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A Review on The Use of Mesoporous Silica Nanoparticles in the Sustained ReleaseFormulation of Ibuprofen

Abstract

Many studies have been conducted on the mesoporous silica nanoparticle (MSN) and its

application in the drug delivery system. Reports show that MSN can act as controlled-release drug

delivery at efficient rates. Furthermore a lot of recent research was highlighted on the synthesis of

MSN and how the modification of MSN can contributed to the controlled-release of !buprofen since

!buprofen is one of the top analgesics drugs being used. "ontrolled-release medicine has much more

advantages compared to the conventional tablets. #he sustained-release form of drug can reduced the

fre$uency of drug administration and increased patience adherence. !n the present wor% there are

many modification has been done on the mesoporous silica for e&ample the particle si'e of

!buprofen pore si'e of silica the morphology of silica and the surface modification of the silica.

#herefore we will review on how the changes of these factors of MSN will affects the controlled-

release of !buprofen.

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1.0 Introduction

!buprofen is widely used as NS! (non-steroidal anti-inflammatory drug) and has been for

more than *+ years ago. #he drug is a propionic acid derivative NS! as seen in figure , (dams

et al ,/). !n ,+s !buprofen was developed to treat rheumatism. Nowadays the !buprofen is

first choice therapy for osteoarthritis and chronic bac% pain (riessens ,*). #he primary

mechanism of !buprofen is to inhibit prostaglandin synthesis. #he S-(0)- !buprofen was reported ,+

times more potent in inhibiting prostaglandin compared to R-(-)-!buprofen during in-vitro

study(dams et al ,/). 1ral formulation such as conventional tablets and sustained-release tablets

are the most common !buprofen administration although other forms are available.

!buprofen is type !! 2S" (2iopharmaceutic "lassification System) has high permeability but

low solubility. #he mechanism of !buprofen is depending on "ycloo&ygenase pathway in which the

!buprofen inhibit the synthesis of 3rostaglandin. !buprofen has a short half-life between , to 4 hours.

2

Figure 15 "hemical structure of

!buprofen

(2ushra 6 slam 7+,+)

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#he short half-life causes the drug to be ta%en at a fre$uent time. 2y incorporating !buprofen in the

MSN not only the solubility of !buprofen will increase but also can treat diseases more efficiently.

Mesoporous silica (MS) which combines the uni$ue properties of nanomaterials and

mesostructured substances are especially promising in gas adsorption sensing catalysis and drug

delivery due to their pore accessibility and rapid molecular diffusion. Since mesoporous M*,S

family has been discovered by the Mobil 1il "ompany in ,7 several novel types of mesoporous

silica materials such as S2-,8 M"M-*9 and MS: have been developed by using template-

assisted method (;resge et al ,7).

MSN has several advantages. Mesoporous silica showed advantages over conventional drug

carriers for desired drug delivery because of their stable mesoporous structures uniform and tunable

pore si'es high silanol-containing surface areas and volumes easily modified surface non-to&ic

nature as well as good biocompatibility. 1ne of the highlighted factors in the modification of MSN

is the pore si'es. #he pore si'e will determined the amount of drug loading and drug release rate

(<imnell 7+,,).

M*,S FSM #: MS: and S2 are the various mesoporous silica that produced for drug

delivery system (S). M"M-*, was synthesi'ed from M*!S family in ,7 by Mobil "orporation

and was proposed to be used in drug delivery system (;resge et a!. ,7). M"M-*, is the most

fre$uently used mesoporous silica nanoparticle (MSN) because they have ordered he&agonal

molecular sieve with large surface are (=,+++ m7>g) high pore volumes (= +./ cm4>g) and a very

uniform pore structure (pore diameter 7-4 nm) (2ec% et a!. ,7? ;resge et a!. ,7). M"M-*, was

incorporated with many pharmaceutical ingredients such as ibuprofen (@allet-Regi et a! 7++,?

ndersson et a!. 7++*? "harnay et a!. 7++*) vancomycin aspirin napro&en and many more drugs.

#heir potential application were not limited to pharmaceutical drug but also for protein anti-

cancer drugs and many more. M"M-*9 is another type of MSN which is cubic ordered silica

materials and has been used for the immobili'ation of protein and to encapsulate small molecule

drugs. FSM- type mesoporous silica is also used to encapsulate #a&ol an anticancer medicine.

1ther than that #:-, was study as S by using !buprofen as model drug and the Aei%%ilaBs

study shown that high amount of !buprofen can be loaded and high efficiency compared to M"M-*,

and M"M-*9. #he #:-, material also has better drug dissolution profile and more diffusion than

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M"M-*, materials (Aei%%ila 7++/). S2 is another mesoporous silica that has 7 he&agonal shaped

mesoporous silica which is also used as Ss. #he drug release %inetics was related to

morphologies and pore si'es of mesoporous silica (Cu et a!. 7++). #he higher or lower drug

molecule >pore si'e ratio are problems to incorporate large amount of drugs for S.

#he conventional !buprofen tablet was compared with the sustained D release !buprofen

(2rufen Retard) on the aspects of efficacy and tolerability (Flavell ,4). #his study revealed that

the SR formulation reduced the day and night pain Eoint tenderness and 3aracetamol consumption.

#he 2rufen retard showed tolerable effects on the patients and has similar adverse event. ;halifa

research in 7+,* showed that the * of the osteoarthritis patients in Ggypt report significant

improvement in their conditions with the treatment of !buprofen Sustained-release (SR). #he

severity of symptoms such as Eoint tenderness pain and morning stiffness reduced from the

treatment. #he medication also reported of 9. of patient compliance.

Objectives:

,. #o review the use of silica as SR of !buprofen

7. #o identify on how the characteristics such as pore si'e of Silica can help in the SR of

!buprofen

4. #o obtain data on the use of Silica as SR of !buprofen

!

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2.0 Literature Review

ccording to Shen (7+,,) !buprofen (!2:) was co-spray dried with mesoporous silica

materials having different pore si'es and particles si'e for dissolution progress.(Shen et al 7+,,) #he

particle si'e of mesoporous silica materials did not have any effect on the dissolution of !2: while

the pore si'e does affecting the physical state of !2:. morphous !2: was obtained when the !2:

was co-spray dried with pore si'e below ,+nm whereas the nanocrystalline !2: was obtained when

the !2: was co-spray dried with pore si'e above 7+nm. #he results is very important due to the fact

that amorphous !2: has higher dissolution rate than nanocrystalline !2:. #he amorphous !2:

displayed high dissolution rate and the pore si'e only contributed little to the rate of dissolution.

<arger particle si'e of !2: e&hibited slower rate of drug release from S2-,8.

#he factor of particle si'e dispersancy of mesoporous spheres in the controlled-release of

!2: with mesoporous silica spheres was studied by Hu (7++). #he study also investigate the effect

of adding of hydrophobic trimethylsilyl (#MS) group on the surface of mesoporous silica spheres to

the rate of drug release. #he pore si'e distribution and pore channel geometry were fi&ed during the

e&periment. #he results shown that the #MS hydrophobic group can delay the drug release. #he rate

of drug release alos decreased with the increase of particle si'e of mesoporous silica.

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#he potential of amorphous microporous silica (MS) for !2: controlled release was studied

by erts 7+,+. #he MS was synthesi'ed in acid-cataly'ed sol-gel process and various MS particle

si'es was created. fter that the drug was loaded into the MS by heat treatment and melt

impregnation. #he MS produced were MS788 MS79+ and MS777+ in which the particle si'e are

increasing in the respective order. #he MS788 has the smallest particle si'e and the study shown that

the particle si'e is too small for sustained-release !2:.

1rdered mesoporous silica materials incorporated with !2: was studied by Santamaria in

7+,*. #he study was done to investigate the benefit of macroporous in the mesoporous silica and

how it will affects the rate of !2: release. !n definition ordered mesoporous silica refers to silica

with 7-8+ nm of pore diameters and possesses long-range order. #he presence of macroporous in the

mesoporous silica increase the mass transport and reduced limitation of diffusion. #he results shown

that the macroporous materials helps the sustained-release of drug and decrease the burst effect.

#he role of !2: in regulating the morphology of porous silica nanospheres during its in situ

encapsulation was studied in 7++ by u. #here are two drug can loaded into the porous silica which

are conventional post-loading and in situ encapsulation. #he in situ encapsulation is much preferred

over the other method due to the simplicity and time-saving. !n the wor% the in situ encapsulation of

!2: in the silica matri& was done by emulsion sol-gel method. From the e&periment it can deduced

that the !2: has a strong electrostatic interaction with "#I and acts as co-surfactant to regulate the

morphology of silica nanospheres.

2esides that mesoporous silica can be further modified to produce dual-stimuli-responsive

drug delivery system with magnetic oriented target and pA-sensitive characters.(Hing et al 7+,7)

#he superparamagnetic properties of mesoporous silica can be directed to the targeted organs or

#

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locations inside the body. #his will allow ma&imum therapeutic efficiency and not damaging the

other tissue due to drug to&icity. #he pA- sensitive character of mesoporous silica is due to the

Gudragit-S,++ that provide drug release at pA /.* and can be used for colon drug delivery.

Surface modification also plays a critical role for the release of !2:. MGS1, and MGS17

release only *+ 1F !2: after 8 hour while S2-,8 release more than 9+ after 8 hours. #he

loading capacity of amine-functionali'ed mesoporous silica was increased due to the modification

and MGS1, has the highest loading capacity. #hus the amine-functionali'ed of mesoporous silica

can increase drug loading capacity and provide sustained-release formulation at the same time (<ee

7+,+).

nother study was done to introduce #MS on the surface of mesoporous silica to produce

controlled-release drug delivery. #he present of #MS can greatly delay the !2: release from

mesoporous silica (#ang 7++). #he in-vitro release e&periment showed that only /8 1F !2:

release from the #MS mesoporous silica after *9 hour but the !2: with only mesoporous silica was

released completely after , hour. Furthermore the increase in grafting of #MS will further reduce

the rate of drug release from silica.

#he MSN synthesi'ed with different microwave power shown different crystal growth and

the evaluation of drug release was done after the MSN was loaded with !2:.(;amarudin et al.

7+,*) #he MSN with *8+ Jatt Microwave power has the highest crystallinity and give more ordered

mesoporous silica. !t can be seen that the microwave power will affects the crystal growth. Aigh

heating power causes the mesoporous silica to have high surface area and slowing the drug release

rate. Aence MSN*8+ has the largest surface area and the lowest rate of drug release.

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<ang 7+,7 studied the pharmacology of !2: after release from M"M-*,. M"M-*, is a pure

mesoporous silica with pore si'e of 7.4-7./ nm and capable to be used in drug delivery system. #he

pharmacology of !2: was investigated using "1H-, inhibitory activity. #he increase in "1H-,

inhibitory activity can be translated as the increase of pharmacology activity of !2:. #he release

study shown that !2: loaded with M"M-*, give similar release rate as the standard !2:. #hus

M"M-*, can be used as !2: sustained-release as it can provide efficient drug delivery system and

high therapeutic efficacy (Fin 7+,7).

study in the year 7++ regarding the influence of mesoporous structure type on the

controlled delivery of drugs and the release of !2: from M"M-*9 S2-,8 and functionali'ed

S2-,8. (Gdesia et al 7++) M"M-*9 has 7-he&agonal structure while S2-,8 has 4-cubic

structure. #he result shown the various mesoporous structure does not affect the rate of !2: release

from mesoporous silica. #he S2-,8 was modified by adding octadecyltrimetho&ysilane on the

surface of S2-,8. #he functional group made the S2-,8 became hydrophobic and causes faster

drug release from the mesoporous silica.

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3.0 Discussion

!2: release from mesoporous material is divided into two stages which are called

burst effect and slow release. #he burst effect caused the release of of !2:. #he effect is due to

easily accessible of physically adsorbed !2: and the second stage is due to the slow diffusion of

!2: from mesochannels to the media along the macroporous channels. #he burst effect continued to

decrease as the macropore material with a dispersed phase increased. #his is because compare to the

mesoporous channel the macropores channel has an additional diffusion barrier (Santamaria 7+,4).

3.1 Siica !artice Si"e

Figure , display the dissolution profile from in-vitro studies. !2: was loaded onto these two

types of mesoporous e&cipients by co-spray drying with the ratio of 8+58+ (w>w). !n terms of

3hysical state the rod-li%e S2-,8 nanoparticles has higher dissolution rate compared to fiber

shaped S2-,8 even though they have similar particle si'e (Shen 7+,,). #he effects is to the

difference in length of pore channels. Short length of pore channels will lead to the decrease the

diffusion resistance for !2: release to the dissolution medium. #he effect of particle si'e is lesser

than the effect of physical state. #he dissolution of nanocrystalline form of !2: (!2:>S2-,8-<3)

has slower dissolution rate compare to amorphous form solid dispersion (!2:>M"M-*, and

!2:>S2-,8).

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Figure 2: #he dissolution

profile of !2: from

!2:>M"M-*, !2:>S2-

,8 !2:>S2-<3 and

untreated !2: crystal.

(Shen 7+,,)

Figure 35 #he release profiles of

!2: from mesoporous spheres in

S!F5 (a) MS, (b) MS7 (c) MS4

and (d) MS-

(Hu 7++9)


3.2 Siica !ore Si"e

#he results from figure 7 shown that large mesoporous spheres had slower drug release rate.

#he larger the mesoporous spheres the longer the time from drug molecules to diffuse into release

medium. 2esides that small spheres possessed large e&ternal surface (Hu 7++9). rugs that

adsorbed in smaller mesoporous spheres would have more chance to diffuse into release fluid. #hat

is why the drug will spends less time than is larger mesoporous spheres. MS- (++nm) has slower

release rate of !2: compared to MS-7 (/8+nm). #he agglomeration of MS- can reduce the

interface between agglomerate spheres and release medium.

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!2: released from MS7 materials was analy'ed in both acidic and neutral condition. #he

MS7 creates a pattern in which the smaller the particle the faster the release of !2:. MS7 9+

release 78 of !2: after one and a half hours *+ after pA .9 and slower release after that. t 9

hours the cumulative release of MS79+ was 97 (erts 7+,+). !n the first hour !2: is released

slowly due to large pores. #here may have been local supersaturation in the fluid film around the

particles causing the pore bloc%age. #hen !2: was much better soluble in higher pA. MS777+

release 4+ of !2: after * hours and 7 after 9 hours.MS777+ e&perience minimal precipitation.

MS788 release !2: very fast in acidic medium and reached ,++ in neutral condition. #herefore

MS788 should not be used for sustained release since the !2: release rate is too fast.

3.3 Sur#ace $odi#ication

#he release of !2:>MMSNs-, and !2:>MMSNs-7 coated and uncoated with ,+ wt

GudragitS-,++ in SKF and S!F respectively (Hing 7+,7). #he amount of !2: released when coated

with GudragitS-,++ is almost a half than uncoated system. #he GudragitS-,++ restrain the drug

release but when the dissolution of GudragitS-,++ occurred the final amount of drug release by the

coated system is similar with the uncoated system. Moreover the drug release of !2:>MMSNs-,

and !2:>MMSNs-7 with GudragitS-,++ is faster is S!F than SKF.

#he release of !2: with modified M*, also showed slow drug release compared to

unmodified M*,. For normal M*,0 !2: the drug release almost completely after , hour but

modified M*, re$uired 9 and 79 hours to reach + of drug release (#ang 7++). #he hydrophobic

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effect derived from #MS group on the mesoporous silica surface is one of leading cause of slower

drug release. #he hydrophobic group retard the process of fluid into the mesoporous channel and

delay the dissolution of !2: out of the mesoporous channels. So it has been proven that by increase

the amount of #MS on mesoporous silica the !2: release rate is decreased.

#he surface modification was done on MGS1 and S2-,8 particles and increased the pore

si'e by adding amine functional group on the surface of mesoporous silica. MGS1, has the highest

loading capacity while S2-,8 has the lowest loading capacity. t pA * the release rate of !2: in

S2-,8 was the slowest compared to MGS1, and MGS17. t pA /.* !2: release for all systems

was the fastest even though the release of !2: of MGS1, and MGS17 was half of S2-,8 drug

release after 8 hours. #he solubility of !2: increase with pA and conse$uently the drug release rate

increase with the increasing pA. S2-,8 particles showed much faster drug release because the

cylindrical pores of S2-,8 provide easier access for !2: than the tortuous pores of MGS1, and

MGS17 (<ee 7++).

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%.0 &oncusion

#he in-vitro release of !2: has proven that the release of drug from mesoporous silica has

two stages which are burst effect and slow release. #he dissolution rate increased with the decrease

diffusion resistance of the silica pore channel. !2: with small mesoporous spheres has large surface

area thus allowing more mesoporous silica to diffuse into the release fluid and the dissolution rate

increase. #he solid state of !2: also determined the dissolution rate. For e&ample the amorphous

form of !2: has higher dissolution rate compared to nanocrystalline. Nanocrystalline form of !2:

has larger particle si'e and thus longer diffusion pathway. high potential of mesoporous silica

carrier of !2: can be produced by adding amine functional group or agglomeration on the surface

the drug release of !2: from mesoporous silica can be prolong. #he limitation of this research is the

lac% of testing all types of MSN in single e&periment.

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1!

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