18_Ketorolac_SiO2

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Hindawi Publishing CorporationJournal o NanomaterialsVolume , Article ID ,pageshttp://dx.doi.org/.//

Research ArticleObtaining of Sol-Gel Ketorolac-Silica Nanoparticles:Characterization and Drug Release Kinetics

T. M. Lpez Goerne,1,2,3 M. G. Lpez Garca,1,2 G. Rodrguez Grada,1,2 I. Ortiz Prez,1,2

E. Gmez Lpez,4 and M. A. Alvarez Lemus2

Laboratorio de Nanotecnologa y Nanomedicina, Departamento de Atencion a la Salud, Universidad AutonomaMetropolitana Xochimilco, Calzada del Hueso , Col. Villa Quietud, Delegacion Coyoacan, Mexico, DF, Mexico

Laboratorio de Nanotecnologa, Instituto Nacional de Neurologa y Neurociruga Manuel Velasco Suarez, Avenida Insurgentessur , Col. La Fama, lalpan, DF, Mexico Department of Chemical and Biomolecular Engineering, ulane University, New Orleans, LA , USA Facultad de Ciencias, Universidad Nacional Autonoma de Mexico, Avenida Universidad , Circuito Exterior

S/N Delegacion Coyoacan, Ciudad Universitaria, Mexico, DF, Mexico

Correspondence should be addressed to M. A. Alvarez Lemus; [email protected]

Received August ; Accepted November

Academic Editor: Yan-Yan Song

Copyright . M. Lopez Goerne et al. Tis is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Nonsteroidal anti-inammatory drugs (NSAIDs) are among most commonly prescribed medications worldwide. NSAIDs play animportant role due to their pronounced analgesic potency, anti-inammatory effects, and lesser side effects compared to opioids.However, adverse effects including gastrointestinal and cardiovascular effects seriously complicate their prolonged use. In thepresent work we prepare SiO2-basednanoparticles with ketorolac, or controlled release proposes. Te nanomaterialswere preparedby the sol-gel technology at acidic conditions and two different water/alcoxide ratios were used. FIR spectroscopy was perormedin orderto characterizethe solids and drug-SiO2interactions. Termal analysis and nitrogenadsorption isotherms showed thermalstability o the drug and conrmed the presence o particles with high surace area. ransmission electron micrographies o thesamples showed the nanosize particles ( nm) orming aggregates. Drug release proles were collected by means o UV-Visspectroscopy and kinetic analysis was developed. Release data were tted and : sample showed a sustained release over tenhours; % o the drug was delivered at the end o the time.

1. Introduction

Nanotechnology drug delivery, diagnosis, and drug develop-ment represent the change in medicine in st century. Tiseld is an area that will produce signicant results, in thiswaythe drug is controlled during days or even weeks, dependingon the disease to treat []. Nanoparticulate drug delivery

vehicles can be organic or inorganic solids but biocompatibleand nontoxic. Tese novel systems allow drug absorption ina controlled way and with less adverse side effects [].

Nonsteroidal anti-inammatory drugs (NSAIDs) areamong most commonly prescribed medications worldwide[]. Approximately % o people older than years havebeen prescribed NSAIDs []. In acute pain as headache,

stomach ache, or u, NSAIDs play an important role due

to their pronounced analgesic potency, anti-inammatoryeffects, and lesser side effects compared to opioids [, ].However, adverse effects including gastrointestinal (GI) andcardiovascular (CV) seriously complicate their prolonged use[].

Ketorolac tromethamine (K),Figure , is a pyrrolizinecarboxylic acid derivative o NSAIDs with potent analgesicand moderate anti-inammatory activity, a relatively avor-able therapeutic agent or the management o moderate tosevere pain [,]. Te benecial effects o K are probablydue to its ability to block prostaglandin synthesis by prevent-ing the conversion o arachidonic acid to the endoperoxides[].


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Journal o Nanomaterials

Si(OC2H5)4 + H2O

C2H5OH

+ C2H5OHSi(OC2H5)4 (OH)

S : Hydrolysis o EOS.

For instance, weight by weight K proved to be times more potent than naproxen in analgesia models butonly times more potent in inammation models [].Tis remarkable dissociation between analgesic and anti-inammatory effects provided the basis or the developmento the drug as excellent anti-inammatory and analgesic.In clinical settings however ketorolac has been involved asa contributing cause o increased postoperative bleeding,renal ailure, and gastritis; the severity o these side effects isprobably dose related [].

For these reasons, many attempts to develop novel or-mulation strategies to deliver K had been made. Sinhaand rehan [] prepared drug-loaded polycaprolactone and

poly lactic-co-glycolic acid microspheres, Rokhade et al. []developed semi-interpenetrating polymer network micro-spheres o gelatin and sodium carboxymethyl cellulose, andrecently, Genc and Jalvand [] produced controlled releasehydrophilic matrix tablets.

Te use o mesoporous silica nanoparticles offers asuitable method to deliver drugs toward specic tissues orcells depending on drug properties []. Sol-gel inorganicnanoparticles exhibit signicantly higher surace area andporosity [] which means more available surace to placemolecules o interest. One o the main advantages o sol-gelprocess is that materials exhibit special eatures like highlyhydroxylated surace which has demonstrated to be one acile

method to achieve unctionalized suraces. Additionally, sol-gel process provides the opportunity to release a great varietyo biomolecules, medicines, or compounds rom the oxidestructure, while unctionalization or surace modication isrelatively easy.

Sol-gel chemistry uses neutral, acidic, or basic conditionsto achieve hydrolysis and condensation o numerous silanemonomers SiO and OSiOH (Scheme ) [].

At present, a great deal o emphasis is being placed on thedevelopment o controlled or sustained release orms or thedrug as this would help in achieving the required therapeuticefficacy and better tolerance. Te main goal o this study wasto develop ketorolac silica reservoir (ketorolac-SiO2) deliverysystem using sol-gel method.

2. Experimental

.. Materials. etraethoxysilane (EOS) %, waspurchased rom Sigma-Aldrich. Ketorolac tromethamine(C15H13NO3, MW . g/mol) by Lyomont laboratorieswas also purchased, all organic solvents were purchased romSigma-Aldrich.

.. Preparation of Reservoir. Silica reservoir was made bysol-gel process at room temperature using two water alkox-ide molar ratios : and : ; the same ethanol : alkoxide

ratios were used. Preparation was as ollows: appropriatedamounts o water and ethanol were placed and mixed in athree neck round-bottom ask. Ten . mL o EOS wasdropwise simultaneously but in a different neck with the drug( mg/gSiO2). Te mixture was lef under stirring or days. Other SiO2nanoparticles wereprepared under the same

conditions but without analgesic. Ten, dried material wascrushed in an agata mortar.

.. Characterization. Inrared absorption spectra, o thenanomaterials were obtained on IRAffinity- FIR system. Atablet with the different samples (%wt) was pressed together

with % wt o KBr ( ton/in2).Termograms were carried out using a Simultaneous

Termal Analyzer SA i-. Samples were placed in aplatinum pan and heated at a rate o C/min, in N2atmosphere rom room temperature to C.

.. Morphology Study. High-resolution transmission elec-

tron microscopy (EM) images were obtained using aEM microscope, JEOL JEM-F, operated at kV andequipped with an energy dispersive spectroscopic (EDS)microanalysis system (Oxord). Te images were obtainedusing a Gatan Orius camera.

.. Nitrogen Adsorption Measurements. Nitrogen adsorp-tion-desorption isotherms were obtained using a Micro-meritics Belsorp II, Bell Japan Inc Te Brunauer-Emmett-eller (BE) method was used to calculate specic suraceareas (BE ). Pore volumes and pore size distributions wereobtained using BJH method.

.. Controlled Drug Release. A tablet made o eachKetorolac-SiO2nanomaterial (: and : ratios) was placedinto a glass with deionized water ( mL). Samplingwas perormed at different periods o time over a totalo hours. Analysis was perormed using ultravioletspectroscopy (Cary- UV-visible, Varian) by ollowing theincrease in main absorption bands reported or ketorolac.Afer measurements, samples were returned to the glassto maintain constant volume. A calibration curve wasperormed and absorbance spectra were collected. In orderto calculate drug concentration Lambert-Beer law was used.Drug release curves were obtained by plotting cumulativedrug concentration versus time. Determinations were made

by duplicate.

.. Applied Methods to Compare Drug Release Proles.Ketorolac release kinetics rom each nanomaterial was ana-lyzed by several mathematical models. Depending on theseestimations, suitable mathematical models to describe dis-solution proles were determined. Te ollowing plots weremade: dissolution % drug release versus time (zero-orderkinetic model); Ln dissolution % drug remaining versus time(rst-order kinetic model); dissolution % drug release versussquare root o time (Higuchi model); cube root o drug %remaining in matrix versus time (Hixson-Crowell cube rootlaw); and dissolution % drug release versus time (hyperbola).


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C

O

COOH3N+

HOH2C

HOH2C

CH2OHN

C

F : Structure o Ketorolac tromethamine.

4000 3500 3000 2500 2000

0

5

10

15

20

25

30

35

40

45

25823481

T(%)

Wavenumber (cm 1)

2943

Ref SiO2 1 : 8

Ket SiO2 1 : 8

(a)

2000 1500 1000 500

1641

1300

1165

455

804948

1246

1097

0

5

10

15

20

25

30

35

40

45

T(%)

Ref SiO2 1 : 8

Ket SiO2 1 : 8

Wavenumber (cm 1)

(b)

4000 3500 3000 2500 20000

5

10

15

20

25

30

35

40

45

50

29583421 2721

Ref SiO2 1 : 4

Ket SiO2 1 : 4

Ket SiO2 1 : 4

T(%)

Wavenumber (cm 1)

(c)

16411454

11611095

968457

0

5

10

15

20

25

30

35

40

45

50

T(%)

2000 1800 1600 1400 1200 1000 800 600 400

Ref SiO2 1 : 4

Ket SiO2 1 : 4

Ket SiO2 1 : 4

Wavenumber (cm1)

(d)

F : IR spectra o (a) and (b) : ratio; (c) and (d) : ratio SiO2based materials.

3. Results and Discussion

.. Characterization. Figure shows the most distinctiveinrared absorption bands o silica or both ratios. In the cm1 region, the OH stretching band due to

residual water and SiOH vibration was observed, this istypical in sol-gel materials, and the presence o OH rommethanol groups o the drug contributes to this band.Presence o adsorbed water is conrmed by the appearance

o a band around cm1 in all the samples. Te signals


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centered at and cm1 are related with the SiOSi bond deormation. Te band around cm1 is splitinto two bands at and cm1 or the : materialand at and cm1 or : ratio; these correspond tostretching vibrations o SiOSi bonds. At and cm1

we observed o SiO exion vibrations or : and :

ratios, respectively. SiOH stretching bands were observedat and cm1, these results are similar to thosereported by Gonzales et al. [] and Kalampounias [],no absorption bands o Ketorolac can be clearly assigned,since most o the signals due to the bonds o the drug areoverlapped white silica bands. However some eatures areslightly distinguished; a more intense band was observed

at cm1 or Ketorolac-SiO2 : and at cm1 or

Ketorolac-SiO2 : . In this region C=C ring antisymmetricelongation can be detected, this band is less intense in bothsilica reerences due to in those samples there still remainsresidual ethanol rom the synthesis, so the band we observedcorresponds to OH deormation.

GA curves are shown in Figure . Weight loss wasvery similar or all samples. For : ratio, the rst loss wasabout % or Ketorolac-SiO2 and ca. % or the reerencearound rom room temperature to C. Tis rst gradualloss is associated with residual ethanol o the synthesis, anddehydratation rom both silica and the drug []. A secondloss was recorded around C (ca. %) in Ketorola-SiO2,this can be due to decomposition o tromethamine salt [ ],the nal gradual loss rom to C is attributable to thelost o structural OH groups rom silica.

When we compared GA in both water ratios, themain difference is that silica reerences initially loss moreweight than those nanomaterials with ketorolac; this can beexplained due to the time o aging in both samples, sincedrug-loaded silica required higher time than silica alone.Regarding to the water ratios, the difference due to theamount o water is barely noticeable.

.. EM and EDS of Reservoirs. Te surace morphology othe Ketorolac-SiO2 reservoirs was studied by transmissionelectron microscopy. Te samples were placed on a coopergrid with a holey carbon support lm. Several areas o thesample were photographed using the bright eld technique(Figure ), where the crystalline parts in Bragg orientationappear dark and the amorphous or not Bragg oriented partsappear bright [], with a kV electron beam.

Te micrographs showed aggregates ormations o SiO2in the drug-silica nanomaterial, with particle size o nm approximately; due to electrostatic orces betweenthese particles, agglomeration occurs, giving rise to nanopar-ticles collection, similar to previously reported by Uddin etal. []. Te images suggest no Ketorolac presence in thecrystalline Silica ormations surace, in comparison with thereerence sample.

Te EDS was obtained rom different large groups oparticles; several hundred nanometers wide showing andconrming the nanomaterial are silica pure not only in thesurace, but also in the whole structure. Te dispersive energybands shown are purely rom silicon and oxygen without any

: Nadsorption parameters.

Sample BE (m/g) (cm

/g) (nm)

SiO : . .

Ketorolac-SiO : . .

SiO : . .

Ketorolac-SiO : . .

peak overlapping (Figure ) with some peaks, in the case othe reerence, due to the dispersive energy o the Cu grid(around , , and keV) where the sample is sustained, andor that must be ignored.

.. Surface Analysis Using Nitrogen Adsorption-Desorption.N2 adsorption-desorption isotherms o the reservoirs mea-sured at K are shown inFigure ; it can be clearly noticedthat introducing Ketorolac modies obtained isotherm. Inboth cases ( : and : ) ketorolac-SiO2 materials showed

lower adsorption, because drug molecules ll the pores,blocking available space to nitrogen molecules to measurereal surace area; this is conrmed byBE values (able ).Isotherm o the sample ketorolac-SiO2 : showed a typeIII according to IUPAC classication. In this case, ketoro-lac molecules showed weak interaction with nitrogen; thusadsorption o high amount o N2 is not achieved and nosignicant hysteresis was observed. Te : ketorolac sampleshowed similar behavior although with a slight hysteresis,however as in reerence sample, adsorbed volume is lowerthan : material, which means that when a larger ratio owater is used, higher porosity is obtained. In the reerencessamples, isotherms are type IV. Microporosity o the samples

can be conrmed by EM images (Figures(g)and(d)).Pore size distributions showed a wide distribution or

reerences; nevertheless we must consider the inuence oadsorbed drug in pore occlusion, while in reerences weclearly observe a sharp peak around nm. Tese results arecomparable with those reported by Guo et al. [].

Te BE surace area values observed in both reerenceswere between and both ketorolac-SiO2 samplesexhibited less area values, conrming the presence o druginside and over the surace o the material. Pore size distribu-tion (PSD) was estimated rom desorption branch using BJHmethod (Figure ). In pure silica, when we used : ratio,a narrow distribution centered around . nm is observed,

while in : ratio material, bimodal behavior with a secondpeak at . nm occurs. Incorporation o drug causes poreocclusion limiting adsorptive access and reducing N2adsorp-tion. In ketorolac SiO2 : , a wide but small distributionrom to nm (inset) can be observed, in the other sample( : ) a minimal volume was adsorbed. Tese results arein agreement with observations made rom correspondingisotherms.

.. In Vitro Drug Release. Several mathematical models areused to evaluate the kinetics o drug release rom pharma-cological ormulations. Te model that best ts the obtaineddata is selected based on the correlation coefficient (r) value.


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100 200 300 400 500 600 700 800

80

85

90

95

100

Ref SiO2

Temperature ( C)

Ket SiO2

Weigh

t(%)

(a)

Temperature ( C)

100 200 300 400 500 600 700 80075

80

85

90

95

100

Weight(%

)

Ref SiO2

Ket SiO2

(b)

F : GA curves o (a) : and (b) : samples.

50 nm

(a)

20 nm

(b)

100 nm

(c)

50 nm

(d)

20 nm

(e)

10 nm

()

5 nm

(g) (h)

F : EM images o ketorolac-SiO2 : in the rst our images and o reerence-SiO2 : in the next our images.

Several attemptshavebeen made in orderto avoidadverseside effects rom oral administration o ketorolac, as the worko Genc and Jalvand [] where they used hydrophilic matrixand achieved a slow release during hours, another exampleis the use o microcapsules most o them made o Eudragit[], and release thedrug or no longer than hours. Releaseprole o both Ketorolac-SiO2samples is different rom eachother (Figure ). Te cumulative % drug release rom : was two times aster than : sample (Figure ). Tis isprobably due to more drug molecules being surace adsorbed

in ketorolac SiO2 : , and these are weakly bonded to thesilica surace, releasing them more easily, and hence releasetime is shorter. For ketorolac SiO2 : we observed that %o the drug was released afer hr. (Figure (a)).

In order to t data to mathematical models, we appliedve dissolution-diffusion kinetic models (zero-order, rst-order, Higuchi, Hixon-Crowell and hyperbola) and calcu-lated the corresponding kinetic parameters and linear corre-lation coefficients (2), these values are showed in ablesand.


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50 nm

(a)

50 nm

(b)

10 nm

(c)

10 nm

(d)

F : EM images o : (a), (b) Ketorolac-SiO2and (c), (d) reerence-SiO2.

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4 3.6 3.8 4

(keV)Full scale 9694 cts Cursor: 0

O

C

Si

Spectrum 1

(a)

O

Si

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5 9 9.5 10(keV)Full scale 21772 cts Cursor: 0

Spectrum 1

(b)

F : EDS spectra o Ketorolac SiO2 : (a) and Reerence SiO2 : (b).

In general, the zero-order-rst-order, Higuchi, andHixon-Crowel models are not suitable to explain the con-trolled drug release data obtained in this study. Te plotsdo not t linear relationships and also have low correlationcoefficients (2 . or both reservoirs; the rate o drug release shows ahyperbole not dependent on the concentration.

Te difference in drug release is not only attributed tothe presence o nanosized pores. Te presence o a smallamount o mesopores in the : material (in pure SiO2)implies that drug molecules can be occluded more easily inwider pores and release occurs aster than in microporescontributing to higher release rate. Also, during synthesis,considerable amount o adsorbed drug on particle suracemight contribute to drug release in the initial phase.


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: Linearization coefficients obtained rom in vitro release o Ketorolac rom SiO .

Reservoir Zero-order First-order Higuchi Hixon-crowel Hyperbola

= 0+ 0 =ln 0 1 = 1/2

1/30

1/3 = /( + )

Ketorolac SiO : . . . . .

Ketorolac SiO : . . . . .

: amount o drug released in timet.0: initial amount o drug in the tablet.0,1,,: release rate constants.b: shape parameter.a: scale parameter.

0 0.2 0.4 0.6 0.8 1

0

50

100

150

200

250

300

350

400

450

Adsorbedvol(

cm3/gSTP)

F : Nitrogen adsorption-desorption isotherms or the reser-voirs at different stoichiometric relation as ollows: () reerence-SiO

2 : , () ketorolac-SiO

2 : , () Reerence SiO

2 : , and

() Ketorolac SiO2 : .

1 10 100

0

0.1

0.2

0.3

0.4

0.5

10 20 30 40 50

0.01

0

0.01

0.02

0.03

0.04

0.05

SiO2 1 : 4Ket-SiO2 1 : 4

SiO2 1 : 8

Ket-SiO2 1 : 8

(nm)

F : Pore size distribution o the SiO2materials.

0 1 2 3 4 5 6 7 8

40

50

60

70

80

90

100

Disso

lution(%)

Time (h)

(a)

0 100 200 300 400 500 600 700 800

40

50

60

70

80

90

100

110

Dissolution(%)

Time (h)

(b)

F : In vitro release prole o ketorolac rom SiO2 : reservoir(a) rst hours and (b) ull time.

4. Conclusion

Te development o new pharmaceutical ormulations toenhance the therapeutic effect o conventional drugs is arising area. Most micro- and nanomaterial used or thispurposes are organic polymers; however since most o them


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0 0.5 1 1.5 20

20

40

60

80

100

120

Dissolution

(%)

Time (h)

F : Release prole rom SiO2 : .

: Drug release rates calculated or the different mathematicalmodels.

Mathematical model Ketorolac SiO : Ketorolac SiO :

Zero-order [%/h] . .

First-order [h] . .

Higuchi [%] . .

Hixon-Crowell [h] . .

Hyperbola [%/h] . .

are commercially available, less control over their physicaland chemical properties can be achieved. In order to bypasstheir limitations, alternative nanostructured materials likesilica can be used. We synthesized silica nanoparticles withketorolac or drug release. Te best molar ratio was : , since% o the drug is released atthe hours with a slower rateinthe ollowing hours reaching the % at the end o the time.Although : material released much aster, the behavior o : material was more homogeneous. Both systems representan alternative to deliver ketorolac in a more controlled way.Sol-gel process is a potential method to obtain designedmaterials with suitable characteristics to host a great varietyo molecules.

Acknowledgments

Te authors would like thank to Universidad AutonomaMetropolitana and National Institute o Neurology an Neu-rosurgery or acilities; special thanks to P. Castillo orEM studies also Project FONCICY-CONACY ornancial support.

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