Scholarly article on topic 'Effect of formulation variables on in vitro release of a water-soluble drug from chitosan–sodium alginate matrix tablets'

Effect of formulation variables on in vitro release of a water-soluble drug from chitosan–sodium alginate matrix tablets Academic research paper on "Chemical sciences"

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Abstract of research paper on Chemical sciences, author of scientific article — Liang Li, Jinfeng Li, Shanshan Si, Linlin Wang, Chenjun Shi, et al.

Abstract The objective of this study is to investigate the feasibility of using chitosan–sodium alginate (CS–SA) based matrix tablets for extended-release of highly water-soluble drugs by changing formulation variables. Using trimetazidine hydrochloride (TH) as a water-soluble model drug, influence of dissolution medium, the amount of CS–SA, the CS:SA ratio, the type of SA, the type and amount of diluents, on in vitro drug release from CS–SA based matrix tablets were studied. Drug release kinetics and release mechanisms were elucidated. In vitro release experiments were conducted in simulated gastric fluid (SGF) followed by simulated intestinal fluid (SIF). Drug release rate decreased with the increase of CS–SA amount. CS:SA ratio had only slight effect on drug release and no influence of SA type on drug release was found. On the other hand, a large amount of water-soluble diluents could modify drug release profiles. It was found that drug release kinetics showed the best fit to Higuchi equation with Fickian diffusion as the main release mechanism. In conclusion, this study demonstrated that it is possible to design extended-release tablets of water-soluble drugs using CS–SA as the matrix by optimizing formulation components, and provide better understanding about drug release from CS–SA matrix tablets.

Academic research paper on topic "Effect of formulation variables on in vitro release of a water-soluble drug from chitosan–sodium alginate matrix tablets"

asian journal of pharmaceutical sciences xxx (2014) 1-8

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Original Research Paper

Effect of formulation variables on in vitro release of a water-soluble drug from chitosan-sodium alginate matrix tablets

Liang Li a, Jinfeng Li a, Shanshan Si a,b, Linlin Wang a, Chenjun Shi a, Yujiao Sun a, Zhenglin Liang a, Shirui Mao a'*

a School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China b Jiangsu Hengrui Medicine Co., Ltd., Lianyungang 222047, Jiangsu, China

ARTICLE INFO ABSTRACT

Article history: The objective of this study is to investigate the feasibility of using chitosan-sodium algi-

Received 20 July 2014 nate (CS-SA) based matrix tablets for extended-release of highly water-soluble drugs by

Received in revised form changing formulation variables. Using trimetazidine hydrochloride (TH) as a water-soluble

9 September 2014 model drug, influence of dissolution medium, the amount of CS-SA, the CS:SA ratio, the

Accepted 11 September 2014 type of SA, the type and amount of diluents, on in vitro drug release from CS-SA based

Available online xxx matrix tablets were studied. Drug release kinetics and release mechanisms were eluci-

__dated. In vitro release experiments were conducted in simulated gastric fluid (SGF) followed

Keywords: by simulated intestinal fluid (SIF). Drug release rate decreased with the increase of CS-SA

Chitosan amount. CS:SA ratio had only slight effect on drug release and no influence of SA type on

Sodium alginate drug release was found. On the other hand, a large amount of water-soluble diluents could

Matrix tablets modify drug release profiles. It was found that drug release kinetics showed the best fit to

Hydrophilic matrices Higuchi equation with Fickian diffusion as the main release mechanism. In conclusion,

Trimetazidine hydrochloride this study demonstrated that it is possible to design extended-release tablets of water-

Extended-release soluble drugs using CS-SA as the matrix by optimizing formulation components, and

provide better understanding about drug release from CS-SA matrix tablets.

© 2014 Shenyang Pharmaceutical University. Production and hosting by Elsevier B.V. All

rights reserved.

1. Introduction

Polymer-based monolithic matrix tablets are the most commonly used to fabricate oral extended-release dosage

forms because of the economic benefits, the relative simplicity of process development and scale-up procedures. For decades, hydrophilic matrices have been widely utilized to prepare matrix tablets. In general, drugs are dispersed or dissolved in

* Corresponding author. School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenhe District, Shenyang 110016, Liaoning, 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.2014.09.002

1818-0876/© 2014 Shenyang Pharmaceutical University. Production and hosting by Elsevier B.V. All rights reserved.

2 ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES XXX (2014) 1-8

hydrophilic matrix and they are available for release as the matrix hydrates, swells (forms a gel), and dissolves [1]. Hy-drophilic matrices have the capability to provide desired release profiles for a wide range of drugs using established and well-characterized excipients. So far, most commercially available controlled-release products are fabricated using nonionic polymers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose and polyethylene oxide [1—3]. At present, a few anionic polymers, such as sodium carbox-ymethyl cellulose, carbomer, xanthan gum and sodium algi-nate (SA), also showed great potential for controlling drug release [2,4].

Among the anionic polymers, SA, a water-soluble salt of alginic acid, is a natural linear unbranched polysaccharide extracted from marine brown algae. It consists of different proportions of b-D-mannuronic acid (M) and a-L-guluronic acid (G) units and can be prepared with a wide range of molecular weight (MW 50—100,000 kDa) [5,6]. Due to its biocom-patibility and ease of gelation, SA hydrogels are particularly attractive in oral drug delivery [5]. For example, verapamil hydrochloride extended-release matrices (Calan®SR, Pfizer) containing a combination of hydroxypropyl methylcellulose and SA produce desired drug release profile in uiuo [1]. The presence of carboxylate groups that can accept or release protons in response to pH change makes SA pH sensitive. At pH values below the pKa of the M (3.38) and G (3.65) monomers, the soluble sodium salt is converted to insoluble alginic acid. In the matrix tablets, pH sensitivity of SA could affect characteristics of the diffusion barrier and as a consequence drug release [1]. Cryogenic electron microscopy reveals the hydrated surface layer formed by SA matrices in simulated gastric fluid (SGF) was particulate and porous, which induced crack formation or lamination of SA matrix tablet, leading to burst release of drug in gastric environment. This compromised the integrity of drug diffusion barrier and resulted in loss of controlling release [7,8]. In contrast, a highly hydrated continuous swollen layer was formed in simulated intestinal fluid (SIF) [7]. However, SA-based matrix tablets usually could not extend drug release for more than 12 h due to its swelling and erosion in SIF [9,10]. To overcome this shortcoming, some innovative approaches have been attempted to modify SA matrices for better control of drug release, such as inclusion of pH-modifiers [8], incorporation of crosslinking agents [5,11] and combination with other hydrophilic matrices [12]. Among them, SA in combination with chitosan (CS) played a key role in controlling drug release.

CS, obtained by deacetylation of chitin from crustacean shells, is a cationic polysaccharide consisting of repeating D-glucosamine and N-acetyl-D-glucosamine units linked via (1—4) glycosidic bonds [13]. It was reported that CS—SA poly-electrolyte complexes could be used as the oral controlled-release matrix. Consequently, the integrity of SA matrices could be improved by the interaction with CS and the drugs entrapped were retained for a longer time. Meanwhile, CS also showed drug release controlling capacity due to gelling [14]. In previous reports, in situ polyelectrolyte complexes formation based on the physical mixtures of SA and CS were found, avoiding the complex process of preparing polyelectrolyte complexes [15]. The new mechanism updated CS—SA based drug delivery systems. SA has been attempted to control the

release of highly water-soluble drugs such as chlorphenir-amine maleate [8], diltiazem hydrochloride [11], and verap-amil hydrochloride [12], but with some limitations. Thus, CS—SA matrix tablets loading a highly water-soluble drug draw more attention as they are easy and economical to prepare by using the common tableting procedures.

Therefore, in the present study, by using trimetazidine hydrochloride as the model drug, which has high aqueous solubility in both acidic and neutral media (both more than 1 g/ml at pH 1.2 and 6.8, respectively, at 20 °C) [16], influence of formulation variables on drug release from CS—SA matrix tables were investigated systemically, and drug release kinetics and transport mechanisms were elucidated using different mathematical models.

2. Materials and methods

2.1. Materials

Trimetazidine hydrochloride was purchased from Hubei-Sihuan Pharmaceutical Co., Ltd. (Wuhan, Hubei, China). Chi-tosan was purchased from Weifang Kehai Chitin Co., Ltd. (Weifang, Shandong, China) with a molecular weight of about 400 kDa and a degree of deacetylation of 86.5%. Sodium alginate (Table 1) [17] and microcrystalline cellulose (MCC, Avicel PH-200) were kindly provided as a gift by FMC Biopolymer (Philadelphia, Pennsylvania, USA). Lactose monohydrate (FlowLac® 100) was kindly provided by Meggle Excipients & Technology (Wasserburg, Germany). Pregelatinized starch and magnesium stearate were kindly provided by Anhui Shanhe Pharmaceutical Excipients Co., Ltd. (Huainan, Anhui, China). Aerosil was purchased from Huzhou Zhanwang Pharmaceutical Company, Ltd. (Huzhou, Zhejiang, China). All other chemicals were of analytical grade.

2.2. Preparation of matrix tablets

The formulations studied are shown in Table 2. Tablets containing CS-SA as polymeric carriers, microcrystalline cellulose, pregelatinized starch and lactose monohydrate as fillers, and magnesium stearate and aerosil as lubricants were prepared by direct compression method. The model drug and the excipients used were all passed through 80-mesh sieve. The model drug and excipients except for magnesium stearate were firstly blended for at least 10 min. Thereafter, magnesium stearate was added and mixed for another 2 min. Tablets were prepared using a single punch tableting machine (DP30A; Beijing Gylongli Company, Ltd., Beijing, China) equipped with

Table 1 - FMC biopolymer commercially available alginate products for controlled-release.

Trade name Viscosity (mPa.s, 1% w/v SA sol., 20 °C) M/G (%)

Protanal LF200M 200-400 55-65/35-45

Protanal LF120M 70-150 55-65/35-45

Protanal LF240D 70-150 65-70/30-35

M/G: manuronate/guluronate [17].

AsiAN joutNAI of pHAiMaceutiGAi sciïncïs xxx (2014) 1-8 3

Table 2 - Composition of the investigated tablet formulations containing 35 mg of trimetazidine hydrochloride (mg).

Batch CS SA LF200M SA SA Microcrystalline Pregelatinized Lactose Magnesium Aerosil

code LF120M LF240D cellulose starch monohydrate stearate

F1 17.50 17.50 - - 178.25 - - 1.25 0.50

F2 52.50 52.50 - - 108.25 - - 1.25 0.50

F3 70.00 70.00 - - 73.25 - - 1.25 0.50

F4 87.50 87.50 - - 38.25 - - 1.25 0.50

F5 105.00 105.00 - - 3.25 - - 1.25 0.50

F6 - 175.00 - - 38.25 - - 1.25 0.50

F7 25.00 150.00 - - 38.25 - - 1.25 0.50

F8 35.00 140.00 - - 38.25 - - 1.25 0.50

F9 43.75 131.25 - - 38.25 - - 1.25 0.50

F10 58.30 116.70 - - 38.25 - - 1.25 0.50

F11 116.70 58.30 - - 38.25 - - 1.25 0.50

F12 140.00 35.00 - - 38.25 - - 1.25 0.50

F13 175.00 - - - 38.25 - - 1.25 0.50

F14 87.50 - 87.5 - 38.25 - - 1.25 0.50

F15 87.50 - - 87.50 38.25 - - 1.25 0.50

F16 87.50 - - 87.50 138.25 - - 1.25 0.50

F17 87.50 - - 87.50 - 138.25 - 1.25 0.50

F18 87.50 - - 87.50 - - 38.25 1.25 0.50

F19 87.50 - - 87.50 - - 138.25 1.25 0.50

an 8 mm (F1-F15, F18) or 10 mm (F16, F17, F19) diameter punch with beveled edges. Hardness of all the tablets was adjusted to 40-80 N. Total tablet mass was around 250 mg (F1-F15, F18) or 350 mg (F16, F17, F19).

2.3. In vitro release studies

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 if f2 < 50. Only one measurement should be considered after 85% dissolution of both the two contrastive formulations [19].

Drug release tests were carried out using a dissolution apparatus (ZRD6-B, Shanghai Huanghai Medicament Test Instrument Factory, Shanghai, China) with the basket method (USP Apparatus I), rotating at 100 rpm at 37 ± 0.5 °C. Unless specially indicated, the tablets were submerged into 900 ml of simulated gastric fluid (SGF: hydrochloric acid solution, pH 1.2, enzyme free) for 2 h, then the tablets were transferred to 900 ml of simulated intestinal fluid (SIF: phosphate buffer, pH 6.8, enzyme free) for additional 10 h. This method was used to simulate the situation of a tablet's transit through the gastrointestinal tract [18]. Aliquots of 10 ml were withdrawn at different time intervals (1, 2, 4, 6, 8, 10 and 12 h) and were replaced with equal amounts of fresh release medium. The sample solution of trimetazidine hydrochloride filtered through a 0.45 mm membrane filter was determined by Agilent 1100 HPLC system (Agilent Technologies, Santa Clara, California, USA). A 20 ml volume was injected into a Diamonsil® C18 column (200 x 4.6 mm, 5 mm; Dikma Technologies, Beijing, China) with 0.05 mol/l potassium dihydrogen phosphate (pH 3.0)/methanol 85/15 (v/v) as the mobile phase. Column temperature was kept at a constant temperature of about 40 °C; the flow rate was 1 ml/min and the detector's wavelength was set at 231 nm.

Drug release studies were carried out in triplicate for each formulation tested and standard deviations were calculated. The difference in dissolution profiles was compared using similarity factor (f2). The similarity factor was calculated using the Eq. (1):

Mathematical analysis

/2 = 50 x log

1 + (1/n)^(Rt - Tt)2

2.4.1. Mathematical analysis of drug release kinetics Drug release kinetics from the prepared matrix tablets was analyzed by fitting the dissolution data into Zero-order equation (Eq. (2)), First-order equation (Eq. (3)) and Higuchi equation (Eq. (4)) [20]:

= feet

M. k t

_L — 1 _ e-k1t

M = k2t1/2

where Mt is the amount of drug dissolved at time t, Mœ is the amount of drug dissolved after infinite time (drug amount in the formulation), Mt/Mœ is the fractional release of the drug at time t, and k0, fea and k2 are the release rate constants.

2.4.2. Mathematical analysis of the drug transport mechanism

The Ritger-Peppas equation was applied (Eq. (5)) to characterize drug release mechanism from the polymeric system [21]:

M = fetn

where the Mt/MOT < 0.6 data are used for calculation, k is a constant incorporating structural and geometric

ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES XXX (2014) 1-8

characteristics of the dosage form, n is the release (diffusion) exponent, which depends on the release mechanism and shape of the matrix tested and t is the release time. Exponent n for polymeric controlled delivery systems of cylindrical geometry has values of n < 0.45 for Fickian diffusion, 0.45 < n < 0.89 for anomalous (non-Fickian) transport and n > 0.89 for Case II (relaxation) transport.

The Peppas-Sahlin equation (Eq. (6)) was further used to account for the coupled effects of Fickian diffusion and Case II (relaxation) transport [22,23]:

Mt _ k tm , k f2m

m! " kFt + kRt2

where the first term of this equation represents Fickian diffusion (F) contribution and the second term refers to the macromolecular relaxation (R) contribution on the overall release mechanism. kF and kR are the diffusion and relaxation rate constants, respectively; the coefficient m is the purely Fickian diffusion exponent for a device of any geometrical shape which exhibits controlled-release. The ratio of Fickian contribution over relaxation contribution is expressed as Eq. (7):

F = kF * 1

R kR tm

3. Results and discussion

3.1. Preliminary evaluation of different pH media

This first experiment was used as a screening procedure to investigate the influence of dissolution media on the in vitro drug release. Fig. 1 illustrates drug release profiles from the CS-SA matrix (F4, CS:SA:TH = 2.5:2.5:1) in different pH media. Although TH is a highly water-soluble drug (>1 g/ml) with pH-independent solubility, the release profiles of TH from the three studied media (i.e., SGF, SIF and SGF followed by SIF) are still very different, indicating pH-dependent release characteristics. The fastest drug release was found in SIF, and the slowest release was in SGF followed by SIF, drug release in SGF was in between. It was reported that release of a highly soluble drug from SA matrix tablets was faster in SGF than in SIF,

especially in the first 2 h, due to the particulate and porous formation in SGF [7,8]. However, as the CS was added into the SA matrices, the opposite effect was observed in the present study. Drug release in SGF and SIF was 35% and 45% after 2 h, respectively. Moreover, drug release in SIF was complete around 8 h. In contrast, drug release in SGF was extended for more than 10 h. This phenomenon might be explained by the physicochemical properties of CS and SA. Although SA could form particulate and porous structure on the surface of SA matrices in SGF, the gelling (swelling) of CS in SGF could compensate for this structure defect, thereby improving the capacity of controlling release. On the other hand, due to erosion of SA and slight disintegration of CS in SIF [9,24], drug was released gradually with the increase of time. Theoretically, the rate of drug release in SGF followed by SIF should be larger than that in SGF and smaller than that in SIF. However, the abnormal results were obtained from the release profiles, which might be associated with the new mechanism of CS-SA based matrix tablets, namely a theory of self-assembled film described in the previous report [15]. It was disclosed that drugs were released from CS-SA matrix tablets in SGF followed by SIF through CS-SA based hydrophilic matrices and CS-SA polyelectrolyte complexes-based film. The film was only formed on the surface of tablets in gastrointestinal environment. The film could decrease the rate of polymer swelling to a degree and also greatly limit the erosion of tablets, therefore extending the release of TH significantly. In order to mimick drug release environment in vivo and combine with the new release mechanism, the release condition, namely SGF followed by SIF, was chosen for the investigation of formulation variables.

3.2. Effect of the amount of CS-SA on in vitro drug release

With the objective of studying the effect of CS-SA amount on TH release from matrices, tablets with various CS-SA to TH ratios were prepared (F1-F5). Fig. 2 shows the release profiles of TH from matrix tablets with varied amount of CS-SA (i.e., 14%, 42%, 56%, 70% and 84% (w/w)) and the same CS:SA ratio (CS:SA = 1:1, w/w). The amount of CS-SA used had a

Fig. 1 - Effect of different pH media on in vitro drug release.

Fig. 2 - Effect of the amount of CS-SA on in vitro drug release.

ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES XXX (2014) 1 —8 5

significant effect on the drug release characteristics. As the amount of CS-SA increased, drug release from matrices slowed down. It was thought that increasing the concentration of hydrophilic polymer made the gel layer or swollen layer become thicker and more tortuous, thereby decreasing drug release [25,26].To understand drug release kinetics from the polymeric matrices, release data were firstly analyzed according to Zero-order, First-order and Higuchi models and the main parameters are listed in Table 3. Due to obvious burst release from F1 (14% CS-SA), data points with Mt/MOT < 0.6 were just one, not suitable for fitting some models. Thus, some results were absent in Table 3. Firstly, no formulations fit the Zero-order kinetics model, meaning that it is very difficult to get Zero-order release profile from highly water-soluble drug loaded CS-SA matrix tablets. In contrast, the R2 values calculated from the Higuchi model (M/M^ < 0.6) suggested best fit. On the other hand, with the increase of CS-SA amount, the R2 values calculated from the First-order model increased. Drug release mechanism was also analyzed according to Ritger-Peppas and Peppas-Sahlin models. For Peppas-Sahlin model, m = 0.435 was determined because the tablets present an aspect ratio (diameter/thickness) around 2.7 [23]. In general, the experimental data obtained from these formulations showed a good fit for the two models with the values of R2 more than 0.99. Using Ritger-Peppas model, the value of the exponent n was calculated. As shown in Table 3, n = 0.446 were obtained for tablets with 42% CS-SA. This result was another indication that the dominant drug transport mechanism appeared to be Fickian diffusion (n < 0.45). As the amount of CS-SA increased to 56%, the drug transport mechanism revealed anomalous transport with the value of n between 0.45 and 0.89. And, the similar mechanism was also found for formulations with 70% and 84% CS-SA. Release mechanism was further elucidated by the Peppas-Sahlin model. As the amount of CS-SA increased, relaxation contribution gradually played a role in drug delivery (Table 3). However, Fickian diffusion still played a decisive role in drug release with F/R > 1 (Eq. (7), data not shown), which was consistent with the good fit to Higuchi model (Table 3). It should be mentioned that Peppas equations were usually utilized to analyze the early stage of drug release [27]. According to the previous studies [15], less erosion of CS-SA based matrix tablets was observed in the late stage of release, and therefore it could be deduced that the data with Mt/M„ > 0.6 might be mainly suitable for diffusion-based release kinetics and the drug was released from the system based on the mechanisms including swelling, diffusion and erosion [2,26,28].

3.3. Effect of CS-SA ratio on in vitro drug release

The physicochemical properties of CS and SA are pH-dependent. Thus, the ratio of CS to SA might influence drug release. Fig. 3 shows TH release characteristics from F4 and F6-F13 with different CS-SA ratios. As the SA was used alone to control drug release, the release of TH could only be extended for 8 h. This was explained by the swelling and erosion of SA in SGF followed by SIF [9]. In contrast, once SA was mixed with CS for controlling release, the drug release rate decreased significantly. For example, when only 10% CS (F7, CS:SA = 1:6) was added into the formulation, drug release in the first 2 h was 43% and was obviously lower compared to that in the pure SA-based tablets with 52% TH released (F6, CS:SA = 0:1). More importantly, F7 (CS:SA = 1:6) could extend drug release for more than 12 h. Moreover, with the increase of CS amount in the matrix, drug release decreased gradually. As the CS:SA ratio changed from 1:6 to 1:1, the corresponding release reduced from 43% to 34% in the first 2 h. After 12 h, release also reduced from 88% (F7) to 79% (F4) (Fig. 3a). However, it seems that change of drug release mainly happened in the first 4 h. Further analysis was conducted with the data obtained in 4-12 h using the Zero-order equation. The release rate constant (k0) was in the range of 4.4-4.7%/h. And, the coefficient of correlation (R2) was in the range of 0.988-0.999. The self-assembled film based matrix tablets, associated with swelling, diffusion and erosion-based release mechanisms, might result in the approximately Zero-order release characteristics in SIF (4-12 h) [15,26,28]. As CS:SA ratio further increased from 1:1 (F4) to 4:1 (F12), no significant change in release profiles was found (Fig. 3b). When CS was used alone as the matrix (F13), TH was released faster compared to F12 (CS:SA = 4:1), probably due to the low capacity of CS for controlling drug release in SIF [29]. However, no significant difference was found among these release profiles withf2 > 50.

3.4. Effect of SA type on in vitro drug release

It has been reported that the viscosity of SA and the ratio of mannuronic acid (M) to guluronic acid (G) in the chemical structure of SA could influence drug release from SA-based matrix tablets [10]. Thus, it is essential to evaluate the effect of SA type on drug release from CS-SA based matrix tablets. Here, three types of SA were chosen for investigation (Table 1). Fig. 4a showed the influence of the SA viscosity on the drug release. No significant difference in drug release was found in the two formulations (F4 vs. F14). Probably although SA LF200 has a higher viscosity than that of SA LF120, the slight

Table 3 - Estimated parameters obtained from fitting drug release data to Zero-order, First-order, Higuchi, Ritger-Peppas and Peppas-Sahlin equations. The amount of CS-SA was in the range of 14%-84%.

Batch code Zero-order First-order Hig uchi Ritg er—Peppas Peppas—Sahlin

k0 R2 k1 R2 k2 R2 k n R2 kF kR R2

F1 (14%) — — 0.679 0.943 — — — — — — — —

F2 (42%) 0.092 0.543 0.243 0.947 0.322 0.993 0.340 0.446 0.995 0.339 0.030 0.995

F3 (56%) 0.083 0.704 0.172 0.950 0.259 0.995 0.276 0.454 0.998 0.270 0.007 0.998

F4 (70%) 0.077 0.814 0.140 0.966 0.223 0.996 0.226 0.493 0.996 0.209 0.019 0.996

F5 (84%) 0.076 0.849 0.135 0.975 0.215 0.997 0.209 0.521 0.997 0.183 0.028 0.997

ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES XXX (2014) 1-8

Fig. 3 - Effect of the ratio of CS-SA on in vitro drug release.

Time (h)

Fig. 4 - Effect of the SA type on in vitro drug release.

variation could not induce significant change in diffusion kinetics due to the very soluble property of TH [28]. Similarly, the different ratios of M-G had no significant influence on drug release (Fig. 4b, F14 vs. F15). Theoretically, based on different gelling and swelling-erosion characteristics induced by the amount of M and G [9], high M (SA LF240D) might be more advantageous than high G (SA LF120M) in sustaining the release of a water-soluble drug in SGF followed by SIF [10]. However, as mentioned in Section 3.1, CS could modify drug release from SA-based matrices in SGF followed by SIF medium, partly reducing the diversity of release profiles. Moreover, CS-SA polyelectrolyte complexes could be formed on the surface of tablets in SGF followed by SIF medium, which also discounted the diversity in swelling and erosion arising from different SA types [15], leading to similar release profiles irrespective of SA type.

3.5. Effect of diluents on in vitro drug release

Diluents are usually used to make the formulation more suitable for industrial scale production. However, it was reported that drug release was sometimes influenced by the

amount and the solubility of diluents [2]. To get more knowledge about drug release characteristics from CS-SA based formulations, a large amount of diluents were added to the matrix tablets (F16, F17 and F19). Fig. 5 shows the release behavior when microcrystalline cellulose (a diluent insoluble in water), pregelatinized starch (a partly water-soluble diluent) and lactose monohydrate (a water-soluble diluent) were added to formulations. Compared to 15.3% (w/w) microcrystalline cellulose formulation (F15), approximately the same release profiles (F15, F16 and F17) were obtained, indicating that the diluents that have low solubility in water had no significant effect on drug release. Similarly, when 15.3% (w/w) lactose monohydrate was added to matrix tablets, drug release had no significant change compared to F15 (f2 > 50). However, as the amount of lactose monohydrate increased to 39.5%, drug release was obviously accelerated with f2 = 48.2 < 50, implying only a large amount of water-soluble diluents could modify the release behavior. This can probably be explained by the mechanism that a large amount of water-soluble diluents could increase the porosity of swollen matrices and decrease gel strength, especially for the CS-SA polyelectrolyte complexes film based tablets [2]. These

ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES XXX (2014) 1-8

Fig. 5 - Effect of diluents on in vitro drug release.

effects could increase drug diffusion coefficient and accelerate the erosion of matrices through porous film [28]. Finally, drug release rate was changed.

4. Conclusions

The present study demonstrated that some formulation variables could indeed influence the release of a water-soluble drug (TH from CS-SA matrix tablets). It was shown that CS could compensate the loss of SA in SGF followed by SIF by the synergistic reaction with SA, further extending drug release for a longer time. The amount of CS-SA had the largest effect on drug release kinetics. In contrast, CS:SA ratio had slight effect on drug release and the type of SA had no significant effect on the release of TH. Meanwhile, drug release rate was changed as a large amount of water-soluble diluents were added to CS-SA matrix tablets. Finally, deep understanding drug release characteristics and release mechanisms from CS-SA matrix tablets could facilitate product optimization and avoid time-consuming and cost-intensive series of trial-and -error experiments.

Acknowledgments

This project is financially supported by Liaoning Institutions excellent talents support plan (No. LR2013047). The authors wish to thank FMC Biopolymer for the supply of sodium alginate and microcrystalline cellulose, Shanhe Pharmaceutical Excipients Co., Ltd. for the supply of pregelatinized starch and magnesium stearate, and Meggle Excipients & Technology for the supply of lactose monohydrate.

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