Design and development of an ethyl cellulose bulk-engineered spherule-based capsule system

Abstract

This study addresses a critical challenge in delivering a drug to prevent angina in the early morning hours, aligning with the heart’s circadian rhythm. For this purpose, we formulated Isosorbide dinitrate (ISDN) – loaded spherules for delayed release (DR) followed by sustained release (SR) using ethyl cellulose by spheronization technique. DOE-led optimisation is done to develop the design of space for optimized spherules. The DR-coated spherules exhibit possible surface modifications, indicating the presence of a coating layer that can influence the release profile and provide marginally better flow characteristics (Angle of repose 31.38 ± 0.02, Carr’s index 10 ± 0.35%, Hausner’s Ratio 1.11 ± 0.037) compared to granules and SR spherules. In vitro drug release in pH 1.2 is 4.8% indicating negligible drug release due to DR coating, whereas, under colonic pH (7.4) conditions, initially 40% is released as a burst release and approximately 60% of ISDN is released over 24 h, which indicates that DR coating modifies the drug release profile. Following the successful modulation of release behaviour via engineering the delivery system, spherules coated with ethyl cellulose and Eudragit S-100 exhibit negligible release in pH 1.2, confirming strong resistance in the gastric environment. The design of space (DOS), optimized through JMP software using the Design of Experiments (DOE) approach, confirms the targeted performance. The results of the DOE to experimental validated results were within 5% deviation.

Introduction

Ethyl cellulose (EC) is a widely used polymer in pharmaceutical oral formulations, valued for its excellent film-forming ability, chemical stability, and its requirement for slow-release properties [1]. As an inert, water-insoluble polymer, it serves as a key component in controlled and sustained drug delivery systems, where it functions primarily as a matrix-forming or coating agent [2]. Its ability to modulate drug release rates by forming diffusion-controlled barriers makes it especially useful in formulating oral dosage forms such as spherules [1], pellets [3], and tablets [4] to achieve prolonged therapeutic effects. Ethyl cellulose and Eudragit S 100, when combined, ensure time-based sustained release [5], with Eudragit S-100 contributing pH-dependent delayed release [6]. This combination enables precise control over when and where the drug is to be released in the gastrointestinal tract. The inner EC layer or dispersed EC component controls the rate at which the drug is released once the pH trigger occurs. The outer Eudragit S-100 layer provides site-specificity, ensuring the formulation remains intact through gastric transit and only begins releasing once it reaches the target intestinal environment [7].

Multiple Unit Pellet System (MUPS) for drug delivery have gained popularity in recent years compared to single-unit dosage forms [8]. These MUPS are made of numerous independent subunits (microparticles), each of which is an individual drug reservoir that desirably releases the drug independently [9]. Multiparticulates are especially suitable for preparing modified-release solid oral dosage forms (delayed- or sustained-release), which offer such benefits as less variable gastrointestinal transit or reduced risk of dose dumping [10]. The most commonly used multiparticulates are coated spherules formulated into oral dosage forms by filling them into hard gelatin capsules [11]. These MUPS comprise several discrete particles: pellets, spherules, granules, powders, or crystals, where the drug is entrapped inside the core or layered around the cores [12].

Although similar drug release profiles can be obtained with both dosage forms, multiple-unit dosage forms offer several advantages over single-unit systems, such as nondisintegrating tablets or capsules. When taken orally, the subunits distribute readily over a large surface area in the gastrointestinal tract [13]. Their small size also enables them to be well distributed along the gastrointestinal tract, which could improve the bioavailability that potentially could result in a reduction of local drug concentration, risk of toxicity, and side effects [14]. In the multiple-unit system, the total drug is divided into many units. The failure of a few units may not be as consequential as the failure of a single-unit system [15]. This is apparent in sustained-release single-unit dosage form, where a failure may lead to dose-dumping of the drug [16].

Angina pectoris, commonly referred to as angina, is a medical condition characterized by chest pain or discomfort that occurs when the heart muscle doesn’t receive enough oxygen-rich blood [17]. This lack of blood flow to the heart is often due to coronary artery disease (CAD), in which the arteries that supply blood to the heart become narrowed and blocked by plaque, a fatty substance composed of cholesterol, calcium, and other substances [18]. Due to reduced oxygen supply to the myocardium, the patients frequently experience angina symptoms, which significantly impair their quality of life [19]. The primary therapeutic aim of angina include managing clinical symptoms and improving quality of life. However, the potential adverse effects associated with the pharmacological treatment cannot be overlooked.

This is a severe issue, particularly after 40 years, leading to nighttime death due to angina [20]. The drug used to treat angina with various nitrate derivatives is delivered as a night-time transdermal patch or as a pill administered four times daily to maintain constant blood levels of the drug, which causes nitrate tolerance due to a high cumulative dose [21]. Generally, Angina in such situations happens in the early morning hours, from 1 am to 6 am. The current strategies adopted in the market fail to reach the plasma concentration at peak hours of nighttime angina and adequately prolong the delivery for the next few hours, failing to meet the requirements. By exploring engineering strategies, Isosorbide dinitrate (ISDN) capsules can be developed as a night-time pill that can be made active at night at the peak hours of angina occurrence, which can significantly reduce the associated mortality risk and also reduce the cumulative dose of ISDN, resulting in reduced drug tolerance [22]. Suppose that pill delivers the medicament 4 to 5 h after intake, which releases the drug for the next 6 h, matching the moment of Angina and its progression, which will reduce the mortality risk and drug tolerance. The present pill includes a time-lagged release to allow for a nitrate-free window, especially overnight. Since, in this approach, the net cumulative dose per day is reduced to one-fourth of the concentration and the release is done for a shorter period (6 h) during the night when angina aggravates, the pill can reduce both the risk and chances of nitrate tolerance. Such a system improves the efficacy while reducing the toxicity of the current therapy. In the management of angina pectoris, chrono delivery systems play a significant role in optimizing treatment outcomes through controlled drug release, improved patient adherence, preventive strategies, enhanced efficacy, and reduced side effects. These systems contribute to better symptom control and overall well-being for individuals living with angina.

This helps maintain consistent drug levels in the body, reduces the frequency of episodes, and delivers medications at specific times of the night, aligning with peak angina episodes or times of increased cardiovascular risk. This targeted approach helps prevent angina attacks and optimise symptom management.

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Materials

Isosorbide dinitrate was purchased from Yarrow Chemicals Mumbai Ltd. Lactose and acetone were sourced from Spectrum Chemicals Pvt. Ltd., Cochin, Kerala. Starch and ethanol were procured from Nice Chemicals. Ethyl cellulose (EC) and hydroxypropyl methylcellulose (HPMC) were supplied by Loba Chemie Pvt. Ltd., Mumbai, India. Eudragit S-100 was bought from Research Lab Fine Chem Industries, Mumbai, India. All the chemicals and reagents used in this study were of analytical grade.

Harika Sapa, K. Kaladhar, Praveen K. Varma, Bhavana Raj, K.P. Althaf Umar, T. Sreejith, Shona Shaji, “Design and development of an ethyl cellulose bulk-engineered spherule-based capsule system”, International Journal of Biological Macromolecules, 2026, 152248, ISSN 0141-8130, https://doi.org/10.1016/j.ijbiomac.2026.152248.

Read also our introduction article on Capsule here: