Application of statistical design on the early development of sustained-release tablet containing ivy leaf extract

Journal of Drug Delivery Science and Technology 54 (2019) 101319

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Application of statistical design on the early development of sustainedrelease tablet containing ivy leaf extract

T

Young-Guk Na, Sung-Hoon Jeon, Jin-Ju Byeon, Min-Ki Kim, Hong-Ki Lee∗∗, Cheong-Weon Cho∗ College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, Republic of Korea

ARTICLE INFO

ABSTRACT

Keywords: Ivy leaf extract Hederacoside C Sustained-release tablet Design of experiment Dissolution

The aim of this study was to develop a sustained-release (SR) tablet of ivy leaf extract (ILE) that exhibits robust dissolution profiles unaffected by pH and mechanical stress in the gastrointestinal (GI) tract using statistical design. The response surface design was used to study the effect of type and amount of sustaining polymer on the drug release over time. The type and amount of sustaining polymers were set as factors. The percentages of dissolved hederacoside C, as an indicator substance of ILE, at 6, 12, and 24 h were set as the responses. The highest desirability value was obtained when 26.09% of HPMC K15 M (hydroxypropyl methylcellulose, 15,000 mPa s) was used among the various polymers tested. The granules and tablets prepared with this composition showed acceptable physical properties (bulk density, tapped density, angle of repose, thickness, hardness, and friability). The drug release profiles of the SR tablet exhibited non-Fickian mechanism close to zero-order release based on the Korsmeyer-Peppas model regardless of the pH of dissolution media and the paddle speed of the dissolution tester. Overall, the present study suggested a new statistical approach to the development of SR tablets containing herbal medicine and successfully developed the tablets.

1. Introduction Ivy leaf is commonly referred to Hedera helix and belongs to a family of Araliaceae [1]. Ivy leaf is extracted using an aqueous-ethanol mixture as an extraction solvent, and this extract is used as herbal medicine. Ivy leaf extract (ILE) is known to contain pharmacologically active saponins, which generally have anti-inflammatory, antiviral, antibacterial, antimicrobial, and antiparasitic effects [2]. Hederacoside C is one of the active ingredients of this extract and is effective in the treatment of acute respiratory infections and chronic inflammatory bronchitis [3,4]. This extract had been developed as a tablet formulation for oral administration. As a commercial product containing ILE, Hebron-F® tablets (SamA Pharm. Co. Ltd., Seoul, Korea) and Ivy Extract® tablets (Enzymatic Therapy™, Green Bay, WI, USA) have been used as a treatment for acute inflammation of the respiratory system with chronic inflammatory bronchial disease and cough symptoms. However, Hebron-F® tablets should be administrated 25 mg three times daily or 50 mg twice daily, which can be inconvenient for frequent administration to patients. Therefore, it is necessary to develop a formulation that can maintain drug efficacy continuously. Sustained-release (SR) tablet is a formulation that can control the drug release over a long period of time, thereby continuously showing ∗

the drug efficacy [5]. The SR tablet allows the plasma concentration of the drug to be maintained within the therapeutic window throughout the dosing interval, thereby reducing the number of doses [6]. Therefore, the tablet improves patient compliance and reduce the side effects of drug reactions. The SR tablets are delivered into the gastrointestinal (GI) tract after oral administration, and then the drug is dissolved by GI fluid and motility of GI tract [7]. The drug dissolution rate of SR tablet is generally influenced by the composition of GI fluids (pH, enzymes, and salts) and the mechanical stress in the GI tract [8]. Since the physical pH and motility of GI tract vary widely among individuals, it is necessary to develop an ideal SR tablet that exhibits a robust release profile regardless of these variables. However, the SR tablet containing ILE (ILE-SR tablet), which are administered once a day, have not yet been developed, because it is difficult to control the release and analyze the indicator substance of herbal medicine. SR tablets are influenced by many variables in the formulation and manufacturing process [9]. Also, the tablets are developed based on an empirical trial and error approaches, resulting in high variability of product quality [10]. For the past decade, statistical design approaches to preparation and optimization of tablet have been applied to understand the interaction between substance attributes, process parameters, and factors affecting tablet quality [11,12]. In particular, a response

Corresponding author. College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, Republic of Korea. Corresponding author. College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, Republic of Korea. E-mail addresses: [email protected] (H.-K. Lee), [email protected] (C.-W. Cho).

∗∗

https://doi.org/10.1016/j.jddst.2019.101319 Received 11 August 2019; Received in revised form 18 September 2019; Accepted 8 October 2019 Available online 09 October 2019 1773-2247/ © 2019 Elsevier B.V. All rights reserved.

Journal of Drug Delivery Science and Technology 54 (2019) 101319

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surface design can be used to effectively characterize these interactions [13]. The design has been used to model the effect of the composition of the tablet and the type of excipient on the quality change of the product. However, few studies have been reported on the implementation of statistical design approaches in the development of herbal medicine tablet to understand the interactions between formulation variables and product characteristics more comprehensively. The study aims to develop the ILE-SR tablet via statistical design. A response surface design was applied to investigate the effect of type and amount of sustaining polymer on the drug release. The ILE-SR tablet was prepared with the optimized composition providing an acceptable drug release profile, and the profile of the tablet was determined in different pH media and paddle speed of dissolution tester.

Table 1 Composition of ILE-SR tablet. Pre-mixture Components

mg

%

ILE Sustaining polymers Avicel PH-102 Pharmatose 100 M PVP K-30 Ethanol Total

100 25–125 7.5–57.5 7.5–57.5 5 q.s 245

12 10–50 3–23 3–23 2.0 q.s 98.0

Components

mg

%

Pre-mixture Aerosil 200 Magnesium stearate Total

245 2.5 2.5 250

98.0 1.0 1.0 100

Post-mixture

2. Materials and methods 2.1. Materials ILE (Extract with 30% ethanol, 5–7.5 → 1, hederacoside C content is 12.4%) was purchased from Martin Bauer Group (Vestenbergsgreuth, Germany). Aerosil 200 (silicon dioxide) was provided by Evonik Industries AG (Essen, Germany). Avicel PH-102 (microcrystalline cellulose) was provided by FMS Corporation (Philadelphia, PA, USA). Several types of hydroxypropyl methylcellulose (HPMC) were provided by Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan). METOLOSE 4000SR (HPMC K4M, 4000 mPa s), METHOLOSE 15000SR (HPMC K15 M, 15000 mPa s), and METOLOSE SR 100000SR (HPMC K100 M, 100000 mPa s) with different viscosities in 2% solutions of polymers were used as HPMC. Pharmatose 100 M (lactose monohydrate) were provided by DFE Pharma (Nörten-Hardenberg, Germany). PVP K-30 (polyvinylpyrrolidone) was purchased from Ashland Inc. (Covington, KY, USA). Magnesium stearate was provided by FACI (Genoa, Italy). Several types of poly(ethylene) oxide (PEO), and Opadry AMB II was provided by Colorcon, Inc. (Harleysville, PA, USA). POLYOX WSR 301 (PEO 301, 3500 mPa s), POLYOX WSR 303 (PEO 303, 8700 mPa s) with different viscosities in 1% solutions of polymers were used as PEO. Hederacoside C standard, ammonium acetate, and ethylamine were purchased from Sigma-Aldrich (St. Louis, MO, USA). Hydrochloric acid, acetic acid, potassium phosphate monobasic, sodium acetate trihydrate, sodium chloride, sodium hydroxide, and phosphoric acid were purchased from Samchun Chemical Co., Ltd (Pyungtaek, Korea). Ethanol, methanol, and acetonitrile were purchased from J.T. Baker® (Phillipsburg, NJ, USA).

fillers. All ingredients of pre-mixture, except for PVP K-30, were blended in a plastic container and mixed for approximately 10 min. The solvent containing PVP K-30 was added to the mixture for granulation and mixed for 5 min. The granule was dried in an oven dryer at 40 °C. The granule was sieved through a 20-mesh sieve, the desiccant and the lubricant were added to the granule and further mixed for 3 min. The tablets were compressed using a single punch column tablet press (Korsh EK0, Korsch AG, Berlin, Germany) equipped with a roundshaped punch (10 mm) and die set at a fixed compression force. The coating of the tablets was carried out using Opadry AMB II as a coating agent for preventing the dampness of the tablet. The coating agent was applied in an amount corresponding to 3% of the tablet weight. For the next study, all samples were stored in closed containers at room temperature. 2.4. Statistical experimental design for ILE-SR tablet The amount and type of sustaining polymers were optimized with response surface design, which is appropriate to screen and investigate interactions between factors with response surface methodology [14,15]. The statistical experimental design and analysis were conducted with Design Expert® 11 (Stat-Ease Inc, Minneapolis, MN, USA). The experiments were designed with the one numeric factor and the one categoric factor (Table 2). The level of amount of sustaining polymer (X1, %) was set as 10–50% and the type of sustaining polymers (X2) was set with 8 kinds of polymers (HPMC K4M, HPMC K15 M, HPMC K100 M, PEO 301, PEO 303, xanthan gum, arabic gum, and alginate). The percentages of dissolved hederacoside C in distilled water at 6 h (Y1), 12 h (Y2), and 24 h (Y3) were set as responses to investigate the influence of the dissolution depending on the type and amount of sustaining polymers. The acceptable ranges of Y1, Y2, and Y3 were 30–40%, 50–70%, and 90–100%, respectively, and the targets of Y1, Y2, and Y3 were 35%, 60%, and 100%, respectively. Total 19 experiments were conducted, and the responses were fitted to one of the suitable models such as linear, cubic, quadratic, special cubic, or quartic model. The statistical parameters such as sequential p-values, squared correlation coefficient (R2), adjusted R2, predicted R2, and adequate precision were evaluated. After fitting the statistical model, the numerical optimization was used to derive the desirability value according to the targets of responses, and the optimal solutions with the high desirability value were selected.

2.2. HPLC analysis Hederacoside C, an indicator substance of ILE, was analyzed with HPLC. A Nexera-i MT series (Shimadzu Corp., Kyoto, Japan) was used to analyze hederacoside C. A Spherisorb® ODS2 column (125 × 4.0 mm, 5 μm; Waters, Milford, MA, USA) was equipped and the mobile phase consisting of acetonitrile and 10 mM ammonium acetate buffer adjusted to pH 8.5 with triethylamine was used (30:70, v/v). The flow rate and the column temperature were set at 1.2 mL/min and 35 °C, respectively. Forty μL of sample was injected and the wavelength of UV–vis detection was set as 205 nm. 2.3. Preparation of ILE-SR tablet The tablets were prepared with different sustaining polymers (HPMCs, PEOs, xanthan gum, arabic gum, and alginate) as described in Table 1 using a wet granulation method. Avicel PH-102 and Pharmatose 100 M were used as fillers. PVP K-30 was used as a binder. Ethanol was used as a solvent. Aerosil 200 and magnesium stearate were added as a desiccant and a lubricant, respectively. In all cases, the amount of ILE in the tablet was 100 mg and the total weight of the tablet was 250 mg. The reduced amount of sustaining polymer was replaced with

2.5. Characterization of ILE-SR granule and tablet Physicochemical properties of the prepared granule according to 2

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Table 2 Factors and responses used in experimental design. Factors

Levels

X1: Polymer amount

Low (−1) 10 1 HPMC K4M

X2: Polymer type

2 HPMC K15 M

Middle (0) 30 3 HPMC K100 M

4 PEO 301

5 PEO 303

6 Xanthan gum

High (+1) 50 7 Arabic gum

8 Alginate

Responses

Acceptable range (%)

Target (%)

Y1: %Dissolved (6 h) Y2: %Dissolved (12 h) Y3: %Dissolved (24 h)

30–40 50–70 90–100

35 60 100

Table 3 Summary of model fitting and statistical analysis. Responses

Suggested model

Model p-value

R2

Adjusted R2

Predicted R2

Adequate precision

Y1: %Dissolved (6 h) Y2: %Dissolved (12 h) Y3: %Dissolved (24 h)

Linear Linear Linear

< 0.0001 < 0.0001 < 0.0001

0.9957 0.9838 0.9326

0.9923 0.9708 0.8786

0.9845 0.9456 0.7611

47.1496 25.8753 14.3166

Note: R2, squared correlation coefficient.

solution 1 were evaluated for the bulk density, tapped density, angle of repose, Hausner ratio, and Carr's index [16]. The bulk density and tapped density of the granule were measured using a powder tester (BT1000, Chongqing Degold Machine Co., Ltd., Chongqing, China). Accurately weighed powders were poured into a calibrated 100 mL cylinder and the volume was measured to calculate the bulk density. The cylinder was then tapped 500 times to measure the tapped density [17]. The bulk density and tapped density (g/mL) were calculated as the ratio of sample mass to the volume before and after tapping, respectively. Carr's index and Hausner ratio were calculated using the bulk density and tapped density. Carr's index of the granule was calculated following the equation: Carr's index = [tapped density – bulk density] × 100/ tapped density [18–20]. The Hausner ratio (HR) was calculated with the equation: Hausner ratio = tapped density/bulk density [18,19]. The angle of repose (θ) of the granule was measured by the conventional funnel method [21]. This method used a funnel fixed to the tip of a given height (H) on a horizontal plane and the granule was poured into the funnel until the top of the conical pile reached the end of the funnel. The angle of repose was calculated using the equation: tan θ = H/R, where R is the radius of the pile [19]. The prepared ILE-SR tablet was evaluated for diameter, thickness, hardness, friability. The diameter and thickness measurements were performed using a digital caliper (Mitutoyo, Kawasaki, Japan) with an accuracy of ± 0.01 mm. Ten tablets were evaluated, and the value of average was reported. The hardness of the tablet was determined with a tablet hardness tester (TBH 125, ERWEKA GmbH, Heusenstamm, Germany). The force to break the tablet was recorded. The measurements were repeated ten times and the average was calculated. The friability of the tablet was measured by a friability tester (PTF3DR, Pharma Test Apparatebau AG, Hainberg, Germany). Ten tablets were randomly selected, weighed (W1), placed in the rotating drum and rotated 100 times. After removing the fragments, the tablet was reweighed (W2) and the friability of tablets was calculated as %weight loss according to the following equation [22]:

Friability (%) =

W1

W2 W1

PVDF membrane filter. The filtered sample was diluted to 1:9 ratio with 50 v/v% ethanol. The standard solution was prepared by dissolving hederacoside C corresponding to 100 mg of ILE in 100 mL of ethanol in a volumetric flask. The solution was diluted in the same way. The concentration of hederacoside C was analyzed by HPLC. 2.6. Evaluation of ILE-SR tablet For the evaluation of suggested solutions, the dissolution tests in the various medium were carried out. The pH 1.2, pH 4.0, pH 6.8, and distilled water were used as dissolution medium, and these mediums were prepared by the USP guidelines [23]. Five hundred mL of medium was used and maintained at 37 ± 0.5 °C with 50 rpm of the paddle speed. In, addition, the dissolution profile according to the paddle speed was evaluated. The paddle speed was set at 50, 100, and 150 rpm, and the experiments were conducted using distilled water as the medium. The dissolution profiles of the tablets were compared with those of Hedera® tablet (commercial product). Sample (5 mL) was collected at predetermined time points (2, 4, 6, 8, 12, and 24 h) and hederacoside C in all samples analyzed by HPLC. Mathematical modeling was used to interpret the drug release profiles of ILE-SR tablets. The hederacoside C release profiles at various dissolution conditions were fitted to the Korsmeyer-Peppas model. The model equation was as follows [24]:

Mt / M = kt Where k is a constant according to the equation. Mt/M∞ is the ratio of drug release at time (t) to the final drug release. n is the diffusional index characterizing the drug release mechanism. The mechanism of drug release was classified according to the n value. For cylindrical shaped tablets, n = 0.45 for Fickian release, 0.45 < n < 0.89 for nonFickian release (anomalous release), n = 0.89 for case II release (zeroorder release), and n > 0.89 for super case II release [25]. This was calculated by fitting the value of the dissolution data for the initial 60% drug release data to the logarithmic form of the equation [26].

× 100 2.7. Statistical analysis

A friability of less than 0.5% was considered acceptable. To determine the drug content, five tablets were taken and finely crushed. Then, a sample equivalent to 100 mg of ILE was accurately weighed and dispersed in 100 mL of ethanol. The dispersion was sonicated for 30 min to extract hederacoside C and filtered with a 0.45 μm

All values in this study were presented as mean ± standard deviation (SD). The significant difference was evaluated using the Student t-test (P < 0.05). Statistical analysis was performed with Prism 8 (GraphPad Software, CA, USA). 3

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Fig. 1. One factor plots of responses. (A) Plots with X2 set to HPMC K4M, HPMC K15 M, HPMC K100 M, and PEO 301. (B) Plots with X2 set to PEO 303, xanthan gum, arabic gum, and alginate. The dotted mark and black line represent the observed response and the predicted response from a linear model, respectively. The green line and red line indicate the range of 95% confidence interval and the acceptable range of each response, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

4

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Table 4 Coded equations of responses according to factors. The low and high limits of X1 are coded as −1 and +1, respectively, and range from −1 to +1 depending on the polymer amount. X2 is coded as 0 or 1 depending on the presence or absence of the sustaining polymer. Responses

Coded equations

Y1 Y2 Y3

44.22 – 9.06X1 – 12.81X2[1] – 10.99X2[2] – 20.40X2[3] – 10.74 X2[4] – 10.81X2[5] – 30.70X2[6] + 49.23X2[7] 62.97 – 17.50X1 + 0.1996X2[1] – 4.38X2[2] – 13.26X2[3] – 5.55 X2[4] – 3.97X2[5] – 32.35X2[6] + 33.68X2[7] 88.11 – 7.17X1 + 5.78X2[1] + 9.30X2[2] – 6.47X2[3] + 0.8444X2[4] + 4.11X2[5] – 23.31X2[6] + 9.10X2[7]

Notes: X2[1] = HPMC K4M; X2[2] = HPMC K15 M; X2[3] = HPMC K100 M; X2[4] = PEO 301; X2[5] = PEO 303; X2[6] = Xanthan gum; X2[7] = Arabic gum.

Fig. 2. Residual plots. (A) Y1: %Dissolved (6 h). (B) Y2: %Dissolved (12 h). (C) Y3: %Dissolved (24 h). Table 5 The experimental composition and observed responses of suggested design. Values are represented as the mean ± SD (n = 3). Run

Factors

Responses

X1

X2

Y1

Y2

Y3

Hardness

Friability

Polymer amount

Polymer type

%Dissolved (6 h)

%Dissolved (12 h)

%Dissolved (24 h)

–

–

%

%

%

kp

%

99.47 ± 2.73 64.80 ± 2.49 96.22 ± 3.41 92.22 ± 3.48 98.39 ± 4.51 89.22 ± 3.45 70.23 ± 2.31 64.80 ± 2.61 81.22 ± 3.41 102.60 ± 2.31 92.21 ± 3.16 96.22 ± 4.56 93.46 ± 3.21 94.94 ± 3.55 79.45 ± 4.51 98.41 ± 1.32 98.45 ± 2.16 88.09 ± 3.41 89.43 ± 3.23

7.1 6.7 9.5 7.6 9.7 7.4 7.9 6.8 8.6 8.7 7.5 8.5 9.2 7.4 7.4 8.9 9.8 6.2 6.4

% 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Extra responses

30 30 10 30 10 50 50 30 30 30 30 30 10 30 50 30 10 30 30

Arabic gum Xanthan gum HPMC K4M PEO 303 HPMC K15 M HPMC K4M HPMC K100 M Xanthan gum HPMC K100 M HPMC K15 M PEO 303 HPMC K4M HPMC K100 M Arabic gum PEO 301 HPMC K15 M PEO 301 Alginate Alginate

94.56 13.52 35.88 33.26 45.15 25.88 12.57 13.52 24.90 31.26 33.56 32.46 33.99 92.34 23.45 32.34 43.52 90.55 92.34

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

3.56 2.54 3.13 2.88 3.65 4.31 2.76 2.91 3.29 3.51 2.79 1.59 0.95 3.59 2.76 1.97 2.69 3.23 2.86

97.86 30.62 75.27 58.22 81.14 51.27 31.23 30.62 46.53 55.99 59.78 62.98 71.38 95.45 39.51 56.16 75.34 86.88 90.31

3. Results and discussion

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

3.48 4.67 5.61 3.95 5.61 3.41 2.14 1.89 1.57 3.45 4.41 3.10 4.61 3.42 4.14 1.42 3.56 2.77 2.14

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

0.6 0.3 1.2 1.3 0.4 0.7 0.3 5.1 0.6 1.0 1.1 0.7 0.6 0.6 0.6 0.6 0.2 0.9 0.7

0.21 0.17 0.09 0.12 0.09 0.14 0.12 0.21 0.10 0.09 0.12 0.09 0.08 0.16 0.17 0.11 0.10 0.17 0.19

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

0.04 0.05 0.02 0.03 0.03 0.04 0.03 0.02 0.05 0.04 0.03 0.01 0.02 0.04 0.05 0.03 0.02 0.02 0.03

important for drug release from the tablets. Tablets containing a low amount of polymers completed the drug release in a shorter time, while the drug release slowed as the amount of polymers increased, thus confirming that the sustaining polymer plays a dominant role in controlling the release of hederacoside C in the tablet [27]. The tablets containing the lowest amount (< 10%) of polymers could not control the release of hederacoside C and dissolved early within 6 h. Therefore, the range of polymer amount was set as 10–50%. In addition, the percentages of dissolved hederacoside C were set as responses to investigate the effect of polymer amount and polymer types on the kinetics of drug release. The statistical models of all Y responses were proposed for linear

3.1. Preparation of ILE-SR tablet Response surface design was used to prepare the ILE-SR tablet. The experimental results of responses were entered into Design Expert® 11 software. Statistical analysis was performed to determine the relationship between the fitting model and the response. The percentage of dissolved hederacoside C at 6 h (Y1), 12 h (Y2), and 24 h (Y3) were crucial responses in the preparation of ILE-SR tablet with a sustained release profile for 24 h. The rational reasons for choosing each factor are as follows: The type of sustaining polymers and their amounts are 5

Journal of Drug Delivery Science and Technology 54 (2019) 101319

Y.-G. Na, et al.

Fig. 3. Interaction plots of responses. (A) Y1: %Dissolved (6 h). (B) Y2: %Dissolved (12 h). (C) Y3: %Dissolved (24 h). The red line is the target value of each response. (D) Y: Desirability values using numerical optimization. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

models (Table 3). To determine the appropriate statistical model, we investigated the statistical parameters such as sequential p-value, R2, adjusted R2, and predicted R2 [28]. Sequential p-value was < 0.05 in all suggested models indicating that the model fitting was significant at the 95% confidence level [29,30]. The R2 and adjusted R2 values reflected how the variability of the suggested model matched the experimental data [31]. Both R2 and adjusted R2 values for Y1 and Y2 were > 0.9, indicating that the models of the experimental data were statistically similar to the suggested models [32]. The adjusted R2 value of Y3 was 0.8786, slightly lower than 0.9, but the precision of Y3 was 14.3166 indicating that the Y3 model could be reflected in the investigation of the design space (adequate precision > 4) [33]. In addition, the difference between the R2 and adjusted R2 of all responses was < 0.2. Similar values of R2 and adjusted R2 were reports as a good fitting indicator [34]. The relationships between the factors were described with interaction plots and coded equations (Fig. 1 and Table 4). And, Fig. 2 shows the residuals of each response with good fitness between actual values and predicted values. Table 5 shows the aspects and actual values of the responses. As X1 increased, all Y decreased. The drug release was decreased as the amount of polymer increased from 10 to 50%. This result is because as the polymer amount of the tablet increased, the water uptake in the tablet increased and the tablet swells proportionally, thereby controlling the drug release [35]. Simultaneous erosion of the surface could also help control the release process. High viscosity polymers could maintain the integrity of the tablet matrix and slow down the erosion process by keeping highly the hydrated layer intact [36]. However, the increment of responses by the amount of sustaining polymer varied depending on the type of sustaining polymer. For HPMC K4M, Y2 decreased from 80% to 45% as X1 increased. In the case of HPMC K100 M, the Y2 decreased from 67% to 32% as X2 increased. The use of high viscosity polymers provided the lower %dissolved value even with the same amount of polymer. The extra responses including the hardness and friability were determined to investigate the effects of polymer type on the characteristics of ILE-SR tablets. Microcrystalline cellulose, as a filler, enhances the compactability of tablet, thereby improving the hardness and friability levels of tablet [37]. In this experiment, the amount of microcrystalline cellulose decreased as the amount of sustaining polymer

increased, but in the case of tablets using HPMC as the sustaining polymer, HPMC also tended to increase the hardness as the amount increased, so only a slight decrease in hardness was observed [38]. For other sustaining polymers, the hardness of the tablets decreased as the amount of microcrystalline cellulose decreased. In contrast to hardness, the value of friability increased, but this was less than 0.5%, an acceptable criterion. The optimal factors were determined using the numerical optimization reflecting all responses except for the extra responses. The targets of Y1, Y2, and Y3 were set as 35%, 60%, and 100%, respectively. Fig. 3 represents the interaction plots drawn considering the influence of factors on the three responses. Solution 1 exhibited the highest desirability value (0.889) and the factors were set to 26.09% (X1) and HPMC K15 M (X2). Solution 2, 3, and 4 showed the desirability values of 0.651, 0.487, and 0.399, respectively. Table 6 lists the predicted responses and the actual responses of all solutions. The error between the predicted value and actual value of each response was calculated to evaluate the accuracy of the predictions as an error percentage. The percentages of Y1 (1.60%), Y2 (1.98%), and Y3 (0.36%) associated with solution 1 were lower than 5%, indicating that the ILE-SR tablet was successfully prepared. As a result of the dissolution test, the similar dissolution profiles were observed except solution 4 (Fig. 4). In the case of solution 2, the error percentages of Y1 and Y2 showed low percentages (< 5%), but Y3 (88.57%) was not included in the acceptable range and the error percentage of Y3 was > 5% (5.24%). Solution 3 and 4 had the error percentages > 5%. The drug release from SR tablets is caused by the contact with media and is controlled by the interaction between media, polymers, and drugs. The mechanisms of drug release are the diffusion of drug through the gel layer produced on the tablet surface and the transport of drug through the pathway produced by the polymer or diluent [39]. The dissolution of drug is dependent on the diffusion through the gel layer and the erosion of tablet matrix. Among the factors, drug solubility is one of the most influential factors for designing a drug release pattern. Highly water-soluble drugs require a higher amount of sustaining polymer in the tablet or higher viscosity of sustaining polymer [39,40]. In the case of hederacoside C, the drug is soluble in the different dissolution media (data not shown) and thus an excess amount of drug in the gel layer may be released at the initial stage. The use of low viscosity sustaining polymers in solution 3 and 4 6

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Table 6 Predicted and actual values of suggested solutions. Actual values are represented as the mean ± SD (n = 3). Suggested solutions

Selected factors

Responses

95% CI low predicted value

Predicted value

95% CI high predicted value

Actual value

Error percentage (%)

Solution 1

X1: 26.09%

Y1: %Dissolved (6 h) Y2: %Dissolved (12 h) Y3: %Dissolved (24h) Y1: %Dissolved (6 h) Y2: %Dissolved (12 h) Y3: %Dissolved (24h) Y1: %Dissolved (6 h) Y2: %Dissolved (12 h) Y3: %Dissolved (24h) Y1: %Dissolved (6 h) Y2: %Dissolved (12 h) Y3: %Dissolved (24h)

31.82

35.00

38.18

35.56 ± 3.34

1.60

57.23

62.02

66.81

63.25 ± 2.45

1.98

93.60

98.81

104.03

98.45 ± 1.24

0.36

31.10

35.00

38.90

36.31 ± 2.64

3.74

56.21

62.08

67.94

63.51 ± 3.75

2.30

87.08

93.47

99.86

88.57 ± 3.22

5.24

29.74

32.93

36.12

38.45 ± 2.14

16.76

61.31

66.11

70.91

67.29 ± 3.51

1.78

89.86

95.09

100.32

98.85 ± 5.41

3.95

32.59

36.54

40.48

53.25 ± 1.25

45.73

57.39

63.33

69.27

78.56 ± 5.31

24.05

84.90

91.37

97.84

95.44 ± 4.87

4.45

X2: HPMC K15 M Solution 2

X1: 26.48% X2: PEO 303

Solution 3

X1: 26.64% X2: HPMC K4M

Solution 4

X1:23.26% X2: PEO 301

resulted in excess dissolution at 2 and 6 h due to the initial erosion of tablet matrix, thereby providing a higher actual dissolution than the predicted dissolution. In addition, HPMC matrices exhibit a continuous swelling, while PEO matrices have quick hydration and gelation of the matrix for polymer types with similar viscosity. In this way, the solution 2 and 4 with the PEO matrix system were more susceptible to erosion process and the erosion speed is greater than the solution 1 and 3 with HPMC matrix system. Therefore, solution 1 was chosen as the best solution because the solution showed the lowest error percentage values. Subsequent studies have proceeded with this solution.

the die cavity and is not possible to press a tablet. The bulk density and tapped density of the granules were determined to be acceptable values of 0.65 g/mL and 0.78 g/mL, respectively. The flowability of granule is an important factor in tablet production. The powder with low flowability cannot be guaranteed the uniformity of tablet weight and content due to the high variability in filling in the die cavity from the hopper [42]. The angle of repose, Carr's index, and Hausner's ratio were investigated to evaluate the flowability of the granule. The angle of repose indicates the inter-granular friction or cohesion. The value of that would be low for the non-cohesive granule with good flowability and be high for non-flowable cohesive granule [43]. Generally, the granule with an angle of repose of < 40 and a Carr's index of < 25 is considered an acceptable flowability [44]. In addition, a Hausner's ratio of < 1.25 represents good flowability due to low inter-granular frictions [44]. Solution 1's granule showed the acceptable flowability with Hausner ratio of 1.20 and Carr's index of 17.2, respectively. Moreover, the angle of repose of the granules was 34.1°. In addition, the physical properties of the round-shaped tablet, such as thickness, hardness, and friability, were also at acceptable levels. The drug content of solution 1 was 99.4 ± 2.8%. These results indicate that ILE-SR tablets were successfully prepared.

3.2. Characterization of ILE-SR tablet We prepared granules and tablets containing 26.09% of HPMC K15 M as solution 1. Physical properties of solution 1's granules and tablets were evaluated (Table 7). The following properties were investigated: Bulk density, tapped density, angle of repose, Hausner ratio, Carr's index, and drug content. The bulk and tapped densities represent the granule characteristics. The high values of these factors indicate that the volume of the granule is small [41]. When the volume of granule is large, it cannot be filled in

3.3. Evaluation of ILE-SR tablet We investigated the drug release profiles in various medium pH and paddle speed to determine the effects of mechanical stress and pH in the GI tract. Fig. 5 shows the dissolution profiles of solution 1 and HebronF® in various dissolution condition. The drug release from solution 1 was constant regardless of medium pH (Fig. 5A) and was independent of the paddle speed (Fig. 5B). In the case of Hebron-F® tablets, the drug release did not vary significantly with the pH of the dissolution medium but increased with faster paddle speed. At a paddle speed of 150 rpm, the drug release was very high and within 30 min more than 90% of the dose was released. These results indicated that HPMC in the tablet was dominant in controlling the release of hederacoside C as observed in the dissolution profiles. The constant drug release is due to the constant thickness of gel layer and diffusion pathlength associated with the

Fig. 4. Dissolution profiles of solutions suggested through numerical optimization in distilled water. Values are represented as the mean ± SD (n = 3).

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Table 7 Physical properties of ivy leaf extract granule and tablet. Values are represented as the mean ± SD. Granule

Tablet

Bulk density (g/mL)

Tapped density (g/mL)

Hausner ratio

Carr's index

Angle of repose (°)

Thickness (mm)

Hardness (kp)

Friability (%)

0.65 ± 0.07

0.78 ± 0.08

1.20 ± 0.01

16.7 ± 0.4

35.1 ± 0.5

3.62 ± 0.05

8.2 ± 0.6

0.09 ± 0.03

Fig. 5. (A) Dissolution profiles of solution 1 and Hebron-F® in various medium (pH 1.2, pH 4.0, pH 6.8, and distilled water). (B) Dissolution profiles of solution 1 and Hebron-F® in distilled water with various paddle speeds (50 rpm, 100 rpm, and 150 rpm). The small figure is the dissolution profiles of Hebron-F® for 2 h. Values are represented as the mean ± SD (n = 3).

swelling of HPMC, which may result in zero-order release [45]. To determine the mechanism of drug release, the release profiles of hederacoside C were analyzed to fit the Korsmeyer-Peppas model. Table 8 gives the n values for all dissolution conditions tested, and the mechanisms of drug release were classified according to the mechanism that n values assume [46]. The n values of the solution 1 tablet were found to be between 0.77 and 0.89 in all dissolution medium, indicating that the mechanisms of drug release were classified as non-

Fickian (anomalous) or Case II (zero-order). Tablets consisting of HPMC K15 M, microcrystalline cellulose, and lactose monohydrate exhibited zero-order or Case II release with n values close to 0.89. In addition, HPMC K15 M was primarily effective in controlling the release of hederacoside C up to 12 h in combination. And, the values of the kinetic constant k depend on the value of n, diffusion index. k has a lower value for the release mechanism by Case II and higher for the mechanism by Fickian diffusion [25]. The lowest value was 0.07 in pH 1.2 medium 8

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References

Table 8 Parameters of Korsmeyer-Peppas models in various dissolution conditions. Conditions

n

k

R2

Release mechanism

Distilled water pH 1.2 pH 4.0 pH 6.8 100 rpm (distilled water) 150 rpm (distilled water)

0.86 0.89 0.80 0.77 0.81 0.83

0.08 0.07 0.08 0.09 0.10 0.10

0.97 0.98 0.99 0.99 0.98 0.99

Non-Fickian Case II Non-Fickian Non-Fickian Non-Fickian Non-Fickian

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and 0.08–0.09 in other media. In addition, the n values of the solution 1 tablet according to paddle speed were 0.81 and 0.83 at 100 rpm and 150 rpm, respectively, which was similar to that at 50 rpm. Regardless of the paddle speed, the dissolution profiles followed the non-Fickian mechanism. As shown in the R2 values (0.97–0.99), the KorsmeyerPeppas model fitted well with most dissolution profiles [47]. From these results, the drug release from ILE-SR tablet in the GI tract was estimated as follows: ILE, HPMC, and filler formed a matrix structure inside the tablet. When it contacts with water, HPMC absorbs water and swells to form a gel layer around the tablet [48]. These properties could provide sufficient strength for mechanical stresses and diffusion barriers allowing the tablet shape to be maintained in multiple mediums [49]. In addition, the incorporation of microcrystalline cellulose (water-insoluble polymer) into the hydrophilic matrix modulates the drug release, because it reduces the penetration of water into the matrix [50]. The use of water-insoluble polymer contributed in part to prevent the disintegration of tablet matrix [51]. Thus, these results indicated that the dissolution of the tablet would not be significantly affected by the physical pH and mechanical stress of the GI tract and follow a constant release profile. 4. Conclusion ILE-SR tablets showing sustained release for 24 h were successfully prepared with a statistical experimental approach. Response surface design was applied to evaluate the drug release, which was controlled by the amount and type of sustaining polymers. The tablet was prepared with 26.09% of HPMC K15 M as a sustaining polymer and exhibited appropriate physical characteristics. In addition, the tablet showed constantly sustained release profiles in various dissolution medium and paddle speed. Hederacoside C in the tablet was mainly released by non-Fickian mechanism with polymer relaxation regardless of dissolution medium and paddle speed. Therefore, we have found that our statistical approach is useful in developing tablets containing herbal extract and have established an approach to efficiently control the properties of the sustained release tablet. At the development stage, further clinical trials are still needed to confirm the oral absorption pattern of this tablet. Declaration of competing interest The author reports no conflicts of interest in this wok. Acknowledgments This work was supported by the Basic Science Research Program (2019R1H1A2080111) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology.

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