Further enhancement of the sustained-release properties and stability of direct compression gel matrix bilayer tablets by controlling the particle size of HPMC and drug microencapsulation

The Theophylline and Salbutamol Bilayer Sustained-release Tablets (Yi Xi Qing®), prepared via wet granulation, discolor during long-term storage, and the process is less reproducible and more cumbersome. In this study, the direct compression (DC) method was used to prepare equivalent and stable theophylline-salbutamol bilayer sustained-release (TBS) tablets, using Yi Xi Qing® as a reference formulation (the relative bioavailabilities for theophylline and salbutamol were 96.3 % and 103.9 %, respectively, with release similarity factors of 60.12 and 80.99). Lipid microencapsulation of salbutamol via hot-melt extrusion (HME) and the use of HPMC with a particle size of less than 96.55 μm (D₉₀) in the theophylline layer enhanced the stability of salbutamol during long-term storage and controlled the release of theophylline from a minimal amount of gel matrix material, respectively. The results of this study may offer insights into the preparation of DC hydrophilic gel matrix bilayer tablets with high drug loading capacity.

Highlights

• Effective slow-release products were formulated with a very low level of release rate controlling polymer.
• Polymer entrapment of drug via HME was used to improve the stability of drug.
• Modifications to the manufacturing process without changing the composition compared with the reference product.
• The mechanism of drug release from bilayer tablets was explored and the migration phenomenon was observed.

Introduction

Bilayer tablets, featuring a two-layer configuration, offer distinctive advantages over monolayer tablets, including convenient regulation of the drug release rate [1,2], enhanced efficacy through formulation adjustments [3], and high drug loading capacity [4]. These tablets are classified into immediate-release-retarded-release and biphasic controlled-release types. Commonly, ‘chronic-rapid’ single-drug bilayer tablets (Fig. 1 a) combine an immediate-release layer for rapid symptomatic relief with an extended-release layer to maintain an effective dose [5,6]. Besides single-drug versions, many bilayer tablets incorporate two different drugs, enhancing the synergistic effect and achieving a biphasic release (Fig. 1 b) [[7], [8], [9]].

Bilayer tablets are primarily produced through wet granulation and direct compression (DC) of powder [10]. While DC offers the advantages of high efficiency and minimal batch variation, becoming the preferred method for tablet production, few studies have explored the production of gel matrix bilayer tablets using DC [11,12]. Additionally, DC products are generally more stable, as the manufacturing process avoids exposure to moisture and heat. This stability is critical for maintaining drug quality, as some interactions can lead to drug degradation under prolonged hot and humid conditions. For instance, the Maillard reaction can occur in storage that can degrade the drug affecting efficacy and safety, as many drugs contain primary or secondary amines and excipients include reducing sugars [[13], [14], [15], [16], [17]]. This aspect is particularly crucial for bilayer tablets, which often contain multiple drugs, increasing their susceptibility to drug-excipient incompatibility issues.

Asthma is now one of the most common chronic diseases worldwide, with an estimated 1 in 20 people affected by it globally. From 2012 to 2015, the China Pulmonary Health (CPH) study reported a 4.2 % prevalence of asthma among individuals over 20 years old in China, totaling approximately 45.7 million people [18]. Theophylline, a non-selective phosphodiesterase inhibitor, has been used since the 1940s and remains one of the most widely prescribed treatments for respiratory diseases, due to its affordability and efficacy. However, its unstable metabolism and narrow therapeutic index necessitate careful administration and monitoring of blood levels. Salbutamol, a selective β2 agonist, is frequently used clinically in combination with theophylline to enhance theophylline therapy [[19], [20], [21]]. Yi Xi Qing®, the only theophylline-salbutamol bilayer sustained-release (TBS) tablet marketed in China, combines two drugs to treat asthma, achieving significant synergistic effects through various segments and mechanisms [22]. However, issues such as discolouration of the salbutamol layer during production and storage, observed in Yi Xi Qing® tablets prepared by the wet granulation process, have impacted both the aesthetic and the quality of salbutamol, potentially affecting its efficacy. In-depth research identified the cause as a Maillard reaction between salbutamol, which contains secondary amines, and lactose, a common reducing sugar. Literature reviews [23,24] suggest that the Maillard reaction is likely at high temperatures or with 10 %–15 % water content, but is less likely under completely dry conditions. Consequently, switching to a DC method for powder could mitigate this instability during storage.

Hydrophilic gel matrix tablets are a common oral sustained-release drug delivery system in bilayer tablets, offering the advantages of easy release modulation and a high safety profile [25]. Among all hydrophilic polymers, HPMC is the most widely used due to its non-ionic nature, which ensures minimal risk of drug interactions and generally yields reproducible drug release profiles [26]. The particle size of HPMC significantly influences the performance of the polymer in hydrophilic matrices [27].

This study focuses on transitioning gel matrix bilayer tablets from the traditional wet granulation process to a powder DC method. In the study, the DC method was employed to prepare equivalent and stable TBS tablets using Yi Xi Qing® as a reference formulation, without altering the prescription. The low HPMC content in the theophylline layer made achieving a similar slow-release effect to Yi Xi Qing® difficultly via the DC method. We enhanced the slow-release effect by reducing the HPMC particle size without altering the type and content (Fig. 2 a) and investigated the release mechanism. Additionally, physical separation of salbutamol through microencapsulation with a wax material was used to further improve stability based on the DC method (Fig. 2 b). The findings of this study may offer new insights into addressing the issue of moist heat instability in other drugs without prescription modifications.

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Materials

Theophylline was sourced from Jilin Shulan Synthetic Pharmaceutical Co., Ltd. (China). Salbutamol was obtained from Changzhou Yabang Pharmaceutical Co., Ltd. (China). Lactose (FastFlo 316) was supplied by KERRY (United States). Hydroxypropyl methyl cellulose (HPMC K4M and HPMC K15M) were provided by Colorcon (Shanghai, China), with detailed properties described in the supplementary material. Microcrystalline cellulose (MCC VIVAPUR 12) was purchased from JRS Corporation (Germany). Povidone K30 (Vivapharm PVP K 30) was provided by JRS Pharma.

Tong Liu, Jiahui Wang, Yupeng Feng, Haoran Wang, Yunlong Xu, Tian Yin, Yu Zhang, Haibing He, Jingxin Gou, Xing Tang, Further enhancement of the sustained-release properties and stability of direct compression gel matrix bilayer tablets by controlling the particle size of HPMC and drug microencapsulation, Powder Technology, 2024, 120256, ISSN 0032-5910, https://doi.org/10.1016/j.powtec.2024.120256.

Read also our introduction article on Direct compression (DC) here: