Calcium Phosphate Microcapsules as Multifunctional Drug Delivery Devices

Abstract

More challenging active pharmaceutical ingredients are entering the market, spurring the introduction of novel drug delivery strategies that necessitate a paradigm shift from exhausted excipients to materials with combined actions and multiple functionalities. In this study, an inorganic calcium phosphate microparticle with a hollow internal structure is introduced as a biocompatible and multifunctional microcapsule: the template inverted particle (TIP). A robust process is presented to create a unique particle geometry, which is characterized by a particle size of 20 µm and a hollow cavity enclosed by a specially engineered porous shell. This study focuses on the characterization of TIP as an excipient for the design of solid dosage forms.

The cavities in the particle centers serve as an encapsulation space, resulting in boosted water uptake capacity of 5.3 cm³ g⁻¹. Benefiting from the material’s high wettability and water uptake rates, TIP tablets immediately disperse in the oral cavity. Mechanistic studies reveal a viscoelastic behavior of empty TIP microcapsules in accordance with the Kelvin–Voigt model of a parallel spring-dashpot configuration. The unique particle geometry is maintained during compaction thanks to its exceptional structural integrity. This study demonstrates how multifunctional TIP microcapsules can be applied as a pharmaceutical drug delivery device.

Introduction

Inert particulate drug carriers offer promising opportunities in oral drug delivery.[1] They represent a new class of multifunctional excipients which assist in formulating poorly soluble active pharmaceutical ingredients (APIs).[2-4] Examples include organic drug carriers such as polymer nanoparticles and lipid-based carriers designed mainly for parenteral drug administration, and inorganic materials such as mesoporous silicon particles, functionalized calcium carbonate (FCC), or spherically granulated dibasic calcium phosphate for oral drug delivery.[5-8] Our previous work highlighted multiple applications for FCC.[2, 9, 10] These porous carriers have excellent compatibility (i.e., an ability to keep desired properties after the application of compressive force)[11] and form tablets extremely resistant to crushing.[12] Despite their hardness, these tablets disintegrate (i.e., disperse) within seconds when exposed to water. The rapid disintegration results from the high porosity and significant specific surface area (SSA) of the micrometer-sized drug carriers.[13, 14] This facilitates rapid liquid uptake by capillary forces and weakens the van der Waals forces, which hold the particles of the tablet together. The reported short disintegration times of under 10 s outperform many tablet formulations made of traditional excipients like microcrystalline cellulose (MCC) and are comparable to the reconstitution time of lyophilisates.[2]

The latter effect eliminates the risk of choking and allows one to overcome dysphagia, which is prevalent in the pediatric and geriatric patient populations.[15-18] Rapid disintegration within the oral cavity leads to prolonged buccal mucosa exposure, enhancing oral bioavailability and an immediate onset of therapeutic action.[19, 20] Orally dispersible tablets (ODTs), made of FCC, have an excellent mouthfeel and are well accepted by children.[21, 22] Moreover, concerning dosage form administration, solid dosage forms like tablets have several advantages over liquid dosage forms such as syrups. That includes chemical stability, accurate dosing, and taste masking, enhancing patient acceptance and compliance.[23-25] There are only a few porous drug carriers, such as modified anhydrous dibasic calcium phosphate (Fujicalin), FCC, or amorphous magnesium aluminometasilicate (Neusilin), which support direct compaction at a large scale and offer cost-effective manufacturing process.[6, 26, 27] With these components, no filler or diluent is required resulting in minimal amounts of additional excipients (i.e., a few percentages of a superdisintegrant and the lubricant magnesium stearate) and small tablet sizes.

Surface morphology and structure elucidation. The intermediate product TIP S1 and final product TIP were studied by SEM and FIB-SEM analysis. a) SEM images of sputtered particles. b) FIB-SEM image of a single TIP S1, TIP particle, and TIP loaded with 30% ivermectin. c) SEM images of particle cross-sections embedded in epoxy resin. TIP particles containing residual Ca(OH)2 are indicated with an arrow. Ivermectin-loaded TIP embedded in magnesium stearate. Intraparticular drug depositions (shell and cavity) in (b) and (c) are indicated with arrows. Scale bars of (a–c): 30 µm.

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Despite the features mentioned earlier, porous inorganic carriers, including FCC, share a common limitation: their limited loading capacity. Insufficient pores interlink, as found in many inorganic carriers, makes efficient drug loading difficult.[28, 29] Sub-optimal loading results in drug deposition on the carrier’s surface instead of filling the internal structures. Consequently, the carrier loses its multifunctionality, specifically its ability to produce tablets that disintegrate quickly and with high mechanical strength.[30]

Given these limitations, we have explored in the present study the properties of a novel inorganic carrier material, namely calcium phosphate-based microcapsules.[31] These microcapsules, designated as template inverted particles (TIP), have a uniform size and inner geometry characterized by a single large cavity enclosed by a porous calcium phosphate shell. The shell’s microcapillary structure was engineered and manufactured to facilitate drug loading by solvent-based methods. Particles consist of pure calcium phosphate in the form of hydroxyapatite, which can be considered to be safe since it is widely used as a supplement and food additive. Furthermore, it has been explored for oral drug delivery and tissue engineering, such as the design of bone fracture healing aids.[3, 32-34] Hydroxyapatite is a naturally occurring mineral known to be a major component of bone.[35] It is listed as a compendial material in the United States Pharmacopeia (USP) and European Pharmacopeia (Ph. Eur) and is further categorized as a generally recognized as safe (GRAS) food additive and dietary supplement.[36-38] There are reports of hollow hydroxyapatite particles; however, many are not designed for drug delivery, and their manufacturing process includes substances with unknown toxicological limits.[39-41]

The present study aims to confirm TIP’s chemical and structural composition and visualize its morphology and internal geometry. It describes the physical–chemical properties of TIP such as pore size distribution, intrusion volume, and water uptake capacity. In addition, this study determines if the hollow TIP particles withstand compressive forces applied during compaction.

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Jonas Kost, Jörg Huwyler, Maxim Puchkov, Calcium Phosphate Microcapsules as Multifunctional Drug Delivery Devices, First published: 22 May 2023 https://doi.org/10.1002/adfm.202303333

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