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1 -{ { ~ ~ } 341/51141

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: 82/11/58 : 11/6/68

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nanoparticles,

chitosan, ionic gelation,

optimization, Taguchi method

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5523-6101 : NSSI

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Bioedegradable nanoparticles are intensively investigated for their potential applications in drugdelivery systems. Being a biocompatible and biodegradable polymer, chitosan holds great promisefor use in this area. This investigation was concerned with determination and optimization of theeffective parameters involved in the production of chitosan nanoparticles using ionic gelationmethod. Studied variables were concentration and pH of the chitosan solution, the ratio of chitosanto sodium tripolyphosphate therein and the molecular weight of chitosan. For this purpose, Taguchistatistical method was used for design of experiments in three levels. The size of chitosan nanopar-ticle was determined using laser light scattering. The experimental results showed that concentrationof chitosan solution was the most important parameter and chitosan molecular weight the least effec-tive parameter. The optimum conditions for preparation of nanoparticles were found to be 1 mg/mLchitosan solution with pH=5, chitosan to sodium tripolyphosphate ratio of 3 and chitosan molecularweight of 200,000 daltons. The average nanoparticle size at optimum conditions was found to beabout 150 nm.

Abstract

Key Words

* { |:ri.ca.seradom@fve

(*) To whom correspondence should

be addressed.

E-mail: evf@modares.ac.ir

Determination of the Optimum Conditions forProduction of Chitosan Nanoparticles

A. Dustgani1, E. Vasheghani-Farahani1* and M. Imani21. Tarbiat Modares University, P.O. Box: 14115/143, Tehran, Iran

2. Iran Polymer and Petrochemical Institute, P.O. Box: 14965/115, Tehran, Iran

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1. Illum L., Chitosan and Its Use as a Pharmaceutical Excipient,

Pharm. Res., 15, 1326-1331, 1998.

2. Dodane V. and Vilivalam V.D., Pharmaceutical Applications of

Chitosan, Pharm. Sci. Technol. Today, 1, 246-253, 1998.

3. Felt O., Buri P. and Gurny R., Chitosan: A Unique Polysaccha-

ride for Drug Delivery, Drug Dev. Ind. Pharm., 24, 979-993,

1998.

4. Yao K.D., Peng T., Yin Y.J. and Xu M.X., Microcapsules/Micros-

pheres Related to Chitosan, J. Macromol. Sci., Rev. Macromol.

Chem. Phys., 35, 155-180, 1995.

5. Kas H.S., Chitosan: Properties, Preparations and Application to

Microparticulate Systems, J. Microencapsulation, 14, 689-711,

1997.

6. Varshosaz J. and Alinangri R., Effect of Citric Acid on Insulin

Loaded Chitosan Microspheres, Iran. Polym. J., 14, 647-656,

2005.

7. Mahdavi H., Taghizadeh S.M., Mivehchi H. and Khanbeigi F.,

The Effect of Chitosan Molecular Weight on the Rate of Drug

Release of Prednisolone Sodium Phosphate from Chitosan

Microspheres Prepared by Spray Dryer, Iran. J. Polym. Sci.

Technol., 19, 231-237, 2006.

8. Fernandez-Urrusuno R., Calvo P., Remunan-Lopez C., Vila-Jato

J.L. and Alonso M.J., Enhancement of Nasal Absorption of

Insulin Using Chitosan Nanoparticles, Pharm. Res., 16, 1576-

1591, 1999.

9. Janes K.A., Fresneau M.P., Marazuela A., Fabra A. and Alonso

M.J., Chitosan Nanoparticles as Delivery Systems for Doxoru-

bicin, J. Control. Release, 73, 255-267, 2001.

10. Chew J.L., Wolfowicz C.B., Mao H.Q., Leong K.W. and Chua

K.Y., Chitosan Nanoparticles Containing Plasmid DNA Encod-

ing House Dust Mite Allergen, Der p 1 for Oral Vaccination in

mice, Vaccine, 21, 2720-2729, 2003.

11. Akbuga J. and Durnaz G., Preparation and Evaluation of

Crosslinked Chitosan Microspheres Containing Furosemide, Int.

J. Pharm., 111, 217-222, 1994.

12. Berger J., Reist M., Mayer J.M., Felt O., Peppas N.A. and

Gurny R., Structure and Interactions in Covalently and Ionical-

ly Crosslinked Chitosan Hydrogels for Biomedical Applications.

Eur. J. Pharm. Biopharm., 57, 19-34, 2004.

13. Kawashima Y., Handa T., Takenaka H., Lin S.Y. and Ando Y.,

Novel Method for the Preparation of Controlled-release Theo-

phylline Granules Coated with a Polyelectrolyte Complex of

Sodium Polyphosphate-chitosan, J. Pharm. Sci., 74, 264-268,

1985.

14. Kawashima Y., Handa T., Kasai A., Takenaka H. and Lin S.Y.,

The Effect of Thickness and Hardness of the Coating Film on the

Drug Release of Theophylline Granules, Chem. Pharm. Bull.,

33, 2469-2474, 1985.

15. Bodmeier R., Oh K.H. and Pramar Y., Preparation and Evalua-

tion of Drug-Containing Chitosan Beads, Drug Dev. Ind.

Pharm., 15, 1475-1494, 1989.

16. Shirashi S., Imai T. and Otagiri M., Controlled Release of

Indomethacin by Chitosan-Polyelectrolyte Complex: Optimiza-

tion and In Vivo: In Vitro Evaluation, J. Control. Release, 25,

217-225, 1993.

17. Sezer A.D. and Akbuga J., Controlled Release of Piroxicam

from Chitosan Beads, Int. J. Pharm., 121, 113-116, 1995.

18. Aydin Z. and Akbuga J., Chitosan Beads for the Delivery of Sal-

mon Calcitonin: Preparation and Characteristics, Int. J. Pharm.,

131, 101-103, 1996.

19. Calvo P., Remunan-Lopez C., Vila-Jata J.L. and Alonso M.J.,

Chitosan and Chitosan/Ethylene Oxide-Propylene Oxide Block

Copolymer Nanoparticles as Novel Carriers for Protein and Vac-

cines, Pharm. Res., 14, 1431-1436, 1997.

20. Calvo P., Remunan-Lopez C., Vila-Jata J.L. and Alonso M.J.,

Novel Hydrophilic Chitosan-Polyethylene Oxide Nanoparticles

as Protein Carriers, J. Appl. Polym. Sci., 63, 125-132, 1997.

21. Shu X.Z. and Zhu K.J., A Novel Approach to Prepare

Tripolyphosphate/Chitosan Complex Beads for Controlled

Release Drug Delivery, Int. J. Pharm., 201, 51-58, 2000.

22. Calvo P., Boughaba A.S., Appel M., Fattal E., Alonso M.J. and

Couvreur P., Oligonucleotide-Chitosan Nanoparticles as New

Gene Therapy Vector, Proceedings of 2nd World Meeting

APGI/APV, Paris, 1111-1112, 1998.

23. Katas H. and Alpar H.O., Development and Characterization of

Chitosan Nanoparticles for SIRNA Delivery, J. Control.

Release, 115, 216-225, 2006.

24. Gan Q., Wang T., Cochrane C. and McCarron P., Modulation of

Archive of SID

www.SID.ir

{ { } }

{ } 5 - 6831 464

Surface Charge, Particle Size and Morphological Properties of

Chitosan-TPP Nanoparticles Intended for Gen Delivery, J. Col-

loid Surfac., 44, 65-73, 2005.

25. Zhang H., Oh M., Allen C. and Kumacheva E., Monodisperse

Chitosan Nanoparticles for Mucosal Drug Delivery, Biomacro-

molecules, 5, 2461-2468, 2004.

26. Janes K.A. and Alonso M.J., Depolymerized Chitosan Nanopar-

ticles for Protein Delivery: Preparation and Characterization, J.

Appl. Polym. Sci., 88, 2769-2776, 2003.

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www.SID.ir

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