2
distribution of the nanoparticles can be effectively tuned by varying the experimental conditions. Hydrophobic molecules or semiconductor nanocrystals can be encapsulated in the nanoparticles during the formation process, which makes it possible to apply such hybrid nanoparticles in the fields of drug delivery, detection or bioimaging. Acknowledgements We gratefully acknowledge funding for this work provided by the Chinese Ministry of Education with the Program of New Century Excellent Talents in University (NCET-10-0398), Initiatory Financial Support from HUST (01-24-013015) and the Program for Chutian Scholars of Hubei Province. The authors appreciate the help from Prof. Xiangling Ji and Dr. Wei Nie of CIAC for synthesizing CdSe nanocrystals. We also thank the HUST Analytical and Testing Center for allowing us to use its facilities. References [1] J.M. Anderson, M.S. Shive, Biodegradation and biocompatibility of PLA and PLGA microspheresAdv. Drug Deliv. Rev. 28 (1997) 524. [2] P. Johansen, Y. Men, H.P. Merkle, B. Gander, Revisiting PLA/PLGA microspheres: an analysis of their potential in parenteral vaccination, Eur. J. Pharm. Biopharm. 50 (2000) 129146. [3] J.L. Cleland, Solvent evaporation processes for the production of controlled release biodegradable microsphere formulations for therapeutics and vaccines, Biotechnol. Progr. 14 (1998) 102107. [4] S. Freiberg, X. Zhu, Polymer microspheres for controlled drug release, Int. J. Pharm. 282 (2004) 118. [5] J.A. Champion, A. Walker, S. Mitragotri, Role of particle size in phagocytosis of polymeric microspheres, Pharm. Res. 25 (2008) 18151821. [6] M. Koval, K. Preiter, C. Adles, P.D. Stahl, T.H. Steinberg, Size of IgG-opsonized particles determines macrophage response during internalization, Exp. Cell Res. 242 (1998) 265273. [7] S.K. Sahoo, J. Panyam, S. Prabha, V. Labhasetwar, Residual polyvinyl alcohol associated with poly (d, l-lactide-co-glycolide) nanoparticles affects their physical properties and cellular uptake, J. Control. Release 82 (2002) 105114. [8] H. Yabu, T. Higuchi, M. Shimomura, Unique phase-separation structures of block- copolymer nanoparticles, Adv. Mater. 17 (2005) 20622065. [9] W.W. Yu, X.G. Peng, Formation of high-quality CdS and other IIVI semiconductor nanocrystals in noncoordinating solvents: tunable reactivity of monomers, Angew. Chem. Int. Ed. 41 (2002) 23682371. doi:10.1016/j.jconrel.2011.08.170 Preparation and evaluation of injectable sustained-release microspheres of rivastigmine Yunfeng Zhu, Zhixin Zhu, Qingri Cao, Dawei Chen, Jinghao Cui Department of Pharmaceutics, School of Pharmacy, Medical College of Soochow University, Suzhou 215123, China E-mail address: [email protected] (J. Cui). Abstract summary Rivastigmine tartrate, a novel acetyl cholinesterase (AChE) inhibitor, was entrapped in polymeric microspheres made from poly(lactide-co- glycolide) (PLGA) and poly (lactic acid) (PLA) by various techniques in order to obtain sustained-release microspheres. Microspheres which can release rivastigmine over 1 week and 1 month were prepared by the O 1 / O 2 emulsificationsolvent evaporation method. The results of an in vivo study with rats indicated that a stable rivastigmine plasma concentration could be maintained for longer than 7 days after administration of sustained-release microspheres. Keywords: PLGA/PLA, Sustained-release, Rivastigmine, Pharmacokinetics Introduction Alzheimer's disease (AD) is a progressive and fatal neurodegen- erative disorder manifested by cognitive and memory deterioration, progressive impairment of activities of daily living, and a variety of neuropsychiatric symptoms and behavioral disturbances [1,2]. Here, we made an attempt to establish a preparation method for sustained- release of PLGA microspheres containing rivastigmine tartrate, a novel acetyl cholinesterase (AChE) inhibitor used for AD therapeutics [3]. The pharmaceutical behavior in vitro as well as the pharmaco- kinetic performance of the microspheres was studied. Fig. 1. Structure of rivastigmine. Experimental methods The microspheres were manufactured by four different methods: (1) water-in-oil-in-water (W 1 /O/W 2 ) double emulsificationsolvent evapora- tion, (2) oil-in-water (O/W) single emulsificationsolvent evaporation, (3) spray drying method, and (4) oil-in-oil (O 1 /O 2 ) emulsificationsolvent evaporation. PLGA/PLA microspheres were characterized in terms of size, morphology, drug loading capacity and encapsulation efficiency, drug existence state and release profile, respectively [4,5]. Gas chromatography was employed to determine the residual amount of organic solvents in rivastigmine-containing microspheres. The concentration of rivastigmine in plasma was determined by LSMS/MS, and a preliminary pharmaco- kinetic study was carried out by subcutaneous administration of micro- spheres in rats and following the release of rivastigmine for 1 week [6]. Fig. 2. Microscopy of rivastigmine-loaded PLGA/PLA microspheres (a: formulation a, b: formulation b). Results and discussion Microspheres manufactured by O/W, W 1 /O/W 2 emulsificationsolvent evaporation method and spray drying showed relatively high release rates of rivastigmine during the first period of 24 h. When Fig. 3. In vitro release profiles of optimized formulations A and B of rivastigmine- loaded microspheres. Abstracts / Journal of Controlled Release 152 (2011) e1e132 e131

Preparation and evaluation of injectable sustained-release microspheres of rivastigmine

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Page 1: Preparation and evaluation of injectable sustained-release microspheres of rivastigmine

distribution of the nanoparticles can be effectively tuned by varying theexperimental conditions. Hydrophobic molecules or semiconductornanocrystals can be encapsulated in the nanoparticles during theformation process, which makes it possible to apply such hybridnanoparticles in the fields of drug delivery, detection or bioimaging.

AcknowledgementsWe gratefully acknowledge funding for this work provided by the

Chinese Ministry of Education with the Program of New CenturyExcellent Talents in University (NCET-10-0398), Initiatory FinancialSupport from HUST (01-24-013015) and the Program for ChutianScholars of Hubei Province. The authors appreciate the help fromProf. Xiangling Ji and Dr. Wei Nie of CIAC for synthesizing CdSenanocrystals. We also thank the HUST Analytical and Testing Centerfor allowing us to use its facilities.

References[1] J.M. Anderson, M.S. Shive, Biodegradation and biocompatibility of PLA and PLGA

microspheresAdv. Drug Deliv. Rev. 28 (1997) 5–24.[2] P. Johansen, Y. Men, H.P. Merkle, B. Gander, Revisiting PLA/PLGAmicrospheres: an analysis

of their potential in parenteral vaccination, Eur. J. Pharm. Biopharm. 50 (2000) 129–146.[3] J.L. Cleland, Solvent evaporation processes for the production of controlled release

biodegradable microsphere formulations for therapeutics and vaccines, Biotechnol.Progr. 14 (1998) 102–107.

[4] S. Freiberg, X. Zhu, Polymer microspheres for controlled drug release, Int. J. Pharm. 282(2004) 1–18.

[5] J.A. Champion, A. Walker, S. Mitragotri, Role of particle size in phagocytosis ofpolymeric microspheres, Pharm. Res. 25 (2008) 1815–1821.

[6] M. Koval, K. Preiter, C. Adles, P.D. Stahl, T.H. Steinberg, Size of IgG-opsonized particlesdeterminesmacrophage response during internalization, Exp. Cell Res. 242 (1998) 265–273.

[7] S.K. Sahoo, J. Panyam, S. Prabha, V. Labhasetwar, Residual polyvinyl alcohol associatedwith poly (d, l-lactide-co-glycolide) nanoparticles affects their physical properties andcellular uptake, J. Control. Release 82 (2002) 105–114.

[8] H. Yabu, T. Higuchi, M. Shimomura, Unique phase-separation structures of block-copolymer nanoparticles, Adv. Mater. 17 (2005) 2062–2065.

[9] W.W. Yu, X.G. Peng, Formation of high-quality CdS and other II–VI semiconductornanocrystals in noncoordinating solvents: tunable reactivity of monomers, Angew.Chem. Int. Ed. 41 (2002) 2368–2371.

doi:10.1016/j.jconrel.2011.08.170

Preparation and evaluation of injectable sustained-releasemicrospheres of rivastigmine

Yunfeng Zhu, Zhixin Zhu, Qingri Cao, Dawei Chen, Jinghao CuiDepartment of Pharmaceutics, School of Pharmacy,Medical College of Soochow University, Suzhou 215123, ChinaE-mail address: [email protected] (J. Cui).

Abstract summaryRivastigmine tartrate, a novel acetyl cholinesterase (AChE) inhibitor,

was entrapped in polymeric microspheres made from poly(lactide-co-glycolide) (PLGA) and poly (lactic acid) (PLA) by various techniques inorder to obtain sustained-release microspheres. Microspheres which canrelease rivastigmine over 1 week and 1 month were prepared by the O1/O2 emulsification–solvent evaporation method. The results of an in vivostudy with rats indicated that a stable rivastigmine plasma concentrationcould be maintained for longer than 7 days after administration ofsustained-release microspheres.

Keywords: PLGA/PLA, Sustained-release, Rivastigmine,Pharmacokinetics

IntroductionAlzheimer's disease (AD) is a progressive and fatal neurodegen-

erative disorder manifested by cognitive and memory deterioration,progressive impairment of activities of daily living, and a variety ofneuropsychiatric symptoms and behavioral disturbances [1,2]. Here,

we made an attempt to establish a preparation method for sustained-release of PLGA microspheres containing rivastigmine tartrate, anovel acetyl cholinesterase (AChE) inhibitor used for AD therapeutics[3]. The pharmaceutical behavior in vitro as well as the pharmaco-kinetic performance of the microspheres was studied.

Fig. 1. Structure of rivastigmine.

Experimental methodsThe microspheres were manufactured by four different methods: (1)

water-in-oil-in-water (W1/O/W2)doubleemulsification–solventevapora-tion, (2) oil-in-water (O/W) single emulsification–solvent evaporation,(3) spraydryingmethod, and (4)oil-in-oil (O1/O2) emulsification–solventevaporation. PLGA/PLA microspheres were characterized in terms of size,morphology, drug loading capacity and encapsulation efficiency, drugexistence state and release profile, respectively [4,5]. Gas chromatographywas employed to determine the residual amount of organic solvents inrivastigmine-containing microspheres. The concentration of rivastigminein plasma was determined by LS–MS/MS, and a preliminary pharmaco-kinetic study was carried out by subcutaneous administration of micro-spheres in rats and following the release of rivastigmine for 1 week [6].

Fig. 2. Microscopy of rivastigmine-loaded PLGA/PLA microspheres (a: formulation a,b: formulation b).

Results and discussionMicrospheres manufactured by O/W, W1/O/W2 emulsification–

solvent evaporation method and spray drying showed relatively highrelease rates of rivastigmine during the first period of 24 h. When

Fig. 3. In vitro release profiles of optimized formulations A and B of rivastigmine-loaded microspheres.

Abstracts / Journal of Controlled Release 152 (2011) e1–e132 e131

Page 2: Preparation and evaluation of injectable sustained-release microspheres of rivastigmine

rivastigmine was encapsulated into microspheres by the O1/O2

emulsification–solvent evaporation method and PLGA 502H wasemployed (called formulation A), microspheres were obtained with asize range of 80–150 μm, which showed sustained release over a one-week period in vitro.

Microspheres prepared by a blend of PLGA 752H and PLA 202S at aratio of 1:3 with a size distribution of 50–100 μm (called formulationB, Fig. 2) showed sustained release for 1 month in vitro. The in vitrorelease profiles are shown in Fig. 3.

The results of X-ray diffraction indicated that rivastigmine entrappedin the microspheres existed in a molecular or amorphous state. Theresidual amount of organic solvent in the microspheres prepared byformulation A did not exceed relevant limits. The residual amount ofacentonitrile in microspheres prepared by formulation B was also withinthe limits. However, the residual amount of dichloromethane exceededthe limits. The results of a preliminary pharmacokinetic study ofmicrospheres in rats suggested that after some initial burst release, astable rivastigmine plasma concentration could bemaintained for severaldays.

ConclusionPreparation methods for rivastigmine tartrate-loaded injectable

microspheres were successfully established. The microspheresshowed a sustained release both in vitro and in vivo.

AcknowledgementsWe are grateful to the financial support from the Key International

Cooperation Projects of National Ministry of Science and Technology(2009DFA31330) and Jiangsu Province University Basic ResearchProject (08KJB350003).

References[1] K. Wesnes, Rivastigmine tartrate with a focus on dementia associated with Parkinson's

disease, Drugs Today 43 (2007) 349–359.[2] N. Bodor, P. Buchwald, Barriers to remember: brain-targeting chemical delivery systems

and Alzheimer's disease, Drug Discov. Today 7 (2002) 766–774.[3] C. Roney, P. Kulkarni, V. Arora, et al., Targeted nanoparticles for drug delivery through

the blood–brain barrier for Alzheimer's disease, J. Control. Release 108 (2005) 193–214.[4] J. Herrmann, R. Bodmeier, Biodegradable, somatotatin acetate containing microspheres

prepared by various aqueous and non-aqueous solvent evaporation methods, Eur. J.Pharm. Biopharm. 45 (1998) 75–82.

[5] R.A. Graves, S. Pamujula, Effect of different ratio of high and low molecular weight ofPLGA blend on characteristics of pentamidine microcapsules, Int. J. Pharm. 270 (2004)251–262.

[6] J. Bhatt, G. Subbaiah, S. Kambli, et al., A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC–MS/MS) method for the estimation of rivastigmine inhuman plasma, J. Chromatogr. B 852 (2007) 115–121.

doi:10.1016/j.jconrel.2011.08.171

Abstracts / Journal of Controlled Release 152 (2011) e1–e132e132