Evaluation of chitosan-anionic polymers based tablets for extended-release of highly watersoluble drugs

Yang Shao,Liang Li,Xiangqin Gu,Linlin Wang,Shirui Mao

School of Pharmacy,Shenyang Pharmaceutical University,Shenyang 110016,China

Original Research Paper

Evaluation of chitosan-anionic polymers based tablets for extended-release of highly watersoluble drugs

Yang Shao,Liang Li,Xiangqin Gu,Linlin Wang,Shirui Mao＊

School of Pharmacy,Shenyang Pharmaceutical University,Shenyang 110016,China

ARTICLEINFO

Article history:

Received 1 May 2014

Received in revised form

8 July 2014

Accepted 4 August 2014

Available online 27 August 2014

Extended-release

The objective of this study is to develop chitosan-anionic polymers based extendedrelease tablets and test the feasibility of using this system for the sustained release of highly water-soluble drugs with high drug loading.Here,the combination of sodium valproate(VPS)and valproic acid(VPA)were chosen as the model drugs.Anionic polymers studied include xanthan gum(XG),carrageenan(CG),sodium carboxymethyl cellulose (CMC-Na)and sodium alginate(SA).The tablets were prepared by wet granulation method. In vitro drug release was carried out under simulated gastrointestinal condition.Drug release mechanism was studied.Compared with single polymers,chitosan-anionic polymers based system caused a further slowdown of drug release rate.Among them,CS -xanthan gum matrix system exhibited the best extended-release behavior and could extend drug release for up to 24 h.Differential scanning calorimetry(DSC)and Fourier transform infrared spectroscopy(FTIR)studies demonstrated that polyelectrolyte complexes(PECs)were formed on the tablet surface,which played an important role on retarding erosion and swelling of the matrix in the later stage.In conclusion,this study demonstrated that it is possible to develop highly water-soluble drugs loaded extendedrelease tablets using chitosan-anionic polymers based system.

©2015 Shenyang Pharmaceutical University.Production and hosting by Elsevier B.V.All rights reserved.

1.Introduction

Hydrophilic gel-forming matrix tablets are widely used as oral extended-releasedosageformsduetotheirsimple preparation process and cost-effectiveness.The key factors controlling drug release are the capacity of the gel-forming polymers to imbibe large amount of water or biological fl uids and forming three-dimensional,hydrophilic networks [1].Since the gel layer formation,which de fi nes the kinetics ofdrug release from the matrix system,is controlled by the concentration,viscosity and chemical structure of the polymers,it is of greatly importance to select appropriate hydrophilic polymers for the design of extended-release tablets.

Chitosan,a cationic biopolymer,derived from chitin by partial deacetylation,is well known for its good biocompatibility,biodegradability,low toxicity and relatively low production cost from abundant natural sources[2,3],and it has been wildly applied as a polymeric drug carrier in the f i eld of pharmaceutics.However,although chitosan is a very promising biopolymer as a release-controlling agent in drug delivery,ithaslimitedcapacityforcontrollingdrugreleasewhen used alone due to its easy disintegration characteristics at neutral pH[4,5].Thus,combination of CS with anionic polymers as the carrier of oral controlled-release preparations has been suggested,with increased controlled-release capability and reduced pH dependence[6-8].In most cases,extendedrelease effect of the combination system was achieved by forming the polyelectrolyte complexes(PECs)between CS and anionic polymers in solution f i rst and then the PECs was further used for tablet preparation.Since PECs preparation was an energy-consuming and lengthy process with complicated operations[9],the superiority of simple preparation process of this type of hydrophilic matrix tablets was greatly discounted.

In order to avoid this drawback,some new strategies have been taken.It was reported that when CS-sodium alginate (SA)physical mixture was used as the matrix to prepare tablets,in situ PECs could be formed on the surface of the tablets in the simulated gastrointestinal f l uid due to self-assembly or spontaneous association[10].However,drug release from this CS-SAbased systempresented obviousdrugsolubility dependence and it is not suitable to control the release of highly water-soluble drugs[11].Thus,it was absolutely essential to search for alternative drug delivery system with better extended-release ability for highly water-soluble drugs. We assume that by changing the type of anionic polymers used in combination with chitosan,it is possible to change the strength and permeability of the PECs formed on the tablet surface,therefore making the release of highly water-soluble drugs under control as well.This hypothesis was tested in this study.

Valproic acid(VPA)and sodium valproate(VPS)are generally regarded as the f i rst-line antiepileptic drugs[12]. Sodium valproate(VPS)is the sodium salt of 2-propyl pentanoic acid with a high solubility(1000 mg/ml)in neutral pH. They are usually used in combination[13].Despite their effi cacy for controlling epilepsy,they both suffer from relative short half-life[14].Thus,an extended-release preparation of the combination has attracted considerable attention in order to minimize plasma peak-related adverse effects and reduce the inconvenience caused by frequent dosing of conventional products.In addition,to meet the clinical needs for once-daily administration,they were usually formulated intoextended-releasedosageformswithhighloading (500 mg/tablet).

Therefore,in this study,by using VPA and VPS combination as the model highly soluble drugs,the feasibility of using CS and other anionic polymers based system for controlling the release of highly water-soluble drugs with high drug loading was tested,and inf l uence of the type of anionic polymers,CS:anionic polymer ratio,molecular weight of CS, on the drug release behavior was screened,and drug release mechanism from CS and anionic polymers based tablets were further explored.

2.Materials and methods

2.1.Materials

Chitosan(50 kDa,100 kDa and 400 kDa)were all purchased from Weifang Kehai Chitin Company,Ltd.(Weifang,Shandong,China)with degrees of deacetylation of 86.5%,VPA and VPS were purchased from Yan Cheng Lang De chemicals Company,Ltd.SodiumAlginate(SA,LF200M,G/M=40:60)and carrageenan(CG,GP 209NF)were gifts from FMC Biopolymer Company,Ltd(Drammen,Norway).Sodium carboxymethyl cellulose(CMC-Na)was from Anhui Shanhe Pharmaceutical Excipients Co.,Ltd(Anhui,China).Xanthan gum was from Zibo Zhongxuan Biological Products Co.,Ltd.(Shandong, China).Magnesium stearate was from Tianjin Bo di Chemical Company,Ltd.(Tianjin,China).Colloidal Silicon Dioxide was purchased from Hubei ZhanWang Pharmaceuticals Company, Ltd.(Hubei,China).All other chemicals were of analytical grade.

2.2.Preparation of compound VPA and VPS extendedrelease matrix tablets

The matrix tablets containing drug(500 mg calculated by VPS and the mole ratio of VPS to VPA was 2/1),CS-anionic polymers(200 mg),colloidal silicon dioxide(80 mg as adsorbent and 11 mg as antisticking agent),magnesium stearate(11 mg) as lubricants were prepared using conventional wet granulation method.All the components used were passed through 80-mesh sieve and mixed for at least 15 min,then 70%ethanol was used as wetting agent to prepare the damp mass,the granules were prepared by passing through 16 mesh sieve and dried at 55°C.The dried granules were mixed with lubricants and compressed using single punch tableting machine(ZDY-8,Shanghai far-east-pharmach company,Ltd.,Shanghai, China)with a caplet punch.Hardness of all the tablet formulations was adjusted to 120-140 N(Shanghai Huanghai Instruments Company,Ltd.,Shanghai,China;hardness tester; n=6).The weight of each tablet was controlled within 780±0.5%mg.

2.3.In vitro drug release study

Drug release from the tablets was tested using a dissolution apparatus(ZRD6-B,Shanghai Huanghai Instruments Company,Ltd,Shanghai,China),ChP Apparatus II(paddle method) operating at 50 r/min and 37±0.5°C.Unless specially indicated,the tablets were immersed in dissolution vessels(n=6) with simulated gastrointestinal conditions(500 ml of pH 1.2 HCl solutions for the f i rst hour,900 ml of pH 6.8 phosphate buffer for additional 23 h)as dissolution medium.Aliquots of 10 ml were withdrawn at different time intervals(0.5,1,2,3,4, 6,8,10,12,15,and 24 h)for analysis and were replenishedwith equal amounts of fresh release medium.The amount of drugreleasedat differenttimeintervalswasdeterminedusing high-performance liquid chromatography(HPLC)method[15].

The differences in release prof i les of the designed formulations were compared using similarity factor(f2).The similarity factor was calculated using the Eq.(1)[16].

where n is the number of time points,Rtis the dissolution value of the reference at time t,and Ttis the dissolution value of the test at time t.The release prof i les were signif i cantly different if f2＜50.

2.4.Differential scanning calorimetry(DSC)

Thermal analysis was performed using a Mettler Toledo model 30TC 15 equipment(Mettler,Zurich,Switzerland).The samples(2-4 mg)were scanned in sealed aluminum pans under nitrogenatmosphere.The samples were cooled to room temperature and then reheated from 25 to 320°C at a constant rate of 10°C/min.

2.5.Fourier transforms infrared(FTIR)spectroscopy

The infrared absorption spectra of the samples were analyzed using an FTIR spectrophotometer(IFS-55,Bruker Co.,Ltd., Switzerland,Faellanden).The tablets were prepared by compressing the samples with potassium bromide.The peak variation of adsorption between 400 and 4000 cm-1was detected.

2.6.Erosion and swelling behavior of the combined matrix

The erosion and swelling behaviors of the developed matrix system were evaluated simultaneously by measuring the amount of water uptake and weight loss in a dissolution tester.Brief l y,the weighed tablets were placed in the dissolution vessels and were taken out of the vessels at predetermined time intervals and weighed after removing the excess liquid.Swollen tablets were dried at 50°C for 2 days and then the weight of dried tablets was determined.The erosionand swellingratioswerecalculatedaccording to Eq.(2) and Eq.(3),the remaining ratio was calculated according to Eq (4)[17,18].

Where ER is erosion ratio,SR is swelling ratio,RM is remaining ratio,W0is the initial weight of the dry tablet,Wdis the weight of drug released at time t,Wris the weight of remaining dry tablet after swelling at time t,Wtis the weight of the swollen matrix tablet at time t.The erosion and swelling studies were carried out in triplicate for all the samples tested.

3.Results and discussion

3.1.Evaluation of CS-anionic polymers as extendedrelease system

The anionic polymers were indispensable components in this matrix system and the choice of anionic polymers type was of special importance in developing the controlled-release system.In this study,three other kinds of anionic polymers including xanthan gum(XG),carrageenan(CG),and sodium carboxymethyl cellulose(CMC-Na)were chosen to combine with CS(400 kDa)to explore their extended-release capability for VPA-VPS,and compared with that of CS-sodium alginate (SA)based system.

First of all,by keeping the total amount of polymer in each formulation 200 mg,inf l uence of single anionic polymers on drug release was investigated.As shown in Fig.1,these polymers presented diverse release behavior when used alone. Among them,SA and CMC-Na could only control drug release for 8-10 h due to their swelling and erosion characteristics [19].When CG or XG was used as the matrix,controlled drug release up to 14 h can be achieved.However,none of these anionic polymers has the capacity to extenddrug release up to 24 h when used alone.This phenomenon can be explained by the fact that drug release from conventional hydrophilic matrix is mainly controlled by drug solubility,swelling and erosion properties of the polymer[20].For single anionic polymer based matrix tablets,due to the poor gel-forming ability and large extent of polymer erosion,together with the high drug solubility(1000 μg/ml)at neutral pH,a large amount of drug was released in a short period of time.

《物权法》对于业主的共有权及共同管理权的行使进行了具体规定。第七十五、七十六、七十八条规定，业主可以设立业主大会、选举业主委员会;业主可以共同决定业主大会议事规则、选举业主委员会或更换业主委员会成员、选聘和解聘物业服务企业或其他管理人等;业主大会或者业主委员会的决定，对业主具有约束力。业主的成员权，主要是通过业主参加业主大会行使权利来体现的。由业主大会选举产生的业主委员会执行业主大会的决议，代表和维护业主的利益，决定小区的日常事务，其行为后果由全体业主承担。业主参与业主大会和业主委员会的活动，也就是业主基于私法上的权利而实现业主自治的过程。

Thus,in order to further prolong drug release to 24 h, combination of these anionic polymers with CS was subsequently investigated.Fig.2 shows the drug release prof i les from the combined matrix systems at CS and anionic polymers ratio 1:1.Compared with the results in Fig.1,when CS and these anionic polymers were used in combination,the drug release behaviors were improved to different degrees andtheextended-releasecharacteristicsbecamemoreremarkable.In agreement with the previous report[11], release of highly water-soluble drugs from CS-SA system was the fastest,with 93.8%of the drug released within 6 h.For the CS-CMC-Na and CS-CG based systems,although the drug release was slower than that of single polymer based systems, most of the drugs were released in 12 h.In contrast,24 h sustained drug release was obtained by using CS-XG-based matrix system.The mechanism for this extended-release behavior was further explored in the followed studies.

3.2.Effect of CS and XG ratio on drug release

The ratio between CS and anionic polymers might greatly infl uence the hydration property and drug diffusion coef fi cient in the extended-release system.Since drug release from CS-XG-based tablets exhibited the best extended-release behavior, therefore theCS-XG systemwas selected for this investigation. BykeepingthetotalamountofCS(400kDa)andXGbeing200mg ineachformulation,effectofCS/XGratioat3/1,1/1,1/3,ondrug release was evaluated and the results are shown in Fig.3.

No signif i cant difference in release was found when changingtheratioofCStoXGfrom3/1to1/1(f2=92).Although a slight f l uctuation in drug release occurred when CS to XG ratiowas1/3,thesimilarlyfactorswerestilllargerthan50(f2(3/1-1/3)=71,f2(1/1-1/3)=67),indicating that the weak f l uctuation didnotleadtolargedeviationfromthewholetrend.Thus,drug release was less inf l uenced by CS to XG ratio in the range studied.CS:XG ratio 1:1 was selected for the followed studies.

3.3.Effect of CS molecular weight on drug release

The molecular weight(MW)of the polymer is directly related to gel strength and is of great importance in drug release since it is decisive for the passage of water through the gel layer during swelling.In this study,keeping CS-XG ratio 1:1,effect of chitosan molecular weight on drug release was investigated by usingthreekindsofCSwithlow(50kDa),medium(100kDa) and high(400 kDa)molecular weights.The release prof i les are presented in Fig.4.

It was noted that no apparent difference in drug release was found in the f i rst 6 h and thereafter slightly decreased release rate was observed with the increase of chitosan molecular weight.On the whole,the drug release prof i les from these three kinds of CS based systems was similar to each other(f2(CS LMW-MMW)=67＞50,f2(CS LMW-HMW)=69＞50,f2(CSMMW-HMW)=74＞50).It was reported that,for hydrophilic matrices,gel strength determines the erosion capacity of the polymer,while solubility of the drug incorporated into the polymer matrix will govern the release mechanism[21].Due to the high solubility of VPS and its high loading,it might be released from the tablets mainly by diffusion through the gel layer[22].This is in good agreement with the comparable drug release prof i les from different molecular weight chitosan based systems.

3.4.Characterization of the CS/XG PECs

Fig.5 shows DSC curves of CS,XG,physical mixtures of CS and XG,and the outer layer of CS-XG-based matrix tablets after 24 h of release test.An exothermic peak appeared at approximately 310°C(Fig.5a)corresponding to the degradation of CS[23].Similarly,XG(Fig.5b)presented the exothermic peak of decomposition at 288°C[24].As for the physical mixture of CS-XG(Fig.5c),due to the overlap of the exothermic peaks of CS and XG,only a peak at 303°C was found,indicating no obvious interaction between each other. However,compared with the single polymers and physical mixture,the outer layer of CS-XG-based matrix tablets showed different properties(Fig.5d).On one hand,although the exothermic peak at 288°C was still visible,it was very weak.On the other hand,a new broad peak ranging from 150 to 280°C appeared,which was signif i cant distinguished with the single exothermic peaks of CS and XG and similar to the exothermic peak of PECs reported in the literature[11].These results implied the in situ PECs were formed on the surface of the tablets during drug release process.

Moreover,FIIR was further used to demonstrate the formation of PEC on the tablet surface.In the spectrum of CS (Fig.6a),the band situated at 1659 cm-1and 1605 cm-1were assigned to the amine groups of the 2-aminoglucose unit and the carbonyl group of the 2-acetaminoglucose unit,respectively[25].Meanwhile,the characteristic peak of XG at 1725 cm-1corresponding to C=O stretching vibration of carboxylic groups was presented in the spectrum of XG(Fig.6b) [26,27].In comparison with IR spectra of the single polymers, no new characteristic peak was found in the physical mixtures(Fig.6c).However,in the spectrum of the outer shell of the CS-XG-based tablets,the characteristic peaks of XG were not apparent or even disappeared.Meanwhile,a new weak peak at 1542 cm-1was observed,which might be attributed to the ionic interaction between the ionized carboxylic groups and the protonated amino groups(-NH3+)of CS[8,28].These results were in accordance with previous observations from the PECs formed between poly(acrylic acid)or carrageenan with CS[29,30].

Therefore,both visual observation and DSC,FTIR studies suggested that PEC was formed in situ on the CS-XG based matrix tablets.

3.5.Drug release mechanism

For traditional hydrophilic matrices,the erosion and swelling of the polymeric carrier play an important role in controlling drug release[4,31].This study demonstrated that PECs can be formed on the surface of CS-XG-based matrix tablets.It is notclear how this PEC can inf l uence drug release mechanism. Therefore,the erosion and swelling properties of the selected CS-XG-based system were further evaluated by weighing method during the release process.

As shown in Fig.7a,the remaining ratio was quite high in the initial stage,82.66%in 0-1 h,and then slowed down gradually with erosion rate 2.38%/h in 1-6 h.The remaining ratio was 68.07%at 6 h and no signif i cant decrease was observed in the followed time period.This is in great agreement with our previous study indicating that the formation of PEC on the tablet surface may prevent erosion in the later stage[10,11],leading to further prolonged drug release.

Similarly,three-stage swelling processes were observed in Fig.7b.Initially,the tablets exhibited fast swelling behavior and the swelling ratio increased almost linearly at a rate of 57.96%/h,and swelling ratio reached 474%at 6 h.Thereafter, the swelling rate slowed down gradually with the average rate being approximately 16.76%/h during 6-24 h.After 12 h,the swelling ratio was almost leveled off and it was 775.4%at 24 h.

Taken together,it was found that swelling ratio increased slightly with limited change in remaining ratio of the tablet after 6 h.This can probably be explained by the preventing function of the PEC formed on the surface of CS-XG based tablets during drug release process.Meanwhile,this result implied that complete PEC was formed in 6 h.Similarly,it has been demonstrated that polyion complex formation in chitosan and xanthan gum gel layer prevented over-swelling, strengthened the wet matrices and sustained the drug release[32].Since the formation of the PECs was a progressive and gradual process,signif i cantly decreased erosion and swellingwas only observed after itscompleteformationat 6 h. Basedontheaboveanalysis,itcanbeconcludedthatlaterstage drug release from CS-XG matrix based tablets were greatly dependent on the properties of PECs on the tablet surface.

4.Conclusions

In this study the feasibility of using CS-anionic polymers based matrix system for sustained release of highly watersoluble drugs,the combination of sodium valproate and valproic acid were demonstrated.Among them,drug release fromCS-XG-basedmatrixsystemexhibitedthebest extended-release behavior and was less inf l uenced by the change of CS:XG ratio and CS molecular weights.Differential scanning calorimetry and Fourier transform infrared spectroscopy studies demonstrated that polyelectrolyte complexes(PECs)were formed on the tablet surface.The PECs played an important role on retarding erosion and swelling of the matrix,and therefore drug release in the later stage.In conclusion,CS-anionic polymer system was suitable for developing extended-release preparations of highly watersoluble drugs with high drug loading and this broadened current views on hydrophilic polymers based matrix tablets.

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*Corresponding author.School of Pharmacy,Shenyang Pharmaceutical University,103 Wenhua Road,110016 Shenyang,China.Tel./fax: +86 24 23986358.

E-mail addresses:maoshirui@syphu.edu.cn,maoshirui@vip.sina.com(S.Mao).

Peer review under responsibility of Shenyang Pharmaceutical University.

http://dx.doi.org/10.1016/j.ajps.2014.08.002

1818-0876/©2015 Shenyang Pharmaceutical University.Production and hosting by Elsevier B.V.All rights reserved.

Chitosan

Anionic polymers

Sodium valproate-Valproic acid