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.

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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: jhcui@suda.edu.cn (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

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).

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doi:10.1016/j.jconrel.2011.08.171

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