NATIONAL INSTITUTE OF TECHNOLOGY WARANGAL

Department of chemistry A Seminar Talk On

“Ordered Mesoporous Materials for Drug Delivery”

BY VAMSI KATTA

2nd M.Sc. Analytical Chemistry (146956)

INDEX Abstract Introduction Definition Over View of Present Research Work on Mesoporous Materials for Drug

Delivery Drug/mesoporous-silica systems for sustained release of various drugs Types of Mesoporous Materials and Drug Delivery

– MCM-41 based mesoporous materials– SBA-based mesoporous materials– HMS-based mesoporous materials– MSU-based and other mesoporous materials

Drug release profile and the kinetics Effect of factors influencing the drug release Kinetics of drug release Stimuli-responsive control release system Biocompatibility of mesoporous silica/drug system Conclusion 1

Abstract: Mesoporous materials, which have unique pore size, higher

surface area and pore- volume, have been widely employed as carriers for controlled drug delivery.

Mesoporous silicas exhibit higher loading of drugs and provide a controlled drug release if modified by functionalisation.

Several mesoporous materials such as M41S, SBA, MSU and HMS in drug loading and release profile.

Two systems of drug delivery mechanism, sustained release and stimuli-responsive controlled release

Bioactivity of various mesoporous solids is also presented.

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Introduction Porous materials have been widely used as catalysts,

adsorbents, molecular sieves, ion exchangers and chromatographic agents in fine chemicals industry because of their particular properties such as uniform pore size, large surface area and flexible frameworks.

By the IUPAC, porous materials can be grouped into three classes based on their pore diameter (Ø):

microporous, Ø < 2.0 nm; mesoporous, 2.0 < Ø < 50 nm; and macroporous, Ø > 50 nm.

Zeolites are crystalline porous solids containing pores and cavities of molecular dimensions, cavities in the molecular size range of 0.3 to 1.5 nm.

M. Vallet-Regi, A. Ramila, R.P. del Real, J. Perez-Pariente, Chem. Mater. 13 (2001) 308–311. 3

Definition: A material can be recognized as porous if its internal voids can

be filled with gases. The history of porous materials began with the zeolites having

aluminoisilicates framework which was synthesized by the use single template molecule with small pore.

The Mobil scientist in the year of 1992 by successfully synthesizing the mesoporous materials (MCM-41 and MCM-48) by using soft template strategy

Z.Z. Li, L.X. Wen, L. Shao, J.F. Chen, J. Control Release 98 (2004) 245–254. 4

Over View of Present Research Work on Mesoporous Materials for Drug Delivery:

Owing to high chemical and thermal stabilities, large surface areas and good compatibilities with other materials, porous silica has also found wide application in adsorption, enzyme immobilization and drug delivery.

On the basis of silica-embedding and biocompatibility The new developed sol–gel technology offers the possibilities for

incorporating biologically active agents within silica gel and for controlling their release kinetics from the gel matrix.

In 2001 using MCM-41 as a new drug delivery system a lot of investigations have been done in this area.

Developing different types of mesoporous materials with varying porous structure and functionality for sustained drug released and stimuli-responsive release.

P.B. Malafaya, G.A. Silva, E.T. Baran, R.L. Reis, Curr. Opin. Solid St. Mater. 6 (2002) 283–295. 5

Mesoporous-silica systems for sustained release of various drugs:

Capable of releasing a carried bioactive agent in a specific location at a specific rate.

The aim of this type of system is to facilitate the dosage and duration of the drug effect,

- The minimal harm to the patient

- Improving human health - They allow for the reduction of the dosage frequency MCM-41 has been firstly employed as drug delivery matrix. MCM-41 shows hexagonal arrays of cylindrical mesopores.

C.T. Kresge, M.E. Leonowicz, W.J. Roth, J.C. Vartuli, J.S. Beck, Nature 359 (1992) 710–712. 6

The structure of the wall of the pores consists of a disordered network of siloxane bridges and free silanol groups that could act as reacting nuclei against appropriate guest chemical species, behaving as a matrix for controlled adsorption and liberation of organic molecules.

Other groups of mesoporous materials with larger pore size such as SBA including SBA-15, SBA-16, SBA-1, SBA-3, HMS and MSU were also used for drug delivery.

In those new drug/mesoporous-solid systems, ibuprofen, an anti-inflammatory agent, is the widely tested drug, other drugs are also employed

P.B. Malafaya, G.A. Silva, E.T. Baran, R.L. Reis, Curr. Opin. Solid St. Mater. 6 (2002) 283–295. 7

M. Vallet-Regi, A. Ramila, R.P. del Real, J. Perez-Pariente, Chem. Mater. 13 (2001) 308–311. 8

Mesoporous solid SBET

(m2/g)Pore diameter (Å)

Drug Loading (wt %)

MCM-41 1157 36 Ibuprofen 34Si-MCM41-A 1024 35.9 Aspirin 3.88Si-SBA-15 787 61 Gentamicin 20.0Si-SBA-15 787 88 Erythromycin 34Si-SBA-15 602 86 Bovine serum

albumin9.9

Si-SBA-15 787 49 Amoxicillin 24SBA-3 1000 26 Ibuprofen 33SBA-1 1000 18 Ibuprofen 25SBA-16 490 85 ZnNIA 14.3SBA-16 490 85 ZnPCB 18.3MCM-48 1166 36 Ibuprofen 28.7MCM-48 1166 36 Erythromycin 28.0

MCM-41 based mesoporous materials: The first investigation using Si-MCM-41 for drug delivery system

was reported by Vallet-Regi and her colleagues.Two kinds of MCM-41 with different pore sizes were

tested and the drug employed is ibuprofen.

Study of influence of pore size of MCM-41 materials on drug delivery rate revealed that ibuprofen in SBF solution decreased as the pore size decreased in the range of 2.5–3.6 nm.

Four anti-inflammatory agents such as diflunisal, naproxen, ibuprofen and its sodium salt have been used and performed at pH 1.1 and 6.8

I. Izquierdo-Barba, A. Martinez, A.L. Doadrio, J. Perez-Pariente, M. Vallet-Regi, Eur. J. Pharm. Sci. 26 (2005) 365–373. 9

The drug-loading amount is correlated to the BET surface area and surface hydrophilicity and hydrophobicity of the MCM-41.

While drug release profiles could be controlled by tailoring the surface properties and pore size.

MCM-48 and LP-Ia3d have recently attracted much attention due to their unique penetrating bicontinuous channels networks

–easy molecular accessibility and fast molecular transport.

F.Y. Qu, G.S. Zhu, S.Y. Huang, S.G. Li, S.L. Qiu, Chemphyschem 7 (2006) 400–406. 10

Izquierdo-Barba et al. investigated MCM-48 and LP-Ia3d with ibuprofen and erythromycin systems for delivery studies and results showed that are good carriers for drug delivery.

Organic modification of the silicates permits precise control over the surface properties and pore sizes of the mesoporous sieves for specific applications.

It is generally found that functionalisation usually will affect the adsorption and delivery.

Organic modification with aminopropyl group of two MCM-41 materials having different pore sizes was carried out in order to control the delivery rate of ibuprofen from the siliceous matrix.

I. Izquierdo-Barba, A. Martinez, A.L. Doadrio, J. Perez-Pariente, M. Vallet-Regi, Eur. J. Pharm. Sci. 26 (2005) 365–373. 11

SBA-based mesoporous materials:

SBA-15 is another important mesoporous material with large, controlled pore size and highly ordered hexagonal topology. The pore size of SBA-15 is usually 6 nm in diameter, larger than the 3 nm pore of MCM-41.

Therefore, SBA-15 is expected to have less restriction for the delivery of bulky molecules.

Doadrio et al. investigated SBA-15 for application as gentamicin drug delivery system.

To evaluate the delivery calcined powder and disk conformed. No significant difference between the powder and disk was observed in the tests

A.L. Doadrio, E.M.B. Sousa, J.C. Doadrio, J.P. Pariente, I. Izquierdo-Barba, M. Vallet-Regi, J. Control Release 97 (2004) 125–132. 12

Vallet-Regi et al. also tested the antibiotic amoxicillin with a calcined SBA-15 material. Dependent upon the solvent, pH, and amoxicillin

concentration, reaching a value of 24 wt% under optimum conditions.

Doadrio et al. then reported functionalisation of SBA-15 for controlling drug delivery.Compared calcined samples and the samples functionalized

with long alkyl chains such as OTMS and ODTMS in delivery patterns.

The samples were charged with the macrolide antibiotic erythromycin, observed the release rate decreases as the population of hydrophobic –CH2 moieties in the host increases.

M. Vallet-Regi, J.C. Doadrio, A.L. Doadrio, I. Izquierdo-Barba, J. Perez-Pariente, Solid State Ionics 172 (2004) 435–439. 13

Song et al. also reported mesoporous SBA-15 materials functionalised with amine groups through post synthesis and one-pot synthesis as drug matrixes. Ibuprofen (IBU) and bovine serum albumin (BSA) were

selected as model drugs and loaded onto the unmodified and functionalised SBA-15.

adsorption capacities- on the different surface properties of SBA-15 materials.

The release rate of ibuprofen from the SBA-15 functionalized by post synthesis - effectively controlled.

one-pot synthesis due to the ionic interaction between carboxyl groups in ibuprofen and amine groups on the surface of SBA-15.

J. Andersson, J. Rosenholm, S. Areva, M. Linden, Chem. Mater. 16 (2004) 4160–4167. 14

HMS-based mesoporous materials

Zhu et al. reported a facile route for preparation of HMS and employed for drug storage and delivery using ibuprofen. – They compared the drug loading with MCM-41 and found

that the HMS exhibited much more storage capacity than MCM-41

– Higher storage amount of aspirin than conventional MCM-48 and MCM-41 due to its higher surface area and pore volume with hollow core structure.

– Release process of HMS–aspirin, MCM-48–aspirin and MCM-41–aspirin were found to have a sustained-release property and followed a Fickian diffusion mechanism.

Y.F. Zhu, J.L. Shi, H.R. Chen, W.H. Shen, X.P. Dong, Turret Mat. 84 (2005) 218– 222. 15

They then investigated the functionalized hollow mesoporous silica spheres using N-TES,NN-TES and NNN-TES for ibuprofen drug storage and release.

Highest storage amount of 969 mg/g had been obtained by using hexane as solvent and sustained-release property.

With the increase of the amount of functional groups introduced, the drug storage capacity decreases and meanwhile the release rate become lower.

At the same amount of functional groups, the release rate from NNN-HMSC–ibuprofen system is the lowest.

Y.F. Zhu, J.L. Shi, Y.S. Li, H.R. Chen, W.H. Shen, X.P. Dong, J. Mater. Res. 20 (2005) 54–61. 16

MSU-based and other mesoporous materialsTourne-Peteilh et al. employed MSU for the storage of drug pentapeptide. – They found that pentapeptide could be encapsulated in the

mesoporous silica and would be released instantly upon the solid washing with DMF.

– Investigation on preparation of MSN materials with various particle morphologies, including spheres, ellipsoids, rods, and tubes, using room-temperature ionic liquid (RTIL).

– These materials were then used as controlled-release delivery nanodevices to release antibacterial ionic liquids against Escherichia coli K12.

– Dependent on the rate of diffusional release of the pore encapsulated RTIL, which was governed by the particle and pore morphology of the MSN materials.

V.P. Lehto, K. Vaha-Heikkila, J. Paski, J. Salonen, J. Therm. Anal. Calori. 80 (2005) 393–397. 17

Drug release profile and the kinetics

Several issues are of interest regarding this new property of mesoporous materials and all of them point to the possibility of gaining control over the releasing pattern of the guest drug, a critical parameter for clinical applications.

Several factors could affect the release profile of the hosted molecule, the nature of the host–guest chemical interaction and the pore size of the matrix among them.

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Effect of factors influencing the drug release

• It has been found that two factors could affect drug/matrix interaction

– the structure of pore wall surface– the functional groups present in the organic

molecule. • Effect of pore size, smaller pore size will restrict the adsorption

and release of drug molecules.• The dynamic release of ibuprofen from MCM-41 synthesized

with different carbon chain of surfactants and pore size. It is shown that delivery rate decreased with the decreasing pore size for ibuprofen/MCM-41 system.

A. Ramila, B. Munoz, J. Perez-Pariente, M. Vallet-Regi, J. Sol–Gel Sci. Technol. 26 (2003) 1199–1202. 19

Babonneau et al. employed 13C and 1H solid state NMR spectroscopy to characterize ibuprofen encapsulated in mesoporous MCM-41 type-silica functionalized or not by amino groups.

High mobility of the ibuprofen molecules when the matrix is not functionalized, which suggests the absence of any interactions between the ibuprofen molecules and the silica surface, despite the presence of a COOH function.

On the contrary, when the silica matrix was functionalized by amino groups, the 13C NMR experiment indicated a more restricted mobility of the ibuprofen molecules suggesting possible interactions between the amino groups and the carboxylic groups.

P. Horcajada, A. Ramila, J. Perez-Pariente, M. Vallet-Regi, Micropor. Mesopor. Mat. 68 (2004) 105–109. 20

Release of ibuprofen from organic functionalized SBA-15 prepared by different methods, PS0, PS2, and OPS2

Kinetics of drug release

Higuchi was the first to derive an equation to describe the release of a drug from an insoluble matrix as the square root of a time-dependent process based on the Fickian diffusion,

» = – Qt is the amount of drug released in time t– D is the diffusion coefficient– S is the solubility of drug in the dissolution medium– ε is the porosity, – A is the drug content per cubic centimeter of matrix tablet,

and– kH is the release rate constant for the Higuchi model.

In general, the Higuchi model is valid for the systems where drug concentration is much higher than drug solubility.

H. Li, G.P. Yan, S.N. Wu, Z.J. Wang, K.Y. Lam, J. Appl. Polym. Sci. 93 (2004) 1928– 1937. 21

Korsmeyer–Peppas model as follows.

Mt and M∞ denote the cumulative mass of drug released at time t and at infinite time

k is the proportionality constant and n is the release index.

n > 0.5 - non-Fickian diffusion n = 0.5 Fickian diffusion mechanism. n = 1 provides Case II transport mechanism in which

drug release from hydrogel of slab geometry will be of zero order.

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(○) MCM-41a ( ) c-MCM-41a; ( ) mSBA-3; ( ) μSBA-1; (●) μSBA-3▿ ■ ♢

MCM-41 > SBA-15 > MCM-48 > HMS.

Stimuli-responsive control release system• The stimuli-responsive controlled-release system can achieve a

site-selective, controlled-release pattern, which can improve the therapeutic efficacy

• Fujiwara and co-workers accomplished, for the first time, the photo controlled reversible release of drug molecules from coumarin-modified MCM-41

J.A. Gruenhagen, C.Y. Lai, D.R. Radu, V.S.Y. Lin, E.S. Yeung, Appl. Spectrosc. 59 (2005) 424–431. 23

REFERNCES 24

Cumulative drug release from the two systems in release media of different pH values. : pH 1.4 from ibuprofen–HMS, ■ ●: pH 1.4 from ibuprofen–HMS/@PEM, : pH 8.0 from ibuprofen–HMS,▴ : pH 8.0 from ▾ibuprofen–HMS@PEM.

C.Y. Lai, B.G. Trewyn, D.M. Jeftinija, K. Jeftinija, S. Xu, S. Jeftinija, V.S.Y. Lin, J. Am. Chem. Soc. 125 (2003) 4451–4459. 25

Schematic illustration of two drug-delivery systems which give the different controlled-release patterns

Biocompatibility of mesoporous silica/drug system:

Biodegradability and biocompatibility are the fundamental requirements that determine the possible therapeutic and surgical applications of a polymeric biomaterial.

For mesoporous silica-based drug system, bioactivity is also an important issue for its potential application.

Gomez-Vega et al. first investigated the bioactivity of mesoporous silica films coated on Ti6Al4V.

N.K. Mal, M. Fujiwara, Y. Tanaka, Nature 421 (2003) 350–353. 26

Giri et al. also investigated the biocompatibility of magnet/MSN stimuli-responsive controlled-release system with HeLa (human cervical cancer) cells.

Lately, Yan et al. have synthesized highly ordered mesoporous bioactive glasses (MBG), which showed higher bioactivity than conventional sol–gel bioactive glasses.

It was found MBG had higher ability to induce hydroxyapatite formation and the drug loading was higher. The drug release was sensitive to the pH and ionic concentration.

S. Giri, B.G. Trewyn, M.P. Stellmaker, V.S.Y. Lin, Angew. Chem. Int. Edit. 44 (2005) 5038–5044. 27

Conclusion Ordered mesoporous silica with stable mesoporous structure,

large surface area, good biocompatibility and tailored size of mesoporous and functionalization has exhibited promising application as controlled drug delivery system.

Higher drug loading and controlled sustained release as well as responsive release under certain external stimuli such as light, magnetite, chemical, pH and temperature. Among various mesoporous silicas, HMS silica exhibits the highest drug loading.

Biocompatible and bioactive mesoporous materials with controlled drug delivery will favour the cellular growth and bone regeneration

Future work should be directed to development of non-immunogenic polymer/mesoporous solid as drug carrier, which will show more advantages than glass-polymer systems.

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AcknowledgementThanks to

Dr. Venkatathri NarayananAssistant ProfessorDept. of Chemistry

NIT Warangal

Thank you