dr ability to im ficiency [2
eutical ther reated by re in a high d g the releas
ught to be n
pirin adsorption
n on the perc ized ASA tab
Fig. 8, the ver, the ASA
SBF at 37o omposites in s released in
son on percen commercia ease of ASA vement of SA tablets.
rug behavio mprove the
]. Slow re rapy. It is
petitive dru dosage upta se time and necessary to
n on multiwalle
centage of AS blets in SBF
ASA releas A release in C. For exam n 30 minute n 30 minute
ntage of ASA alized ASA ta A-f-MWCN
time relea In the follo or was obser
pharmacok elease of
because, d ug administr ake, low ef site of AS o improve th
ed carbon nanot
SA released solutions at se trends ar n SBF at 39 mple, at 37 es and 19.19 es and 23.79
A released fr ablets in SBF NTs compos
ase of the owing of d rved. There kinetics, wh the drugs during curre
ration and th fficiency an SA drugs fr
herapy [14].
tubes…
from ASA-f- 37oC (norma e quite simi 9oC is higher 7oC, 5.62%
9% was rele 9% was rele
rom ASA-f-M F solutions a
ite at below e drug mo drug release efore, it reve hich resulted actually h ent clinical hese drugs a nd side effe rom ASA-f-
.
f-MWCNTs c al body temp ilar to the re
r in percent of ASA wa eased after 4 eased after 4
MWCNTs co at 39oC.
w 5 hours at olecules co e of ASA-f eals that the d in the imp has high p l therapy, p are eliminat ects. The co -MWCNTs
composites a perature).
elease of AS tage compar
as released 4 hours, wh 4 hours in S
omposite and
at 37oC and ompared to f-MWCNTs e MWCNT provement o potential to patients are ted quickly ontrolled re
composites and
SA in red to from hereas BF at
d
39oC o the
s, the s also of the o the e still
. This elease s, has
Int. J. Nanoelectronics and Materials 7 (2014) 35-43
43 4. Conclusion
The results obtained show the generation of carboxylic groups on the surface of MWCNTs. The carboxylic groups will increase the dispersibility of MWCNTs in various solvents and help to anchor aspirin molecules by hydrogen bonding with the carboxylic groups. Analysis of loaded CNTs by FESEM-EDX, FT-IR Spectroscopy and UV‐Vis Spectroscopy confirmed the loading of the drug onto the functionalized and non- functionalized MWCNTs. However, ASA-nf-MWCNTs composites have poor suspension stability after 7 days in water compared to the ASA-f-MWCNTs composites which still remains stable. Therefore, functionalized MWCNTs have the potential application in drug administration. The fast release of ASA-f-MWCNTs composite at below 5 hours at 37oC (human body temperature) and 39oC (fever temperature) shows that ASA drug molecules are better released during this time compared to commercialized ASA tablets. The fast release of ASA drug at the early hours (initially) and controlled release for the following hours (finally) by the ASA-f-MWCNTs at temperature of 39oC was proven higher than at 37oC. Therefore, it reveals that the MWCNTs have the ability to improve the pharmacokinetics of aspirin drug in the biomedical applications, thus offering the potential exploitation of carbon nanotubes in the drug development of drug delivery system.
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