Effect of double coating on microencapsulation of levofloxacin using the particles from gas-saturated solutions process as a controlled-release system
Abstract
A novel double-coating technique was employed to encapsulate levofloxacin (LVF), a potent antibacterial drug, using the particles from gas-saturated solutions (PGSS) process to achieve extended release. The primary coating utilized glyceryl tristearate (GT), a lipid with a high melting point (72 °C), followed by a secondary coating with trimyristin (TM), a lipid with a lower melting point (52 °C). For comparison, a single-coating approach was also explored, using the biocompatible polymer poly-(ε-caprolactone) (PCL). The resulting particles were characterized for their shape, size, and LVF encapsulation efficiency, with confirmation of LVF entrapment provided by Fourier transform infrared (FTIR) spectroscopy, and X‐ray powder diffraction (XRD) analysis. The particles, with an average diameter of 95.3 ± 16.5 μm, exhibited an encapsulation efficiency of up to 92.1 ± 2.5%. Furthermore, in vitro release studies revealed that the double-coated microcapsules effectively suppressed the initial burst release and provided controlled, extended release of LVF (t30D = 36.3%), demonstrating the efficiency of this encapsulation method for prolonged drug delivery.
Introduction
Levofloxacin (LVF), a broad-spectrum fluoroquinolone antibiotic, is extensively prescribed to treat a wide range of bacterial infections due to its exceptional oral bioavailability (~ 99%) [1, 2]. Despite its efficacy, LVF’s therapeutic application is hindered by rapid systemic clearance, necessitating frequent dosing and rigorous monitoring, especially in patients with renal impairments [3, 4]. Globally, frequent dosing regimens are associated with lower patient adherence, which further exacerbates treatment challenges and impacts therapeutic success. Furthermore, the increasing prevalence of bacterial resistance to LVF underscores the urgent need for advanced drug delivery systems to enhance its clinical utility and long-term effectiveness [5].
Controlled drug delivery systems (CDDS) offer a promising solution by maintaining consistent drug levels over extended periods, thereby addressing the limitations of conventional LVF administration. By reducing the need for frequent dosing, CDDS improve patient compliance, mitigate the risks of adverse effects, and enhance the overall therapeutic efficacy of LVF [6,7,8]. Among various approaches, microencapsulation stands out as an effective technique to achieve controlled drug release by entrapping the drug within a protective coating that governs its release rate. However, conventional encapsulation methods, such as solvent evaporation and spray drying, rely heavily on organic solvents, raising environmental and safety concerns [9,10,11,12,13]. These methods also tend to produce particles with inconsistent sizes and structural defects, leading to challenges such as the “initial burst effect,” where a significant amount of the drug is released immediately. This rapid release can diminish therapeutic efficacy, increase the risk of bacterial resistance, and cause potential toxicity. Addressing these issues is essential for improving LVF-based drug delivery systems.
The particles from gas-saturated solutions (PGSS) process has recently emerged as a sustainable and efficient method for microencapsulation [14,15,16,17,18,19]. This technique addresses key challenges of conventional encapsulation methods by eliminating the need for organic solvents, reducing environmental concerns, and enabling the formation of microparticles with controlled size and improved structural integrity. The PGSS process uses supercritical fluids, such as CO₂, to form particles without the use of organic solvents, making it an environmentally friendly approach. This technique allows for the formation of microparticles with tunable size and morphology by dissolving CO₂ into a carrier material under moderate pressure, which expands upon depressurization to stabilize the active pharmaceutical ingredients (APIs). However, a common issue with PGSS-derived microcapsules is the formation of surface cracks, particularly when a molten polymer precipitates around the drug. These cracks allow external medium to penetrate the capsules, leading to rapid drug release, which is often undesirable in controlled-release formulations [16, 17].
To mitigate the initial burst release and enhance the controlled-release profile of LVF, a double-coating strategy is employed (Fig. 1). It is anticipated that any cracks in the primary coating will be masked by the secondary polymer coating. Furthermore, any cracks that may occur in the primary polymer film are not expected to be continuous. The secondary coating will serve as an additional barrier, delaying solvent penetration and ensuring a more gradual release of the API. While double coating has been well-established in the context of tablet formulations [20], its application at the microencapsulation level is novel, and this research explores its potential for the first time in the context of LVF encapsulation using the PGSS process.
To validate the efficacy of the double-coating system, this study includes a comparative analysis with poly-(ε-caprolactone) (PCL), a widely used polymer in drug delivery research. Renowned for its biocompatibility and biodegradability, PCL is commonly employed in controlled-release systems due to its ability to sustain drug release over extended periods [18]. By comparing with PCL, this study highlights the double-coating system’s superior encapsulation efficiency, reduced burst effect, and enhanced release profiles. The well-documented properties of PCL as a benchmark material ensure that this comparison provides meaningful validation for the proposed double-coating approach.
In this study, LVF is encapsulated using a combination of two lipids with complementary melting points—glyceryl tristearate (GT, melting point 72 °C) as the primary coating and trimyristin (TM, melting point 52 °C) as the secondary coating. The influence of co-solvents on the encapsulation efficiency of the single-coating system is initially examined, followed by an evaluation of the in vitro release profile of the of both single- double-coating system. The results are compared with a single-coating system using TM and poly-(ε-caprolactone) (PCL) to underscore the advantages of the double-coating strategy in addressing the limitations of conventional single-coating methods, paving the way for its broader application in controlled drug delivery systems.
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Materials
Levofloxacin (MW: 361.37 g/mol, purity > 98.0 wt%, Tokyo Chemical Industry Co., Ltd., Tokyo, Japan), poly(ε-caprolactone) (MW: 10,000 g/mol, Aldrich Chemical Company, Inc., WI, USA), glyceryl tristearate (GT) (MW: 891.48 g/mol), and trimyristin (TM) (MW: 723.16 g/mol, IOI Oleo, Hamburg, Germany) (Fig. 2) were obtained and utilized without further processing. Additionally, CO₂ with a purity of > 99.9 vol.% (Fukuoka Sanso Co., Ltd., Fukuoka, Japan) and ethanol with a purity of > 99.5 wt% (Wako Pure Chemical Industries, Ltd., Osaka, Japan) were purchased and used in their original form.
Sharmin, T., Takeshita, T., Ouchi, M. et al. Effect of double coating on microencapsulation of levofloxacin using the particles from gas-saturated solutions process as a controlled-release system. Discov. Chem. 2, 63 (2025). https://doi.org/10.1007/s44371-025-00140-z
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