Drug loading mechanism of hollow hydroxyapatite microcapsules

Abstract

Inorganic hydroxyapatite microcapsules are innovative drug delivery devices tailored for oral drug delivery. They were designed as novel excipients, the so-called template inverted particles (TIP), to assist in preparing the orally disintegrating tablets. This study characterized the drug loading capacity using 11 clinically relevant drugs covering all BCS classes, focusing on midazolam HCl, ivermectin, ibuprofen, and metronidazole benzoate. An exceptionally high drug loading capacity of 45 % (v/v) was observed for all studied drugs. Compaction of loaded TIP resulted in mechanically stable tablets with tensile strengths of up to 6 MPa and disintegrating in a few seconds upon contact with water. Accelerated dissolution of encapsulated drugs is explained by the microcapsules’ high specific surface area and the inhibited crystallization due to spacial constraints for some tested drugs. Efficient drug loading into TIP’s internal hollow cavity structure is facilitated by a self-loading mechanism, eliminating the need for complex, drug-specific loading strategies. A mathematical model is presented to describe the self-loading mechanism of TIP, which is responsible for exclusive drug deposition within the cavity of the particles. We demonstrate that TIP, being a versatile and cost-effective platform technology, has the potential to facilitate the formulation development process of patient-friendly medicines.

Introduction

Template inverted particles (TIP) have emerged as promising drug delivery systems due to their ability to encapsulate drugs within their inner cavity, their cost-efficient and scalable manufacturing, biodegradability, and regulatory acceptance [1,2]. They are composed of pure calcium phosphate, a commonly used food additive listed in all major pharmacopeias with a Generally Recognized as Safe (GRAS) status [[3], [4], [5]]. TIP carriers have a rough surface and therefore excellent compactability, enabling the formulation of hard tablets that rapidly disintegrate when exposed to water [6,7]. Consequently, these calcium phosphate carriers were proposed to hold significant potential as a platform technology for developing patient-friendly oral dosage forms [8]. Drug loading into the porous domain can protect sensitive cargo such as proteins and peptides, control the drug release or facilitate targeted drug delivery to the colon or buccal cavity [[9], [10], [11], [12]]. However, in order to profit from these multiple carrier functions, it is important to ensure that drugs of interest can be efficiently encapsulated within the internal structures of the carrier without altering its functionality [13]. Drug-loading capacity of the carriers should thereby be maximized to reduce the required amount of carrier material and thus tablet size [14,15]. This is not a trivial task since conventional mesoporous drug carriers designed for oral drug delivery often encounter limitations in drug loading capacity, which is influenced by geometric pore properties such diameter, shape, and volume [16,17]. ‘Overloading’ of the carrier leads to deposition of drug product on the particle surface and significant changes with respect to compactability, tablet disintegration, and drug dissolution [18,19]. Despite significant efforts to improve carrier performance, most porous carriers still exhibit pore geometries that impede efficient drug loading and lead to drug depositions on the carrier surfaces [13,20,21].

Considering these limitations, much effort has been directed towards improving loading procedures to increase the drug loading efficiency [22]. However, there is no universally effective loading approach, and the design, understanding, and optimization of the loading protocol depends on the specific characteristics of the drug [23].

Therefore, selecting the loading strategy is a critical step in developing the drug delivery system, as it directly impacts the amount of incorporated drug and its distribution within the carrier [24]. Consequently, the loading process is highly influenced by solvent and drug properties and requires a tailored development [25,26]. Therefore, complex and time-consuming multistep loading approaches have been developed, often involving toxic solvents to enhance drug solubility and pore penetration or sophisticated technical procedures [27,28]. Furthermore, many loading strategies often require washing steps to remove externally crystallized drugs responsible for poor performance of the endproduct [22,29,30].

Despite numerous excellent publications describing the successful drug loading of inorganic porous drug delivery systems, limited attention has been devoted to developing novel materials with multiple functionalities.[[31], [32], [33]] These materials should, on the one hand, address patient needs such as high acceptability, a well-established safety profile, fast tablet disintegration, and taste masking [34]. On the other hand, they must tackle technological challenges, including ensuring good manufacturability, maintaining the mechanical stability of tablets, achieving high drug loading capacities, and enabling rapid drug release [35].

Given these shortcomings, we have designed and explored the drug-loading capability of multifunctional hydroxyapatite microcapsules known as template inverted particles (TIP). The latter is produced in a three-step process. First, particle activation with phosphoric acid forms a porous calcium phosphate shell around a calcium carbonate template. Second, the calcium carbonate core is thermally degraded into calcium oxide. Subsequently, the calcium oxide core is removed by washing, resulting in a hollow cavity enclosed by a porous calcium phosphate shell [1]. The hollow internal structure of TIP microcapsules facilitates optimal drug loading and provides additional drug encapsulation space [1]. The latter represents a remarkable advancement compared to conventional inorganic carriers characterized by sponge-like pore structures, high pore tortuosities, and constrained pore volumes, which prevent efficient drug encapsulation [36]. The cavity is enclosed by a porous hydroxyapatite shell, which incorporates a microcapillary structure engineered to facilitate drug loading through solvent-based methods like simple drying, vacuum vacuum-assisted rotary evaporation or large-scale fluidized bed processing.[1].

The present study aims to investigate the drug loading capacity of TIP particles and to provide a mechanistic model to describe the involved processes. As the TIP Material is aimed at producing clinically relevant ODT formulations (see Fig. 1), the drug-loaded material in this study is intended for use later in clinical trials. Eleven clinically relevant drugs of all four BCS classes were selected as model substances. Particular attention was paid to the in-depth characterization of midazolam HCl, ivermectin, ibuprofen, and metronidazole benzoate-loaded. Parameters of interest were drug localization within the carrier’s cavity or on the surface of the particle, compressive behavior, tablet disintegration, and drug release from loaded TIP. In addition, the presented study proposes a mathematical model describing the mechanism responsible for TIP’s exceptionally high drug-loading capacity.

Download the full article as PDF here Drug loading mechanism of hollow hydroxyapatite microcapsules

or read it here

Materials

Template inverted particles (TIP) were kindly provided by Galvita AG (Switzerland). Midazolam HCl was purchased from Hänseler (Switzerland). Ibuprofen was obtained from Glatt GmbH (Germany). Ivermectin was purchased from Combi-Blocks (USA), and metronidazole benzoate was supplied by Corden Pharma (Italy). Drug loading was performed using acetone, methanol, and chloroform (Ph. Eur.) from Carl Roth GmbH (Germany). Particle embedding for cross-sectional analysis and tablet lubrication was done using magnesium stearate from Novartis (Switzerland). Mass transfer experiments were carried out in a CaCl2-ethanol solution. The latter was prepared using CaCl2 dihydrate from Merck (Germany) and ethanol from Carl Roth GmbH (Germany). Croscarmellose-sodium (Ac-Di-Sol®) from FMC (USA) was a tablet disintegrant. Dissolution tests were performed in simulated gastric fluid (0.1 N HCl) from Carl Roth GmbH (Germany) and artificial saliva. Artificial saliva (1L, pH 6.8) was composed of 1017 mg sodium chloride, 61 mg magnesium chloride hexahydrate, 204 mg sodium phosphate dibasic heptahydrate from Carl Roth GmbH (Germany), 228 mg calcium chloride dihydrate, 676 mg potassium carbonate sesquihydrate, and 273 mg sodium phosphate monobasic monohydrate from Merck (Germany). Sink conditions were maintained using sodium lauryl sulfate (SLS) from Carl Roth GmbH (Germany).

Jonas Kost, Nathalie Peyer, Jörg Huwyler, Maxim Puchkov, Drug loading mechanism of hollow hydroxyapatite microcapsules, European Journal of Pharmaceutics and Biopharmaceutics, Volume 214, 2025, 114785, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2025.114785.