pH-Dependent Site Specific Dissolution Improvement by Expansion Isolation Layers in Erythromycin Enteric Coated Tablets

pH-Dependent Site Specific Dissolution Improvement by Expansion Isolation Layers in Erythromycin Enteric Coated Tablets

Journal of Drug Delivery Science and Technology 54 (2019) 101233 Contents lists available at ScienceDirect Journal of Drug Delivery Science and Tech...

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Journal of Drug Delivery Science and Technology 54 (2019) 101233

Contents lists available at ScienceDirect

Journal of Drug Delivery Science and Technology journal homepage: www.elsevier.com/locate/jddst

pH-Dependent Site Specific Dissolution Improvement by Expansion Isolation Layers in Erythromycin Enteric Coated Tablets

T

Dongmei Youa, Xiaoyang Lina, Yu Zhanga, Haibing Hea, Tian Yinb,c, Xing Tanga, Yanjiao Wanga,∗ a

Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, China School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, Liaoning, China c School of Chinese Materia Media, Shenyang Pharmaceutical University, Shenyang, Liaoning, China b

ARTICLE INFO

ABSTRACT

Keywords: PVPP Enteric tablets Expansion isolation layers Site specific dissolution improvement

The present research focuses on the formulation and optimization of enteric tablets of erythromycin (EM) based on expansion isolation layers with improved duodenum targeted delivery and dissolution. To achieve this aim, the core of the enteric tablets was formulated as a rapid release tablet. For the purpose of avoiding the enteric layer hindering drug release in the duodenum, cross-linked povidone (PVPP) was introduced as an expansion agent in the isolation layer to exert swelling focus on the enteric layer and fasten the shedding rate of the enteric coating. The influence of composition of the isolation layer (the fraction of PVPP) and also the coating weight gain of the isolation layer on the acid resistance as well as drug release profiles was investigated. Observation of the shedding state of the enteric coating was visually examined, and also was confirmed by theory. EM in the enteric tablet based on expansion isolation layer was successfully delivered both at pH6 and pH6.8 within 15 min after 1 h simulated stomach environment in vitro at an ascending release rate. The experimental results predict PVPP has a potential as an expansion agent in the isolation layer of enteric tablets to facilitate drug release.

1. Introduction Erythromycin (EM) is a macrolide antibiotic, demonstrating a broad-spectrum antibacterial activity against both gram-positive as well as gram-negative micro-organism, and is considered as BCS II class drug [1,2]. The acid-labile EM has the highest permeability coefficient in the duodenum, and thus the duodenum is regarded as the best absorption site [3]. As a primary macrolide, erythromycin is widely used for systemic or topical therapy and is marketed in several dosage forms. However, its immediate release (IR) dosage form suffers from acid degradation and can't achieve site-specific delivery, whereas its delayed release (DR) form fails to provide sufficient drug dissolution for duodenum-specific delivery. Despite the high permeability, EM molecules often have a low oral bioavailability because of liver first-pass effect, and poor oral absorption and/or intestinal first pass metabolism also account for the limited oral bioavailability. Intestinal first pass metabolism is responsible for a more than 41% loss of EM [4]. Related literature demonstrates that the absorption of EM complies with the passive transport mechanism, and an ascending drug concentration of EM solution administered through endoscope to the duodenum could reduce the drug loss and increase absolute bioavailability by up to 13% [5]. Therefore, it is of interest to design a duodenum targeted dosage



form which combines both IR and DR virtue, in the form of enteric coated tablets to achieve clinical benefit [6,7]. Given pH variations across the gastrointestinal tract (GIT), pH controlled release is the most common approach for duodenum targeted delivery, where tablets are coated with corresponding target site pH sensitive polymers to avoid pre-mature drug release. Hypromellose -phthalate (HPMCP-55) is a common coating material for gastro-resistant pH controlled drug release [8–10]. The present investigation aimed to formulate and optimize enteric coated tablets of EM incorporating the dual advantages of IR and DR virtues and preventing drug release in the stomach. The obtained enteric coated tablets of EM could provide targeted release at the site of action (the duodenum) with improved drug dissolution. IR tablets composed of microcrystalline cellulose (MCC) are easy to manufacture and scale up by the wet granulation technique. MCC prevails in the market for IR technology owing to global regulatory acceptance, excellent compatibility and its good water swelling which is the basis of rapid disintegration [11,12]. As the duodenal transit time is short, we proposed to formulate tablets which could release the drug immediately after leaving the stomach [13]. However, HPMCP-55 only starts to dissolve at pH 5.5 and the aqueous intestinal environment is a bad solvent, in addition to the close pH value (4.5–7) of the duodenal

Corresponding author. E-mail address: [email protected] (Y. Wang).

https://doi.org/10.1016/j.jddst.2019.101233 Received 3 June 2019; Received in revised form 5 August 2019; Accepted 20 August 2019 Available online 05 September 2019 1773-2247/ © 2019 Elsevier B.V. All rights reserved.

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environment to pH5.5. Limited solubility of the enteric layer will seriously hinder drug release from the IR tablets core. To increase the drug dissolution, there needs to be a balance between the drug release rate in the core and the swelling and dissolution rate of the enteric layer. Exerting forces on the enteric coating to facilitate the shedding process is a possible strategy. Prior to the enteric coating, a seal coating layer can be introduced to separate the core tablet from the acidic enteric coating polymer to avoid premature degradation [14]. At the same time a seal coating can also help the enteric material adhere to the surface of the tablet and form an intact coating. The conventional seal coating for HPMCP-55 enteric tablets is hydroxypropylmethylcellulose (HPMC-E5) (2%–4% weight gains) for good polymer-to-polymer adhesion and compatibility [15]. However, the slow dissolution of the enteric coating clinging to the surface of the tablet from the HPMC-E5 isolation is an undesirable phenomenon during dissolution. In this case, drug release would be delayed, which is against the original intention of rapid release at the specific site. PVPP is a high molecular weight fining agent composed of crosslinked monomers of poly-vinylpyrrolidone, possessing a high surface area due to its amorphous structure with values around 1.2 m2/g (much lower than silica). Due to its high water-holding capacity, its volume becomes 3 times of its initial with the ingression of water [16]. Therefore, PVPP may be an alternative expansion agent for the isolation layer of EM enteric tablet. Although PVPP has particular value in drug release systems as disintegrating agent [17], it has not been well characterized as an additive for tablet coatings. In this context, the objective was to verify the potential of using PVPP in the isolation layer to accelerate the rupture of the enteric layer in the intestine environment (pH 6, pH6.8) and further improves the drug dissolution at the specific absorption site. X-ray powder diffraction (XRPD) was applied to exclude the influence of crystalline transformation on the process, which is mainly caused by dry temperature and dry time changing. To increase in vivo relevance, a partially non-sink dissolution method, following the transition from acidic pH 2 to pH 6 or pH 6.8, was used to elucidate and characterize the release profiles of our formulations. The release of EM from tablets based on expansion isolation were compared with the dissolution profiles of enteric tablets with conventional isolation layers, and interpreted for the potential of PVPP to be used in expansion isolation layer of EM enteric tablets.

Coating of the core tablet was conducted with an efficient pan coater (Xinyite Co., China). First, a seal coating layer was introduced to separate the core from the enteric coating polymers containing free carboxyl groups. Direct contact between weakly basic EM and enteric coating polymers may cause degradation of EM or destruction of the enteric layer during the coating process or storage. HPMC-E5 was dissolved in a hydro-alcoholic solvent system 80:20 (ethanol: water) at a concentration of 8% (w/v). During coating, 40 g tablets were sampled at different time points for further enteric coating to identify the optimal increment of the isolation coating. Different ratios of PVPP (PVPP:HPMC-E5 = 10%, 20%, 30%; w/w) were then added to the solution and passed through a high speed shear emulsifier at a rate of 3,000 rpm/min for 10 min to generate a uniform suspension. In this way, tablets with an expansion isolation coating were obtained for further investigation. After the process of isolation-coating, the tablets were placed in the pan coater for further drying (10 min) under the high power air blower of the coater and followed by the enteric coating. The enteric-coating suspension was at a concentration of 6% (w/v) in the same hydro-alcoholic solvent system as the seal coating, and consisted of HPMCP-55, TEC, talc and titanium dioxide. In consideration of the disintegration characteristics in the intestine (pH 6.8,6) the formulation screening suggested that the enteric coating was completed at the increment of about 7% of core tablet weight. Enteric-coated tablets with different composition of isolation coating were prepared and further utilized for acid uptake performances as well as dissolution performance. The processing parameters for isolation and enteric coatings of tablets containing EM are given in Table 2. 2.3. XRPD X-ray diffraction patterns were obtained using an X-ray diffractometer ((D8 Advance, Bruker) equipped with Kα copper radiation (λ = 1.5418Â), at a current of 10 mA and voltage of 30 kV. The measurements were performed at room temperature, scanning at 2θ from 5° to 60°, with a 0.04°step size. 2.4. SEM The enteric tablet was cutted to expose the coating section, and the isolation coated tablets and cutted enteric tablet were then mounted onto SEM specimen holders with conductive carbon adhesive tape. The samples were gold coated with a sputter coater using an electrical potential of 2.0 kV at 25 mA for 10min. SEM images were taken using a scanning electron microscope S–3400 N (Hitachi, Japan) with an excitation voltage of 20 kV.

2. Materials & methods 2.1. Materials EM was purchased from Dongyangguan Pharmaceutical Co (batch 20170305; Guangdong, China). MCC, PVPP, HPMC-E5, Talc, Colloidal silicon dioxide, Magnesium stearate and Titanium dioxide were provided by Zhanwang Excipients Corporation (Zhejiang, China). HPMCP55 was obtained from Shine Tsu Chemical Co., Ltd. (Tokyo, Japan). Triethyl citrate (TEC) was purchased from Morimura Bros Inc. (Tokyo, Japan). All other chemicals used were pharmaceutical grade.

2.5. Acid uptake test Acid uptake (%) was conducted to examine gastric resistance of enteric film coated tablets, which is the measure of the hydrophilicity or permeability of the enteric coating to the gastric media. To evaluate the imbibition of gastric fluid and subsequent swelling characteristics, six tablets from each batch were individually weighed and placed in a USP disintegration bath containing 900 mL of 0.1 N HCl (pH 1.2) at 37 °C. After the 2 h disintegration test, the tablets were removed from the bath and excess moisture on the surface was absorbed using a filter paper. The tablets were re-weighed to determine the acid uptake, as shown in Eq. (1):

2.2. Preparation of enteric tablets EM has been classified into BCS Ⅱ, indicating the solubility improvement must be taken into consideration during formulation, thus the rapid release core was designed. The core containing EM was prepared by conventional wet granulation and tableting as shown in Fig. 1. Table 1 lists the composition of tablets. The HPMC-E5 aqueous solution was kneaded with the drug powder, microcrystalline cellulose, and PVPP using a highspeed mixer, and granulated, and then the granules were dried in a 40 °C air oven for approximately 4 h. The dried granules were then sized using a 25 mesh screen (710 μm), lubricated with magnesium stearate and microsilica gel, and then compressed into oval tablets of approximately 400 mg, using a single-punch tablet pressing machine (Tianhe, China). The EM tablets were collected and stored in airtight containers.

Acid Uptake =

Wt

W0 W0

100

Where Wt = Weight of the tablet at time, t = 2 h. W0 = Weight of the tablet at time, t = 0. Disintegration of an enteric coated tablet in the acidic pH is an undesirable quality for an enteric coating. Tablets that disintegrated after testing were regarded as 100% acid uptake. On the condition of 2

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Fig. 1. The manufacturing process of EM enteric tablets.

maintaining its integrity, a qualified enteric coated tablet shouldn't soften, swell or show > 5% acid uptake in the gastric media. It is known that this level of acid uptake would typically correspond to efficacious enteric coating performance.

Table 2 Processing parameters for sealing and enteric coatings of EM tablet.

2.6. In vitro dissolution 2.6.1. Dissolution of granules and core tablet The dissolution characterization of EM, wet-granulated granules and core tablet containing equivalent amount of EM (250 mg) in pH 6.8 phosphate buffer was evaluated. Dissolution studies were performed using the USP II paddle method (50 rpm, 37 ± 0.5 °C, and 900 mL dissolution medium) with a dissolution tester (Tianda Tianfa, Tianjin, China) and 5 mL samples were withdrawn from the dissolution medium at predetermined time intervals and filtered through a 0.45 μm membrane. An equivalent amount of fresh medium was replaced to maintain dissolution volume. The amount of EM released was determined by UV–visible spectrophotometer at 482 nm (T6-2800, Beijing, China) after the chromogenic reaction with a same volume of 75% concentrated sulfuric acid for 40 min. Dissolution experiments were carried out in triplicate.

Parameters

Seal coating

Enteric coating

Inlet temperature (°C) Exhaust temperature (°C) Product temperature (°C) Spray rate (g/min) Pan speed (rpm) Atomization air pressure (Mpa) Air flow (m3/h)

70 45 40 2 6 0.1 80

60 45 30 3 6 0.12 80

2.6.2. Dissolution for enteric-coated tablets The dissolution tests were carried out in accordance with the USP monograph “Delayed-release dosage form dissolution method B”. First, EM enteric tablets (EETs) were placed into 900 mL pH 2 hydrochloric acid maintained at 37 ± 0.5 °C and stirred for 1 h at 100 rpm (Basketstirring Method). An aliquot (approximately 5 mL) was withdrawn at each sample time. The tablets were transferred to the pH 6 and pH 6.8 phosphate buffer and the USP Method II paddle apparatus was used at 75 rpm and 37 ± 0.5 °C for a further 1 h. At predetermined time

Table 1 The optimal formulation of the enteric tablets containing EM. Component

Function

Core tablet (mg/tablet)

Erythromycin (EM) Microcrystalline cellulose (MCC) Magnesium stearate Silica PVPP HPMC-E5 PVPP HPMC-E5 TEC HPMCP-55 Titanium dioxide Talcum powder Total weight Calculated

Active ingredient Diluent Lubricant Glidant Disintegrator Adhesive Expansion agent Film coating agent Plasticizer Enteric coating agent Sunscreen Anti-adhesive

260 120 2 2 4 12

Isolation layer (mg/tablet)

4.8 16

400

20.8

*The formulation of the core tablet comes from reverse analysis of ERY-TAB®. 3

Enteric layer (mg)

0.51 22.12 1.26 2.51 26.4

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intervals, 5 mL dissolution medium was sampled and filtered through a membrane filter with a pore size of 0.45 μm (Millex-HV, Millipore, MA, USA). Filtered samples were appropriately diluted with purified water, and the drug concentration was assayed by UV as described above. The aliquot volume was replaced with fresh dissolution media to maintain the same volume during the dissolution process. Dissolution experiments were carried out in triplicate.

Table 3 Acid uptake of tablets enteric coated with different isolation coating increment and composition. Batch

F1 F2 F3 F4 F5 F6 F7 F8

2.7. Statistical analysis All results are expressed as mean ± SD. The data from different formulations were compared for statistical significance using an ANOVA test among the three means or students t-test between the two means for unpaired data (Origin, version 8.0). The significance level was set at 0.05.

Core tablet (mg/tablet)

Isolation layer HPMC-E5 (mg/tablet)

PVPP (mg/ table)

400 400 400 400 400 400 400 400

0 4 8 16 16 16 16 16

0 0 0 0 1.6 3.2 4.8 6.4

Acid uptake (%) (Mean ± SD) (n = 6)

100 100 20 ± 3.5 (swelling) 3.4 ± 0.52 (no swelling) 4.1 ± 0.48 (no swelling) 3.3 ± 0.88 (no swelling) 3.6 ± 0.90 (no swelling) 4.5 ± 0.86 (no swelling)

XRPD is therefore applied for monitoring any solid-state changes. According to the literature, diffractograms of EM.DH and EM.DD are closely matched with each other. EM.DH has a series of characterized peaks at 9.9°, 10.3° as well as 13.1°. These peaks undergo a shift in location or intensity for EM.DD (9.6°, 10.1° and 13.3°). The characteristic peaks for MCCS were observed at 18.8° and 23.6°. The diffraction patterns of the dried granules containing EM and MCC mainly had consistent characteristic crystalline peaks with the raw drug and MCCS. This confirmed that the raw drug and EM dried granules acquired to develop the tablets were composed of the EM. DH. In summary, there was no transformation occurrence during the granulation process, meaning the EM used in the study was of the same crystal form as the commercial product.

3. Results and discussion 3.1. XRPD X-ray diffraction patterns related to the EM crude drug, MCC, physical mixtures, commercial product and powder of the self-made tablets are shown in Fig. 2. The EM is reported to be a solid API that exists in four crystalline forms, including erythromycin dihydrate (EM.DH), erythromycin dehydrate (EM.DD), erythromycin anhydrate (EM.AD) and amorphous erythromycin (EM.AM) [18,19]. The different crystal forms vary in dissolution rate, bioavailability and storage stability. The pharmaceutically used form of EM is EM.DH, which contains two water molecules in its lattice channels. Thus, manufacturers must ensure that the crystal from remains unchanged during processing. However, there are the chances that EM.DH undergoes solid-state changes during processing. EM.DH may transform to the other three crystal forms during processing, but is mostly prone to convert to EM.DD. Being isomorphic to EM.DH, transformation only requires the loss of the two water molecules in EM.DH, and this conversion needs low activation energy. Excessive processing temperatures or low ambient humidity can cause the transformation, and therefore it is necessary to properly control the drying temperature and time of the granules. Once in the absence of water, other molecules of a suitable size and hydrogen bonding capability may be incorporated into the lattice channels of EM.DD and change the physicochemical properties. For example, the formation EM.DD in tablets containing magnesium hydroxide has led to changes in dissolution rate.

3.2. Acid uptake The acid uptake was determined (Table 3, Fig. 3) for the formulations. A significant difference in the acid uptake was observed upon comparing the two formulations (F1, F3), which were comprised of different weight gain of the isolation layer. It can be seen with the same enteric coating increment, tablets containing no isolation layer showed a significantly greater acid uptake of 100%. However, tablets coated with a formulation of 2% weight gain of HPMC-E5 in the isolation layer showed a lesser acid uptake of around 20%. Typically for enhanced gastric resistance, the acid uptake should be < 5%. To meet the requirement of less than 5% acid uptake, the weight gain of HPMC-E5 in the isolation layer was increased to be more than 4% of the core tablet weight (F4–F7). Another important role the isolation layer plays is to act as a surface render before the enteric coating to help form an even and compact enteric layer. An isolation layer that is too thin will weaken the enteric coating performance. No significant difference in

Fig. 2. The powder x-ray diffraction patterns of the physical mixture of excipient, commercial reference product, self-made granular powder and EM crude drug.

Fig. 3. Comparison of acid uptake (%) of tablets of F1–F8 (**p < 0.05, *p > 0.05). 4

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Fig. 4. The structure of HPMC-E5 and HPMCP-55:R1 represents the substituent of the HPMC-E5; R2 represents the substituent of the HPMCP-55.

acid-resistance among F4, F5, F6, F7 and F8 suggested that the amount of PVPP added into the isolation layer didn't influence the enteric coating performance in acid-resistance. The effect of PVPP existing in the isolation layer only comes into play when in contact with plenty of water. At the acid stage, the dense outside enteric layer blocks the entrance of water from the acid dissolution media [20], and as a consequence the expansion agent doesn't function.

there are some small holes on the surface of the isolation layer, or some particles floating on the surface of the isolation layer. These PVPP particles were about 7 μm in diameter and settled in the isolation layer and were partly exposed to the microscope. Images Fig. 5C and Fig. 5D demonstrates the structure of the enteric coating tablets. There is no obvious boundary between the enteric coating and isolation layer under the scanning electron microscope at low magnification times (400×) due to the chemical structural similarity between HPMCP-55 and HPMC. As Fig. 4 demonstrates, HPMCP-55 is a citrate half ester of HPMC. However when further magnified (650×), the fault in the coating layer can be observed, showing the discontinuity, which indicates the erythromycin tablets are coated with two layers.

3.3. SEM SEM images (Fig. 5A and B) show the worn surface of the isolation coating. Under scanning electron microscopy, it can be observed that

Fig. 5. The SEM A,B show the surface of isolation-coated tablet; C,D show the same fragment of the enteric coated tablets under different magnification times (C was obtained under the 400 magnification times., D under the 650 magnification times). 5

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slower drug release than those prepared by wet granulation with MCC. In the dissolution test, EM was completely released from the granules within 15 min, whereas only 80% of EM was released from the powder of the crude drug, which indicates MCC caused a 1.25 fold increase in the drug dissolution in pH 6.8 media. It is speculated that the dissolution improvement could be even greater in other more distinguishable medium for erythromycin, such as a neutral or alkaline media. The core tablets also had a rapid release performance in pH 6.8, within 15min the dissolution rate was beyond 80%. 3.4.2. Influence of the amount of the expansion agent in isolation layer on ascending drug release The dissolution profiles of EETs are shown in Fig. 7. All enteric tablets exhibited integrity in acid media for the first hour. At pH 6, EETs containing expansion isolation (EETs-ES) layer demonstrated faster dissolution rates than EETs containing conventional isolation (EETs-CS), and more PVPP dosage in the isolation layers promoted improved dissolution. However, no significant difference was observed between F7 and F8, indicating the upper limit of PVPP addition in the isolation coating was 4.8 mg per tablet, and so this addition was used as the preferred one. 8 ± 1.8%, 26 ± 1.2%, 46 ± 1.5%, 60 ± 2.4%, 79 ± 2.5% and 35 ± 0.9%, 82 ± 0.85%,94 ± 1.6%,98 ± 1.5%,105 ± 1.8% of the total drug dissolved from EETs-CS and EETs-ES (optimal formulation) respectively at different sample times in pH6 media. In pH 6.8 media, the difference in dissolution rate between EETs-CS and EETs-ES (optimal formulation) was smaller. The dissolution results were 35 ± 2.5%, 90 ± 1.6%, 96 ± 1.5%, 98 ± 0.82%, 101 ± 2.2% for EETs-ES, and for EETs-CS at the same sample points the dissolution rates were 13 ± 0.67%, 57 ± 0.8%, 82 ± 3.2%, 91 ± 1.3%, 99 ± 2.5%. Fig. 7 (F4–F8) showed that the amount of the expansion agent in the isolation layer affected drug release. As the enteric coating dissolved slowly within the dissolution medium, small cracks emerged to let moisture in. Then,

Fig. 6. Dissolution profile of A EM powder B core tablet C granules at pH 6.8 phosphate buffer.

3.4. In vitro dissolution 3.4.1. Influence of the MCC on solubilizing EM A major concern during formulation development is to enhance the dissolution rate of poorly water-soluble EM. To solubilize the EM, MCC was selected as the only filler of the core tablets. Hydrophilic and hygroscopic MCC facilitates disintegration by promoting media ingress and swelling of the tablet and improve the wettability of the poorly soluble drugs, which will finally improve the water solubility of EM [21–23]. The dissolution profiles of EM granules containing MCC are depicted in Fig. 6. It was shown that EM powder had a significantly

Fig. 7. Dissolution profile of enteric tablets:F4 (with no PVPP in isolation layer), F5 (1.6 mg of PVPP in isolation layer per tablet),F6 (3.2 mg of PVPP in isolation layer per tablet), F7 (4.8 mg of PVPP in isolation layer per tablet),F8 (6.4 of mg PVPP in isolation layer per tablet) at A (pH6 media); B (pH 6.8 media). 6

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Fig. 8. The compared dissolution mechanism of enteric tablets based on expansion isolation layer and HPMC-E5 isolation layer respectively.

Fig. 9. State of the EM enteric tablet based on expansion isolation layer during dissolution (For interpretation of the process the image was art treated to brighten the edge of the object).

and significantly contribute to our understanding of the dissolution mechanisms from tablets. For the EETs-ES, the HPMCP-55 coating on the surface of the tablet starts to dissolve slowly at a pH beyond 5.5 [26], allowing water to enter the tablet from breakage of the enteric coating. When the isolation layer came into contact with water it expanded, and the swelling force made the enteric coating peel off rapidly, rather than slow erosion from the surface of the tablet. The isolation layer HPMC-E5 formed a gel after contacting water, but the PVPP particles settling in destroyed the compactness of the gel layer, and as a result the isolation layer was eroded faster. In this way, the core was exposed to the media more quickly and disintegrated rapidly to release the drug. Therefore, the expansion isolation layer significantly helps to enhance the dissolution rate at the early stages before the core tablet is completely exposed to the medium. Fig. 9 shows the state of expansion isolation layer and enteric coating during the dissolution process, from it we can see the enteric coating on the upper surface of the tablet shed as a whole. Theoretically, material with good expansion after water uptake from the medium can also enable the accelerated release of the drug from the enteric tablet. In the end, an EET-ES with improved dissolution in the duodenum was formulated and has the potential to improve the bioavailability.

the moisture-absorbing PVPP produced expansion forces to facilitate limited swelling or dissolution of the enteric polymer. Thus, the isolation layer was necessary for ascending release, particularly for the first period of drug release. Besides, the expansion agent could increase the hydration rate of the isolation layer. The more the isolation layer swelled, the more pressure was obtained. If the pressure exceeded the limit of the enteric membrane, the membrane would be finally shed. The improvement of dissolution was more pronounced at pH 6 than at pH 6.8, as HPMCP-55 has better solubility at pH 6.8. As a consequence, the expansion isolation plays a more important role to accelerate limited dissolution of the enteric material in the poor solvent. It was apparent that in both pH 6 and pH 6.8, the dissolution rate of EETs-CS was always faster than in EET-ES. 3.5. Drug release mechanisms Drug release kinetics are affected by many factors such as enteric coating erosion, isolation layer gel form and erosion and drug diffusion characteristics [24,25]. For EETs, the core tablets were expected to readily disintegrate, but the enteric coating remaining on the surface of tablet eroded slowly in the poor solvent of aqueous medium, followed by isolation layer erosion. Consequently, the drug release of EETs was mainly limited by the enteric coating and isolation layer. In contrast to EETs-CS, the EETs-ES exhibit quicker drug release, achieving the same amount of drug release 20–30min earlier, as the dissolution profile demonstrates (Fig. 7). The images (Fig. 8) below imitates the compared dissolution process of EETs with different isolation layers, and can be used for explaining the previously observed in vitro dissolution profiles

4. Conclusions Enteric-coated EM tablets based on expansion isolation exhibited excellent acid resistance for 2 h, and then delivered the drug completely within 15 min after switching to pH 6.8 or pH 6 media. This study shows that PVPP is a potential expansion agent that can be utilized in 7

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isolation coatings of enteric tablets, in order to accelerate limited swelling of the enteric coating and accelerate rupture to further improve drug release. A simple process of exerting external forces to accelerate coating shedding and achieve ideal release behavior can be further utilized for delayed-release preparations for clinical benefits. In vivo clinical trials and pharmacokinetic and pharmacodynamics correlation of novel enteric-coated EM tablets should be investigated to fully demonstrate their potential for meeting unmet clinical needs.

[11] [12] [13] [14]

Conflicts of interest statement

[15]

We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.

[16] [17]

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