Scholarly article on topic 'Evaluation of chitosan–anionic polymers based tablets for extended-release of highly water-soluble drugs'

Evaluation of chitosan–anionic polymers based tablets for extended-release of highly water-soluble drugs Academic research paper on "Chemical sciences"

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Abstract of research paper on Chemical sciences, author of scientific article — Yang Shao, Liang Li, Xiangqin Gu, Linlin Wang, Shirui Mao

Abstract The objective of this study is to develop chitosan–anionic polymers based extended-release 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 extended-release tablets using chitosan–anionic polymers based system.

Academic research paper on topic "Evaluation of chitosan–anionic polymers based tablets for extended-release of highly water-soluble drugs"

Accepted Manuscript

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

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

PII: S1818-0876(14)00051-8

DOI: 10.1016/j.ajps.2014.08.002

Reference: AJPS 84

To appear in: Asian Journal of Pharmaceutical Sciences

Received Date: 1 May 2014

Revised Date: 8 July 2014

Accepted Date: 4 August 2014

Please cite this article as: Shao Y, Li L, Gu X, Wang L, Mao S, Evaluation of chitosan-anionic polymers based tablets for extended-release of highly water soluble drugs, Asian Journal of Pharmaceutical Sciences (2014), doi: 10.1016/j.ajps.2014.08.002.

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Title page

Evaluation of chitosan-anionic polymers based tablets for extended-release of

highly water soluble drugs

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

School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China To be submitted to: Asian JPharm Sci

* To whom correspondence should be addressed.

School of Pharmacy

Shenyang Pharmaceutical University

103 Wenhua Road, 110016, Shenyang, China

Tel and Fax: +86-24-23986358

E-mail\ maoshirui@syphu.edu.cn

Abstract

The objective of this study is to develop chitosan-anionic polymers based extended-release 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 hours. 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 extended-release tablets using chitosan-anionic polymers based system.

Keywords: Extended-release; Chitosan; Anionic polymers; Sodium valproate-Valproic acid

1. Introduction

Hydrophilic gel-forming matrix tablets are widely used as oral extended-release dosage forms due to their simple 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 fluids and forming three-dimensional, hydrophilic networks [1]. Since the gel layer formation, which defines the kinetics of drug 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 field of pharmaceutics. However, although chitosan is a very promising biopolymer as a release-controlling agent in drug delivery, it has limited capacity for controlling drug release when 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, extended-release effect of the combination system was achieved by forming the polyelectrolyte complexes (PECs) between CS and anionic polymers in solution first 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 fluid due to self-assembly or spontaneous association [10]. However, drug release from this CS-SA based system presented obvious drug solubility 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 first-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 efficacy 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 into extended-release dosage forms with high loading (500mg/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 influence 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 (50kDa, lOOkDa and 400kDa) 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. Sodium Alginate (SA, LF 200M, 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 extended-release 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 11mg as antisticking agent), magnesium stearate (11mg) 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 55oC. 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 first 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 replenished with equal amounts of fresh release medium. The amount of drug released at different time intervals was determined using high-performance liquid chromatography (HPLC) method [15].

The differences in release profiles 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, Rt is the dissolution value of the reference at time t, and Tt is the dissolution value of the test at time t. The release profiles were significantly different iff2<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 nitrogen atmosphere. The samples were cooled to room temperature and then reheated from 25-320 °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"1 was 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. Briefly, 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 erosion and swelling ratios were calculated according 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, Wo is the initial weight of the dry tablet, Wj is the weight of drug released at time i, IV, is the weight of remaining dry tablet after swelling at time t, Wt is 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.

ER{%) = (W0 - Wr - Wd)/W0 x 100 SR(%) = (Wt - Wr)/Wr x 100 RM(%) = 100 - ER

3. Results and discussion

3.1. Evaluation of CS-anionic polymers as extended-release 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 (400kDa) 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 200mg, influence 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 extend drug 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 (1000p,g/ml) at neutral pH, a large amount of drug was released in a short period of time.

Thus, in order to further prolong drug release to 24 h, combination of these anionic polymers with CS was subsequently investigated. Figure 2 shows the drug release profiles 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 and the extended-release characteristics became more remarkable. 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 hours. 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 influence the hydration property and drug diffusion coefficient in the extended-release system. Since drug release from CS-XG-based tablets exhibited the best extended-release behavior, therefore the CS-XG system was selected for this investigation. By keeping the total amount of CS (400 kDa) and XG being 200 mg in each formulation, effect of CS/XG ratio at 3/1,1/1,1/3, on drug release was evaluated and the results are shown in Figure 3.

No significant difference in release was found when changing the ratio of CS to XG from 3/1 to 1/1 (/2=92). Although a slight fluctuation in drug release occurred when CS to XG ratio was 1/3, the similarly factors were still larger than 50 (f (3/1-1/3) = 71, f2 (1/1.1/3) = 67), indicating that the weak fluctuation did not lead to large deviation from the whole trend. Thus, drug release was less influenced 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 using three kinds of CS with low (50kDa), medium (100kDa) and high (400kDa) molecular weights. The release profiles are presented in Figure 4.

It was noted that no apparent difference in drug release was found in the first 6 h and thereafter slightly decreased release rate was observed with the increase of chitosan molecular weight. On the whole, the drug release profiles from these three kinds of CS based systems was similar to each other

(f (CS LMW-MMW) =67 > 50,_f (CS lmw-hmw) =69 > 50,f2 (cs mmw-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 profiles from different molecular weight chitosan based systems.

3.4. Characterization of the CS/XG PECs

In our previous study, it was found that the self-assembled PECs film was formed on the tablet surface of CS-SA based system during the dissolution process [10]. Therefore, based on the structure properties of the polymers, it was reasonably to assume that in situ PECs can be formed on the tablet surface of CS-XG based system. Indeed, insoluble white film (shell structures) was observed visually on the outer surface of the tablets during the dissolution test, similar phenomenon was reported in CS-SA based system [11]. In order to identify the composition of the film, FIIR and DSC were applied to characterize the physicochemical properties of the films collected from tablet surface.

Figure 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 significant 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-1 and 1605 cm-1 were 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-1 corresponding 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-1 was 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 aid) 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 not clear how this PEC can influence 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 significant 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 hour. 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, significantly decreased erosion and swelling was only observed after its complete formation at 6 h. Based on the above analysis, it can be concluded that later stage 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 water-soluble drugs, the combination of sodium valproate and valproic acid were demonstrated. Among them, drug release from CS-XG based matrix system exhibited the best extended release behavior and was less influenced 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 water-soluble drugs with high drug loading and this broadened current views on hydrophilic polymers based matrix tablets.

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