Engineering Large Porous Mannitol-PVA Microparticles for Extended Drug Delivery via Spray Drying

Abstract

Background: Large porous particles (LPPs) offer significant potential in drug delivery due to their porous structure and suitable particle size and shape, which can improve powder dispersibility and control drug release.

Methods: In this study, sustained-release large porous microparticles of mannitol, PVA, and diclofenac sodium (MPDs) were developed using a spray drying technique. The influence of PVA co-spray drying and its concentration (0–40%) on the characteristics of the spray-dried particles was investigated.

Results: Co-spray drying with PVA enhanced particle morphology, producing MPDs with a spherical shape and smooth surface, which minimized particle adhesion. This improvement correlated with a low Carr’s Index value (17.56%), indicating favorable particle dispersibility and aerosol performance. The large geometric diameter (>5 μm) of the MPDs, coupled with their low bulk density (<0.1 g/cm³), suggested potential for inhalation use. FTIR, XRD, and DSC analyses revealed that PVA altered the polymorphic form of mannitol, with the MPDs exhibiting a mixture of the α and δ forms. In vitro dissolution tests demonstrated that PVA co-spray drying effectively prolonged drug release, with the formulation containing 40% PVA (MPD-4) showing an optimal release profile. The release kinetics followed first-order Higuchi models, suggesting drug release occurred through a matrix diffusion mechanism facilitated by the porous structure.

Conclusions: These findings demonstrate the feasibility of engineering large porous microparticles with tailored release characteristics and physicochemical properties suitable for further development in inhalable or other controlled-release dosage forms.

Introduction

Large porous particles (LPPs) have emerged as a versatile platform in modern drug delivery systems due to their unique structural characteristics, including low density and large geometric size. These attributes enable improved powder dispersibility, reduced particle–particle cohesion, and enhanced aerodynamic performance. In pulmonary applications, LPPs have gained particular attention for use in dry powder inhalers (DPIs), which are established delivery systems valued for their portability, stability, and ease of use [1]. However, conventional carrier-based DPIs rely on drug detachment from large excipient particles and are limited by restricted drug loading, often resulting in inconsistent delivery to the lungs [2].

LPP technology has been explored as an alternative to address these limitations. LPPs are defined as particles with a low-density structure (bulk density < 0.1 g/cm3) and a large geometric particle size (5–30 μm) [3]. These characteristics can also yield calculated aerodynamic diameters that may be suitable for inhalation, potentially improving deposition in the lower respiratory tract [4]. These particle characteristics provide a suitable aerodynamic diameter (<5 μm), a range considered favorable for aerosolization performance [5]. Furthermore, the porous structure of LPP allows for the incorporation of functional excipients and active pharmaceutical ingredients (APIs), providing opportunities to engineer drug release profiles tailored to specific therapeutic needs.

Spray drying is a versatile and widely used technique for producing LPPs, and is a single-step process in the conversion of liquid feed into dry particles. This technique also serves as an effective co-processing technique for producing advanced pharmaceutical particles by integrating APIs and excipients to form particles with tailored characteristics such as size, shape, porosity, and surface morphology. By using the co-spraying technique, the advantages of excipients are combined and undesirable properties are reduced, leading to improved material functionality [6]. In our previous work, LPP particles were developed by co-spray drying mannitol with ammonium bicarbonate (poring agent). This LPP, designed for immediate-release use, showed favorable morphology, particle size, and density characteristics for powder inhalation [7]. There are concerns regarding rapid-release formulations, where the drug concentration peaks quickly and then declines rapidly, which can lead to undesirable side effects initially and insufficient therapeutic effects later, particularly for drugs whose efficacy depends on maintaining specific tissue or blood concentrations [8].

On the other hand, extended-release formulations are designed to retain the drug in the target site for an extended period and gradually release it locally at therapeutic levels. Thus, extended-release formulations offer several advantages over traditional formulations, as they serve to maintain consistent therapeutic drug levels, enhancing local efficacy and reducing systemic side effects [9]. Various synthetic polymers have been studied as drug carriers for DPIs, including polyvinyl alcohol (PVA), which is biologically inert and can prolong drug release. Co-spray drying of PVA has been reported to improve the morphology of microparticles, producing spherical shapes with smooth surfaces and a low tendency for particle shrinkage [10]. Previous work conducted on the composite of ciprofloxacin-loaded PVA particles revealed that high PVA incorporation could extend drug release over 24 h [11].

Mannitol is a sugar alcohol that has been widely utilized as a drug carrier in DPI formulations. It is highly stable, crystalline, non-hygroscopic, and biocompatible, making it ideal for pulmonary applications [12]. Mannitol is also stable at high temperature, which facilitates modifications through spray drying. Spray-dried mannitol was investigated as a drug carrier for inhalation, where the surface morphology was primarily influenced by the outlet temperature, which affected aerodynamic performance [13,14]. In addition, Peng et al. developed nanoporous mannitol as a drug carrier for pulmonary delivery using spray drying. Their study revealed that porous spray-dried mannitol exhibited superior deposition efficiency compared to non-porous particles [15].

Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAID) known for its potent anti-inflammatory, analgesic, and antipyretic properties. It works by inhibiting cyclooxygenase (COX) enzymes, primarily COX-2, reducing the synthesis of prostaglandins that mediate inflammation, pain, and fever. However, its non-selective inhibition of COX enzymes can lead to potential side effects such as gastric irritation, ulceration, and bleeding, especially when administered orally. For these reasons, exploring new delivery routes such as pulmonary drug delivery has gained attention as a strategy to reduce side effects and avoid first-pass metabolism [16]. In addition, a sustained-release inhalable formulation could maintain therapeutic drug concentrations for extended periods, thereby reducing dosing frequency, an advantage particularly relevant for short half-life drugs such as diclofenac sodium, and improving patient adherence. Moreover, sustained release may attenuate peak–trough fluctuations in drug concentration, potentially lowering the risk of local side effects, similar to the benefits reported for other inhaled sustained release therapies [17].

This study focuses on the formulation and physicochemical characterization of large porous spray-dried PVA-mannitol microparticles designed for extended-release formulations. To achieve this, mannitol was co-spray dried with PVA, and diclofenac sodium was a model drug. Ammonium bicarbonate was incorporated as a porogen to create a porous structure via thermal decomposition during spray drying. The effect of PVA co-spraying and its concentration on the porous architecture, particle morphology, physicochemical properties, and polymorphic behavior of the spray-dried particles was systematically investigated. Furthermore, an in vitro dissolution study was performed to evaluate drug release kinetics and evaluated the role of PVA in modulating the porous structure and controlling the release mechanism.

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Materials

Mannitol (CAS No. 1344-09-8; Product code: 2305169781) was purchased from Kamaus (Cherrybrook, NSW, Australia), while polyvinyl alcohol (PVA; Mw 85,000–124,000; CAS No. 9002-89-5; product code: 1003548177) was purchased from Sigma-Aldrich (Burlington, MA, USA). The ammonium bicarbonate (AB) (CAS No. 1066-33-7; Product code: 0122000500) was supplied by Loba Chemie (Wodehouse Road, Colaba, Mumbai, India). Diclofenac sodium was a gift from the Bangkok Lab and Cosmetics Public Company Limited (Ratchaburi, Thailand).

Trisopon, K.; Kittipongpatana, O.S.; Chomchoei, N.; Yaowiwat, N.; Saokham, P. Engineering Large Porous Mannitol-PVA Microparticles for Extended Drug Delivery via Spray Drying. Pharmaceutics 2025, 17, 1135. https://doi.org/10.3390/pharmaceutics17091135

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