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Development of a simple paste for 3D printing of drug formulations containing a mesoporous material loaded with a poorly water-soluble drug
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Nanotechnology and Functional Materials.ORCID iD: 0000-0002-0154-3627
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Nanotechnology and Functional Materials.ORCID iD: 0000-0003-0072-4458
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Macromolecular Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Nanotechnology and Functional Materials.ORCID iD: 0000-0002-5496-9664
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2024 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 198, article id 114270Article in journal (Refereed) Published
Abstract [en]

Poorly soluble drugs represent a substantial portion of emerging drug candidates, posing significant challenges for pharmaceutical formulators. One promising method to enhance the drug’s dissolution rate and, consequently, bioavailability involves transforming them into an amorphous state within mesoporous materials. These materials can then be seamlessly integrated into personalized drug formulations using Additive Manufacturing (AM) techniques, most commonly via Fused Deposition Modeling. Another innovative approach within the realm of AM for mesoporous material-based formulations is semi-solid extrusion (SSE). This study showcases the feasibility of a straightforward yet groundbreaking hybrid 3D printing system employing SSE to incorporate drug-loaded mesoporous magnesium carbonate (MMC) into two different drug formulations, each designed for distinct administration routes. MMC was loaded with the poorly water-soluble drug ibuprofen via a solvent evaporation method and mixed with PEG 400 as a binder and lubricant, facilitating subsequent SSE. The formulation is non-aqueous, unlike most pastes which are used for SSE, and thus is beneficial for the incorporation of poorly water-soluble drugs. The 3D printing process yielded tablets for oral administration and suppositories for rectal administration, which were then analyzed for their dissolution behavior in biorelevant media. These investigations revealed enhancements in the dissolution kinetics of the amorphous drug-loaded MMC formulations. Furthermore, an impressive drug loading of 15.3 % w/w of the total formulation was achieved, marking the highest reported loading for SSE formulations incorporating mesoporous materials to stabilize drugs in their amorphous state by a wide margin. This simple formulation containing PEG 400 also showed advantages over other aqueous formulations for SSE in that the formulations did not exhibit weight loss or changes in size or form during the curing process post-printing. These results underscore the substantial potential of this innovative hybrid 3D printing system for the development of drug dosage forms, particularly for improving the release profile of poorly water-soluble drugs.

Place, publisher, year, edition, pages
Elsevier, 2024. Vol. 198, article id 114270
Keywords [en]
3D printing, Additive manufacturing, Semi Solid Extrusion, Paste, Mesoporous Magnesium Carbonate, Poorly soluble drug, Drug delivery
National Category
Pharmaceutical Sciences Other Materials Engineering
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
URN: urn:nbn:se:uu:diva-523789DOI: 10.1016/j.ejpb.2024.114270ISI: 001219767500001PubMedID: 38537908OAI: oai:DiVA.org:uu-523789DiVA, id: diva2:1840418
Part of project
Additive Manufacturing for the Life Sciences, VinnovaTailoring mesoporous materials for additive manufacturing of personalized medication (MesMatMed), Swedish Research Council
Funder
Vinnova, 2019-00029Swedish Research Council, 2019-03729Available from: 2024-02-23 Created: 2024-02-23 Last updated: 2024-05-28Bibliographically approved
In thesis
1. Additive Manufacturing and Mesoporous Materials for Pharmaceutical Applications
Open this publication in new window or tab >>Additive Manufacturing and Mesoporous Materials for Pharmaceutical Applications
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Additive Manufacturing (AM), over the past decade, has evolved into a versatile technology with significant applications in pharmaceutical research. This technology enables the production of drug formulations tailored to individual patients, offering customization in both dosage and dissolution profiles. While challenges in mass production persist, 3D printing, particularly through techniques like Fused Deposition Modeling (FDM) and Semi Solid Extrusion (SSE), proves ideal for crafting smaller batches of personalized dosage forms.

A prevalent issue in drug development revolves around poor water solubility, impacting bioavailability upon oral administration. To combat this, the integration of mesoporous materials emerges as a promising strategy to enhance the dissolution of poorly water-soluble drugs. Here, the applicability of mesoporous materials is explored, as well as their incorporation with various AM techniques. Overall, the thesis dives into the investigation of combinatorial formulations, incorporating at least one 3D printed component to address specific requirements in drug delivery. 

By combining FDM with Selective Laser Sintering (SLS), a hybrid two-compartmental formulation is developed. The durable FDM-printed shell regulates buffer medium access to the contained SLS-produced inserts loaded with the drug. Varying printing parameters and insert combinations within the shell showcase the adjustability and flexibility of this hybrid approach.

Tablets with different infill percentages, containing drug-loaded mesoporous materials, are developed. Poorly water-soluble drugs are successfully amorphized within mesoporous material pores, formulated into filaments through Hot Melt Extrusion (HME), and printed via FDM. These tablets exhibit improved dissolution compared to the crystalline drug, with the dissolution behavior regulated also by the infill percentage.

The study explores the impact of drug-loaded mesoporous materials on HME-produced filament properties, studying their effect on maximum tensile strength and Young’s modulus. The relationship between these properties and filament printability is investigated. Additionally, a protective effect of mesoporous materials on drugs from thermal degradation is revealed.

For Semi Solid Extrusion (SSE) manufactured formulations, a paste is developed, comprising mesoporous material loaded with a poorly water-soluble drug and an excipient. This paste demonstrates favorable rheological properties and easy extrudability via a syringe. The formulation proves versatile for printing dosage forms for both oral and rectal administration, with the printed tablet and suppository exhibiting effective drug release.

In conclusion, this work presents valuable strategies for developing patient-tailored dosage forms, addressing specific pharmaceutical challenges like poor solubility. The integration of mesoporous materials and various 3D printing techniques showcases a promising direction for personalized medicine in the pharmaceutical field.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. p. 78
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 2369
Keywords
Additive Manufacturing, Fused Deposition Modelling, Semi Solid extrusion, Mesoporous materials, Poorly water soluble drugs, Drug delivery
National Category
Engineering and Technology Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-523234 (URN)978-91-513-2047-2 (ISBN)
Public defence
2024-04-12, Heinz-Otto Kreiss Lecture Hall (Å101195), Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2024-03-22 Created: 2024-02-23 Last updated: 2024-03-22

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Katsiotis, Christos S.Tikhomirov, EvgeniiLeliopoulos, ChristosStrømme, MariaWelch, Ken

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