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J. DRUG DEL. SCI. TECH., 23 (6) 619-621 2013

Mechanism of gentamicin sulphate release in nanocomposite hydrogel drug delivery systems

M. Sirousazar

Faculty of Chemical Engineering, Urmia University of Technology, PO Box 57166-419, Urmia, Iran *Correspondence: m.sirousazar@uut.ac.ir

A series of nanocomposite hydrogel drug delivery systems on the basis of polyvinyl alcohol and organically modified montmorillonite nanoclay loaded with gentamicin sulphate were prepared via the cyclic freezing-thawing method. The drug release kinetics and mechanism of the prepared drug delivery systems were determined in vitro. The results showed incorporating organically modified montmorillonite into the polyvinyl alcohol hydrogel matrix reduces the amount of released gentamicin sulphate from the system and prolongs the drug release duration. The results revealed the gentamicin sulphate release from the nanocomposite hydrogels is more prolonged with slower rate compared to the pure polyvinyl alcohol hydrogel. The results also indicated the gentamicin sulphate release mechanism for all nanocomposite hydrogel drug delivery systems is Fickian diffusion which means the gentamicin sulphate diffusion is the controlling step in the release process.

Key words: Nanocomposite hydrogel – Drug delivery – Release mechanism – Gentamicin sulphate – Nanoclay – Polyvinyl alcohol.

Nanocomposite hydrogels are reinforced three-dimensional networks consisting of at least a cross-linked polymeric matrix and a nanoscale reinforcing agent, e.g., nanoparticle, which are swollen with water or aqueous solutions [1, 2]. Different kinds of nanoparticles, such as gold, silver, carbon nanotubes, and various types of clays, e.g., laponite, montmorillonite, and kaolinite have been used successfully in production of nanocomposite hydrogels [3-11]. In recent years, nanocomposite hydrogels have been created for novel applications in different practical areas such as sensor-actuator and bio-actuator systems, oil recovery, biomedical scaffolds, wound dressing devices, and controlled drug delivery systems [12-20]. Controlled drug delivery systems, which are intended to deliver drugs or any other active agents with predetermined release profiles for predefined periods of time, are utilized to overcome the shortcom- ings of conventional drug formulations [21, 22]. Most controlled drug delivery systems consist of at least of two essential components of a drug and a drug carrier. Some main targets of these systems are to: maintain drug levels within a desired therapeutic range to obtain maximum drug efficacy; to deliver the drug locally to specific sites of the body; to avoid possible toxicity; to minimize side effects; to increase patient comfort by decreasing the dosing frequency; and also to reduce manufacturing costs [23-25]. Previously, nanocomposite hydrogels on the basis of polyvinyl alcohol (PVA) and organically modified montmorillonite (OMONT) nanoclay have been prepared via the cyclic freezing-thawing method [8,19]. Due to the excellent physical, mechanical, and chemical prop- erties of the freeze-thawed PVA-OMONT nanocomposite hydrogels, they have been introduced as novel wound dressing devices and their performance investigated both in vitro and in vivo [19, 20]. However, they have not been used for controlled drug delivery applications. In this work, drug delivery systems on the basis of PVA-OMONT nanocomposite hydrogels loaded with gentamicin sulphate were prepared via the freezing-thawing method. The drug release kinetics of the prepared nanocomposite hydrogel drug delivery systems along with the drug release mechanism were determined in vitro. PVA, having a degree of polymerization of 1700 and a saponi- fication value of greater than 98 %, was purchased from the Nippon Synthetic Chemical Industry Co. Ltd., Japan. Natural montmorillonite (MONT) clay was obtained from Zhejiang Fenghong Clay Chemicals Co. Ltd., PR China. This clay has exchangeable sodium ions, and a cation exchange capacity of 100 meq/100 g. Cetyltrimethylammonium

bromide (CTAB) was obtained from Dishman Pharmaceuticals and Chemicals Ltd., India. Gentamicin sulphate, o-phthaldialdehyde, 2-mercaptoethanol, and sodium borate were purchased from Sigma Chemical Co. Ltd., United States. Potassium hydrogen phosphate, di-sodium hydrogen phosphate, sodium chloride, and isopropanol were purchased from Merck, Germany and used as received without further purification. Phosphate buffered saline solution with a pH of 7.4 was prepared by dissolving 2.38, 0.19, and 8 g of anhydrous di-sodium hydrogen phosphate, potassium hydrogen phosphate, and sodium chloride, respectively, in 1,000 mL of deionized water, according to the British Pharmacopoeia [26]. Since gentamicin sulphate does not absorb ultraviolet or visible light, the routine spectrophotometric methods could not be used to quantify this aminoglycoside antibiotic. Derivatizing agents such as o- phthaldialdehyde are usually utilized to overcome this problem. It reacts with the amino groups of gentamicin sulphate to yield chromophoric products. The procedure for preparation of o-phthaldialdehyde reagent has been described elsewhere [27]. Briefly, the o-phthaldialdehyde reagent was prepared by adding 2.5 g of o-phthaldialdehyde, 62.5 mL methanol and 3 mL of 2-mercaptoethanol to 560 mL sodium borate (0.04 M) in deionized water. The reagent was stored in a brown bottle in darkness and settled for at least a day prior to use. Nanocomposite hydrogel based drug delivery systems loaded with gentamicin sulphate were prepared using PVA as the hydrogel matrix reinforced with OMONT nanoclay via freezing-thawing cyclic method. The organically modification of MONT in order to achieve the OMONT was performed using CTAB as modifier according to the previously reported procedure [19]. In order to prepare the drug delivery systems, aqueous solutions containing 15 wt % of PVA and 0, 2, 5, 7, and 10 wt % of OMONT (based on the mass of PVA) were prepared in deionized water by mixing and heating at 90 °C for 4 h to achieve uniform solutions. Each solution was then cooled to room temperature and an adequate amount of gentamicin sulphate added with continuous stirring to obtain a completely dissolved solution with 10 wt % gentamicin sulphate, based on the mass of PVA in sample. Subsequently, all solutions were poured into flat moulds and placed at -20 °C for 24 h to accomplish the freezing process. Then the samples were allowed to thaw at room temperature for another 24 h. This cyclic freezing-thawing process was repeated three times for each sample. The obtained nanocomposite hydrogel drug delivery systems were

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J. DRUG DEL. SCI. TECH., 23 (6) 619-621 2013

Mechanism of gentamicin sulphate release in nanocomposite hydrogel drug delivery system M. Sirousazar

Table I - Designations, chemical compositions and gentamicin sulphate release characteristics of prepared drug delivery systems.

Designation

PVA

OMONT (wt %, PVA based)

Gentamicin sulphate (wt %, PVA based)

PBS

n

K

(wt %)

(wt %)

PVA

15

0

10

83.50

0.33

0.78

2% OMONT

15

2

10

83.20

0.40

0.64

5% OMONT

15

5

10

82.75

0.43

0.56

7% OMONT

15

7

10

82.45

0.45

0.48

10% OMONT

15

10

10

82.00

0.46

0.43

kept in a refrigerator until performing the release tests. The sample designations and detailed compositions of the prepared drug delivery systems are listed in Table I. In order to perform the drug release tests, nearly 1 g of each prepared drug loaded sheet was cut and immersed in the prepared phosphate buffered saline solution with the proportional mass of sample to the mass of buffered solution of 1:100. The measurements were carried out at 37 °C. At predetermined time intervals, 2 mL of each release solution were withdrawn and stored separately and then replaced by 2 mL of fresh buffered saline solution. Each solution was prepared for spectroscopy by reacting with 2 mL of isopropanol to avoid the precipitation of the products forming and subsequently with 2 mL of the prepared o-phthaldialdehyde reagent. The gentamicin sulphate concentration was then determined by measuring the absorbance at 332 nm in a Varian Cary 50 UV-spectrophotometer. The amount of gentamicin sulphate in each solution as well as the final release kinetics were calculated using the calibration profiles based on concentration versus absorbance using previously designed and standardized curves of absorbance for known concentrations of gentamicin sulphate. The release test was repeated three times for a typical sample (i.e., sample containing 5 wt % of OMONT) to show the precision of the experimental results. The drug release kinetics were determined by plotting the fractional release curves, i.e., M t /M values versus the release time. M t is the cumulative amount of released gentamicin sulphate at time t and M is the mass of initially loaded gentamicin sulphate inside each drug delivery system or the same total amount of releasable gentamicin sulphate from the system. Figure 1 shows nearly identical patterns for the fractional release curves of all drug delivery systems regardless of the amount of incor- porated nanoclay into the system. The obtained results demonstrated that at any given release time, the fractional gentamicin sulphate release from the drug delivery system based on pure PVAhydrogel was always higher than those based on nanocomposite hydrogels. In addition, the fractional release of drug from nanocomposite hydrogel drug delivery systems was decreased by increasing the loading level of OMONT. From the other point of view, the results showed the required time to reach a specified gentamicin sulphate release level, i.e., a specified

amount of M t /M , was shorter for pure PVA drug delivery system compared to the nanocomposite hydrogels. Furthermore, this time was longer for nanocomposite hydrogel drug delivery systems with a higher loading level of incorporated OMONT. The results indicated that the gentamicin sulphate release from the nanocomposite hydrogel based systems were more prolonged with slower rate and they seem to be very good candidates for delivery of drugs where prolonged release is required. The effects of the incorporated OMONT into the PVA hydrogel drug delivery system on the gentamicin release kinetics could be dis- cussed on the basis of the previously reported data on PVA-OMONT nanocomposite hydrogels. It has been reported that the silicate layers of OMONT act as cross-linkers inside the network of PVA hydrogel, and the gel fraction values of PVA-clay nanocomposite hydrogels are increased by increasing the amount of incorporated OMONT, with more entangled structures with higher cross-linking densities being created [8, 19]. It is obvious that in the specimens with higher gel fraction and cross-linking densities, there is less free volume available for transporting transportable molecules, i.e., water and drug mol- ecules. Therefore, the mass transfer process of water and gentamicin sulphate molecules inside the drug delivery systems on the basis of PVA-OMONTnanocomposite hydrogels would be restricted compared to the pure PVA hydrogel. In addition, the silicate layers of OMONT inside the nanocomposite hydrogel drug delivery systems could entrap the gentamicin sulphate molecules and also act as a physical barrier against molecular transport due to creating more tortuous paths which offer a controlling step against the mass transfer as well as the release process. To determine the mechanism of gentamicin sulphate release, the following power law equation was used [28]:

 

M t /M = kt n

Eq. 1

where k is the drug release characteristic constant and n is the charac- teristic exponent of the mode transport of drug molecules. According to the classification of the diffusion mechanism; n = 0.5, n = 1, and 0.5 < n < 1 indicate the Fickian, case II transport, and non-Fickian diffusion mechanisms, respectively [29]. Equation 1 could be re-written in logarithmic form as follows:

Figure 1 - Profiles of gentamicin sulphate release for prepared drug delivery systems containing 0-10

Figure 1 - Profiles of gentamicin sulphate release for prepared drug delivery systems containing 0-10 % of OMONT.

 

log(M t /M ) = n log(t) + log(k)

 

Eq. 2

Plotting the log(M t /M ) against log(t) for M t /M < 0.6 would give the value of n as the slope of the plotted linear curve and the log(k) as the intercept. The graph showing the log(M t /M ) curves versus log(t) for all prepared drug delivery systems is presented in Figure 2. A good linear relationship is observed between log(M t /M ) and log(t) for all gentamicin sulphate delivery systems with coefficients of determination

(R

2 ) higher than 0.99. The values of constants n and k for all systems

were calculated from the slopes and intercepts of lines represented in Figure 2 and were reported in Table I. According to the calculated values for constant n, the mechanism of gentamicin sulphate release for all drug delivery systems is Fickian diffusion which means the PVA chains relaxation is dominant compared to the drug molecules diffusion and the later process is the main controlling step in the gen- tamicin sulphate release process. Table I also shows that the values of

 

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Mechanism of gentamicin sulphate release in nanocomposite hydrogel drug delivery system M. Sirousazar

in nanocomposite hydrogel drug delivery system M. Sirousazar Figure 2 - Linear curves of log(M t

Figure 2 - Linear curves of log(M t /M ) versus log(t) for all samples.

constant k, which could be considered as a criterion for the gentamicin sulphate release rate, are decreased by increasing the OMONT loading level in nanocomposite hydrogel drug delivery systems. In general, it can be concluded that the prepared PVA-OMONT nanocomposite hydrogels are good candidates to be used as drug delivery systems with prolonged release duration and the amount of nanoclay incorporated into the system could be recognized as an ex- cellent key parameter to design systems with desired release duration. The prepared drug delivery systems are also recommended to be used as novel antibiotic releasing wound dressings for infected wounds, where the continuous antibiotic release is required beside the healing process of wound.

REFERENCES

1.

Schexnailder P., Schmidt G. - Polymer nanocomposite hydro- gels. - Colloid. Polym. Sci., 287, 1-11, 2009.

2.

Sirousazar M., Kokabi M. - Intelligent nanocomposite hydrogels. - In: Intelligent Nanomaterials: Processes, Properties, and Ap- plications, A. Tiwari, A.K. Mishra, H. Kobayashi, A.P.F. Turner Eds., John Wiley & Sons Inc., Hoboken, 2012, p. 487-531.

3.

Divsar F., Nomani A., Chaloosi M., Haririan I. - Synthesis and

characterization of gold nanocomposites with modified and intact polyamidoamine dendrimers. - Microchim. Acta, 165, 421-426,

2009.

4.

Thomas V., Yallapu M.M., Sreedhar B., Bajpai S.K. - Breathing- in/breathing-out approach to preparing nanosilver-loaded hydrogels: highly efficient antibacterial nanocomposites. - J. Appl. Polym. Sci., 111, 934-944, 2009.

5.

Sirousazar M., Kokabi M., Hassan Z.M., BahramianA.R. - Mineral kaolinite clay for preparation of nanocomposite hydrogels. - J. Appl. Polym. Sci., 125, E122-E130, 2012.

6.

Satarkar N.S., Johnson D., Marrs B., Andrews R., Poh C., Gharaibeh B., Saito K., Anderson K.W., Hilt J.Z. - Hydrogel- MWCNT nanocomposites: synthesis, characterization, and heating with radiofrequency fields. - J. Appl. Polym. Sci., 117, 1813-1819, 2010.

7.

Abdurrahmanoglu S., Can V., Okay O. - Equilibrium swelling behavior and elastic properties of polymer-clay nanocomposite hydrogels. - J. Appl. Polym. Sci., 109, 3714-3724, 2008.

8.

Sirousazar M., Kokabi M., Hassan Z.M. - Swelling behaviour

and structural characteristics of polyvinyl alcohol/montmorillonite nanocomposite hydrogels. - J. Appl. Polym. Sci., 123, 50-58,

2012.

9.

Sirousazar M., Kokabi M., Hassan Z.M., Bahramian A.R. - Polyvinyl alcohol /Na-montmorillonite nanocomposite hydrogels

prepared by freezing-thawing method: structural, mechanical, thermal and swelling properties. - J. Macromol. Sci. Part B Phys., 51, 1335-1350, 2012.

10.

Sirousazar M., Kokabi M., Hassan Z.M., Bahramian A.R. -

621

J. DRUG DEL. SCI. TECH., 23 (6) 619-621 2013

Nanoporous nanocomposite hydrogels composed of polyvinyl alcohol and Na-montmorillonite. - J. Macromol. Sci. Part B Phys., 51, 1583-1595, 2012.

11. Sirousazar M., Kokabi M., Hassan Z.M., Bahramian A.R. - De- hydration kinetics of polyvinyl alcohol nanocomposite hydrogels containing Na-montmorillonite nanoclay. - Sci. Iran. Trans. F:

Nanotech., 18, 780-784, 2011.

12. Shin M.K., Spinks G.M., Shin S.R., Kim S.I., Kim S.J. - Nano- composite hydrogel with high toughness for bioactuators. - Adv. Mater., 21, 1712-1725, 2009.

13. Li P., Siddaramaiah, Kim N.H., Heo S.B., Lee J.H. - Novel PAAm/ laponite clay nanocomposite hydrogels with improved cationic dye adsorption behavior. - Composites Part B, 39, 756-763, 2008.

14. Gant R.M., Hou Y., Grunlan M.A., Cote G.L. - Development of a self-cleaning sensor membrane for implantable biosensors. - J. Biomed. Mater. Res. B Appl. Biomater., 90, 695-701, 2009.

15. Zolfaghari R., Katbab A.A., Nabavizadeh J., Tabasi R.Y., Nejad M.H. - Preparation and characterization of nanocomposite hydrogels based on polyacrylamide for enhanced oil recovery applications. - J. Appl. Polym. Sci., 100, 2096-2103, 2006.

16. Wang M., Li Y., Wu J., Xu F., Zuo Y., Jansen J.A. - In vitro and in vivo study to the biocompatibility and biodegradation of hy- droxyapatite/poly(vinyl alcohol)/gelatin composite. - J. Biomed. Mater. Res. B Appl. Biomater., 85, 418-426, 2008.

17. Satarkar N.S., Hilt J.Z. - Hydrogel nanocomposites as remote- controlled biomaterials - Acta Biomater., 4, 11-16, 2008.

18. Liu K.H., Liu T.Y., Chen S.Y., Liu D.M. - Drug release behavior of chitosan-montmorillonite nanocomposite hydrogels following electrostimulation. - Acta Biomater., 4, 1038-1045, 2008.

19. Kokabi M., Sirousazar M., Hassan Z.M. - PVA-clay nanocompos-

ite hydrogels for wound dressing. - Eur. Polym. J., 43, 773-781,

2007.

20. Sirousazar M., Kokabi M., Hassan Z.M. - In vivo and cytotoxic assays of a poly(vinyl alcohol)/clay nanocomposite hydrogel

wound dressing. - J. Biomater. Sci., Polym. Ed., 22, 1023-1033,

2011.

21. Qiu Y., Park K. - Environment-sensitive hydrogels for drug delivery. - Adv. Drug Delivery Rev., 53, 321-339, 2001.

22. Okano T. (Ed.) - Biorelated Polymers and Gels: Controlled Re - lease and Applications in Biomedical Engineering. - Academic Press, San Diego, 1998.

23. Kim C.J. (Ed.) - Controlled Release Dosage Form Design. - Technomic Publication, Lancaster, 2000.

24. Mandal A.S., Biswas N., Karim K.M., Guha A., Chatterjee S., Behera M., Kuotsu K. - Drug delivery system based on chrono- biology- a review. - J. Controlled Release, 147, 314-325, 2010.

25. Mashak A., Rahimi A. - Silicone polymers in controlled drug delivery systems: a review. - Iran. Polym. J., 18, 279-295, 2009.

26. British Pharmacopoeia,Vol. II, Appendix ID, HMSO, London, 1993, p. A79.

27. Frutos P., Diez-Pena E., Frutos G., Barrales-Rienda J.M. - Re- lease of gentamicin sulphate from a modified commercial bone cement. Effect of (2-hydroxyethyl methacrylate) comonomer and poly(N-vinyl-2-pyrrolidone) additive on release mechanism and

kinetics. - Biomaterials, 23, 3787-3797, 2002.

28. Peppas N.A., Bures P., Leobandung W., Ichikawa H. - Hydrogels in pharmaceutical formulations. - Eur. J. Pharm. Biopharm., 50, 27-46, 2000.

29. Namazi H., Kanani A. - Investigation diffusion mechanism of β-lactam conjugated telechelic polymers of PEG and b-cyclo- dextrin as the new nanosized drug carrier devices. - Carbohydr. Polym., 76, 46-50, 2009.

ACKNOWLEDGEMENT

A part of this work was performed at Tarbiat Modares University. The author would like to thank Tarbiat Modares University for partial finan- cial support.

MANUSCRIPT

Received 4 August 2013, accepted for publication 14 April 2013.