Chitosan-based spray-dried solid dispersions of apigenin in a 3D printable drug delivery system

This study aims to develop chitosan-based apigenin (AGN) spray-dried solid dispersions (SDSDs) within a 3D pill. AGN SDSDs were prepared using 1:1 (AC1), 1:1.5 (AC2), and 1:2 (AC1) apigenin/chitosan weight ratios. The results of the process yield were found to be (87.5%, 94.2%, and 95.86%) and of drug assay were obtained as (95.2 ± 1.34%), (99.5 ± 0.85%) and (97.6 ± 2.42%) for AC1, AC2 and AC3, respectively. FTIR revealed compatibility between chitosan and apigenin. DSC and XRD revealed an amorphous state of developed solid dispersions. In contrast, SEM images reflected irregular-block and near-spherical-shape elongated particles in the selected AC2. The antimicrobial examination reflected that AC2 was more effective against Gram-positive, −negative, and fungal strains. AC2 SDSDs had more antioxidant property compared to pure AGN. The anti-proliferative activity against A549 lung cancer cell lines showed a better anticancer activity by AC2 SDSDs. Selected AC2 SDSD was filled in a 3D shell pill and was further characterized in terms of stability. The product had a sustained release and similar release profiles after 3 months of storage. The findings suggest that AC2 SDSDs could be a promising candidate for further development as a 3D-printed drug delivery system for treating multiple disease conditions.

Introduction

Chitosan (CTN) is a biocompatible, biodegradable material derived from chitin. It is nontoxic and mucoadhesive, making it ideal for adhering to mucosal surfaces and enhancing drug delivery.1, 2 CTN has a variety of potential applications in industries such as pharmaceuticals, biotechnology, agriculture, and food.3 CTN can be extracted from shrimp, crab, and lobster shells through deproteinization, demineralization, and deacetylation, or from other sources than seafood waste, such as fungi, insects, and algae, including Aspergillus niger and beetles.4, 5 Commercially, CTN is available in various forms like powder and flakes. Its molecular weight, influenced by the chitin source and degree of deacetylation, affects its solubility and viscosity. CTN chitosan exhibits low solubility in water at neutral pH, but adding acetic acid enhances solubility due to its amino groups.4 (Figure 1).

CTN is used in drug delivery for its mucoadhesion, permeation enhancement, and controlled release properties. It is commonly used in nanoparticles, microparticles, hydrogels, and films to deliver therapeutic agents like anticancer drugs, antibiotics, and anti-inflammatory agents.6 Microencapsulation prepared by CTN has been exploited to deliver proteins, peptides, and vaccines.7 Muqtader et al. reported chitosan-based gels for wound-healing activity.8 Studies also reflect the transdermal and buccal films loaded with timolol and nicotine.9 The cation in CTN enhances the adherence of drug delivery systems to mucosal surfaces (ocular, nasal, gastrointestinal, respiratory, rectal, vaginal), improving drug absorption, bioavailability, and residence time at the action site.10 CTN can also improve drug permeation at the blood–brain barrier (BBB) due to its ability to open tight junctions between cells.11 Brigatinib loaded in PLGA nanoparticles coated with CTN was explored for treating non-small cell lung cancer.12 CTN-coated buspirone-loaded nanostructured lipid carriers for intranasal delivery used for a nose to brain delivery.13 In vivo, pharmacokinetic Studies of CTN-coated PLGA-based NPs have shown the enhanced bioavailability of olaparib.14Apigenin (AGN, structure shown in Figure 2) is a flavonoid found in plants such as parsley, chamomile, and celery. AGN has multiple health benefits that some of them has been reported herein.15 AGN has sequestering properties that neutralize free radicals, protecting cells from damage due to cancer, aging, and inflammation. AGN reduces inflammation by inhibiting cyclooxygenases (COX) and lipoxygenases (LOX) enzymes, which produce inflammatory molecules, and blocking nuclear factor-kappa B (NF-κB) activation. This decreases chronic inflammation linked to heart disease, diabetes, and cancer..16, 17 AGN acts as an anticancer agent by regulating signaling pathways involved in cell cycle progression, angiogenesis, and metastasis, inhibiting the growth of various cancer cells and reducing cancer risk. AGN-induced apoptosis helps prevent cancer spread.18 AGN has anxiolytic properties by acting on gamma-aminobutyric acid (GABA) in the brain and modulating serotonin and dopamine neurotransmitters, aiding in anxiety regulation and treatment of Alzheimer’s and Parkinson’s diseases.19 AGN also disrupts bacterial enzyme activity involved in metabolism and DNA replication, enhancing its antimicrobial effects and making it a potentially valuable natural remedy for infections.20 As AGN arrests reactive oxygen species (ROS) in the body, which can help protect against damage to blood vessels and reduce the risk of atherosclerosis.21 Additionally, AGN prevents blood clots and improves endothelial function, reducing blood pressure, improving lipid profiles, and lowering heart disease risk.22, 23 AGN improves insulin sensitivity and glucose uptake, inhibits carbohydrate metabolism enzymes, and may serve as a valuable natural remedy for diabetes and related complications.24

AGN is a yellow crystalline powder with a bitter taste and it is sparingly soluble in water but not in organic solvents such as dichloromethane, chloroform, ethanol, methanol, and dimethyl sulfoxide (DMSO).25, 26 Studies show that AGN combined with doxorubicin has better anticancer effects compared to doxorubicin alone.27 Another study showed that AGN bound to mucous membranes in the body and improved drug absorption.28 Additionally, AGN nanoparticles of curcumin showed an improved solubility and bioavailability of curcumin, leading to enhanced therapeutic effects.29

Solid dispersion (SD) systems have shown promising results in improving the bioavailability of poorly soluble drugs, in which the drug can exist in various forms, including crystalline, amorphous, or both. An amorphous form of the drug has a relatively better dissolution rate and therapeutic effects with reduced doses.30-32 Technologies employed in preparing SDs are solvent evaporation, freeze-drying, hot-melt extrusion, and spray drying.33 Spray-drying technology is commonly used for preparing SDs in the pharmaceutical industry and lab setups and was chosen in this study as it offers low operating costs and is an energy-efficient technology, making it a cost-effective choice for large-scale production. Additionally, the fast processing times and high encapsulation efficiency of this technique help maintaining the stability and effectiveness of the active ingredient during scale-up.34 The process involves dissolving the drug (AGN) and a polymer (CTN) in a solution, atomizing it into an air chamber supplied with hot air, and producing a powder of drug–polymer particles known as spray-dried solid dispersions (SDSDs).35 MM Ahmed et al. reported the improved dissolution and aphrodisiac activity of sildenafil and tadalafil SDSDs using glycyrrhizin.31, 36, 37 A spray-dried amorphous solid dispersion of diosmin in Soluplus was prepared by MK Anwer et al. and reported to show improved hepato-renoprotective and antioxidant properties.38

Three-dimensional (3D) printing is a promising technology in the pharmaceutical industries and drug development, especially for personalized medicines which offers the advantage of precise customization, allowing for the creation of complex geometries and optimized drug formulations tailored to individual needs. It enhances efficiency by minimizing waste and enabling rapid prototyping of new soft capsules’ designs. However, it comes with high costs, require advanced technical expertise, face challenges in scaling up production, and may not be compatible with all drug formulation. Also, the printed capsules may have limited flexibility once formulated due to the potentially shorter shelf lives depending on the stability of the encapsulated compounds.39, 40

To the best of our knowledge, the investigation of spray-dried solid dispersion of apigenin with chitosan has not yet been reported. The study aimed to develop and characterize chitosan-based spray-dried solid dispersions (SDSDs) of apigenin. First, we prepared the chitosan-based SDSDs of apigenin by optimizing the process parameters, such as the chitosan concentration, the ratio of apigenin to chitosan, and the spray-drying conditions. Characterization techniques included Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy (SEM). Finally, we fabricated a three-dimensional (3D) printer using polyvinyl alcohol (PVA) filament (used as support material) filled with AGN-CTN SDSDs and assessed their release behavior and content analysis.

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Amer S. Alali, Mohammed Muqtader Ahmed, Farhat Fatima, Md. Khalid Anwer, Mutasim Ibnauf, M. Ali Aboudzadeh, Chitosan-based spray-dried solid dispersions of apigenin in a 3D printable drug delivery system, First published: 21 September 2024 https://doi.org/10.1002/app.56310, © 2024 The Author(s). Journal of Applied Polymer Science published by Wiley Periodicals LLC.