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Pharmaceutics
Special Issues
Hot-Melt Extrusion: Applications in Pharmaceutics
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Hot-Melt Extrusion: Applications in Pharmaceutics

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: closed (20 December 2020) | Viewed by 22827

Special Issue Editors

Prof. Dr. Michael A. Repka

E-Mail Website
Guest Editor
Distinguished Professor, Department of Pharmaceutics and Drug Delivery, University of Mississippi, University, MS 38677, USA
Interests: hot-melt extrusion (HME) for enhancing solubility and bioavailability of poorly soluble drugs; pharmaceutical novel dosage forms and devices; HME and fused deposition modeling for complex patient centric delivery to pediatric, geriatric and special needs patients; polymeric drug delivery design and stabilization; formulation and process development for natural products; antifungal/antibacterial agents; research on several drug delivery areas including oral, transdermal/trans-nail, nose-to-brain, and transcorneal delivery
Special Issues, Collections and Topics in MDPI journals
Dr. Suresh Bandari

E-Mail Website
Guest Editor
Research Scientist, Department of Pharmaceutics and Drug Delivery, University of Mississippi, University, MS 38677, USA
Interests: oral drug delivery; hot melt extrusion and fused deposition modeling 3D printing for complex patient focused dosage forms; controlled drug delivery; floating drug delivery; chronotherapeutic systems; lipid-based systems; transdermal delivery; self-emulsifying drug delivery systems with special emphasis on improvement of solubility and bioavailability of poorly soluble drugs

Special Issue Information

Dear Colleagues,

Hot melt extrusion offers some distinct advantages over traditional pharmaceutical formulation and processing techniques. Namely, it is a solvent-free technology, can entail a continuous operation (necessitating fewer processing steps), does not require major downstream processing such as compression, and is known to improve bioavailability due to molecular dispersion of the drug in the final dosage form. Thus, HME has become a technology for solving many issues for the pharmaceutical industry. This “green” technology has been an essential tool in resolving oral bioavailability problems of poorly water-soluble drugs. Although HME’s use has been predominantly devoted to preparation of solid dispersions, other uses continue to be discovered and implemented in product development. Furthermore, the combination of HME with other technologies, such as nanotechnology, powder coating, and complexation, has demonstrated the versatility and inclusiveness of HME processing.

However, whilst FDA-approved products have reached the market in the past few years, HME technology for various novel drug delivery applications still needs to be explored. This Special Issue also serves to capture the current progress in the field of hot melt extrusion and fused deposition modeling 3D printing techniques.

Prof. Michael A. Repka
Dr. Suresh Bandari
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • hot melt extrusion
  • amorphous solid dispersions
  • solubility
  • twin screw granulation
  • fused deposition modeling 3D printing
  • continuous manufacturing
  • taste masking
  • bioavailability
  • novel drug delivery applications

Published Papers (5 papers)

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Research

16 pages, 2206 KiB  
Article
Particle Forming Amorphous Solid Dispersions: A Mechanistic Randomized Pharmacokinetic Study in Humans
by Andreas Schittny, Samuel Waldner, Urs Duthaler, Alexander Vorobyev, Rimma Abramovich, Stephan Krähenbühl, Maxim Puchkov and Jörg Huwyler
Pharmaceutics 2021, 13(3), 401; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13030401 - 17 Mar 2021
Cited by 2 | Viewed by 3887
Abstract
Amorphous solid dispersions (ASDs) are a promising drug-delivery strategy to overcome poor solubility through formulation. Currently, the understanding of drug absorption mechanisms from ASDs in humans is incomplete. Aiming to gain insights in this matter, we conducted a randomized cross-over design open-label clinical [...] Read more.
Amorphous solid dispersions (ASDs) are a promising drug-delivery strategy to overcome poor solubility through formulation. Currently, the understanding of drug absorption mechanisms from ASDs in humans is incomplete. Aiming to gain insights in this matter, we conducted a randomized cross-over design open-label clinical study (NCT03886766) with 16 healthy male volunteers in an ambulatory setting, using micro-dosed efavirenz as a model drug. In three phases, subjects were administered (1) solid ASD of efavirenz 50 mg or (2) dissolved ASD of efavirenz 50 mg or (3) a molecular solution of efavirenz 3 mg (non-ASD) as a control in block-randomized order. Endpoints were the pharmacokinetic profiles (efavirenz plasma concentration vs. time curves) and derived pharmacokinetic parameters thereof (AUC0–t, Cmax, tmax, and ka). Results showed that the dissolved ASD (intervention 2) exhibited properties of a supersaturated solution (compared to aqueous solubility) with rapid and complete absorption of the drug from the drug-rich particles. All interventions showed similar AUC0–t and were well tolerated by subjects. The findings highlight the potential of particle forming ASDs as an advanced drug-delivery system for poorly soluble drugs and provide essential insights into underlying mechanisms of ASD functioning in humans, partially validating current conceptual models. Full article
(This article belongs to the Special Issue Hot-Melt Extrusion: Applications in Pharmaceutics)
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15 pages, 3057 KiB  
Article
Amorphous Solid Dispersions and the Contribution of Nanoparticles to In Vitro Dissolution and In Vivo Testing: Niclosamide as a Case Study
by Miguel O. Jara, Zachary N. Warnken and Robert O. Williams III
Pharmaceutics 2021, 13(1), 97; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13010097 - 14 Jan 2021
Cited by 31 | Viewed by 5081
Abstract
We developed an amorphous solid dispersion (ASD) of the poorly water-soluble molecule niclosamide that achieved a more than two-fold increase in bioavailability. Notably, this niclosamide ASD formulation increased the apparent drug solubility about 60-fold relative to the crystalline material due to the generation [...] Read more.
We developed an amorphous solid dispersion (ASD) of the poorly water-soluble molecule niclosamide that achieved a more than two-fold increase in bioavailability. Notably, this niclosamide ASD formulation increased the apparent drug solubility about 60-fold relative to the crystalline material due to the generation of nanoparticles. Niclosamide is a weakly acidic drug, Biopharmaceutics Classification System (BCS) class II, and a poor glass former with low bioavailability in vivo. Hot-melt extrusion is a high-throughput manufacturing method commonly used in the development of ASDs for increasing the apparent solubility and bioavailability of poorly water-soluble compounds. We utilized the polymer poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP–VA) to manufacture niclosamide ASDs by extrusion. Samples were analyzed based on their microscopic and macroscopic behavior and their intermolecular interactions, using differential scanning calorimetry (DSC), X-ray diffraction (XRD), nuclear magnetic resonance (NMR), Fourier-transform infrared (FTIR), and dynamic light scattering (DLS). The niclosamide ASD generated nanoparticles with a mean particle size of about 100 nm in FaSSIF media. In a side-by-side diffusion test, these nanoparticles produced a four-fold increase in niclosamide diffusion. We successfully manufactured amorphous extrudates of the poor glass former niclosamide that showed remarkable in vitro dissolution and diffusion performance. These in vitro tests were translated to a rat model that also showed an increase in oral bioavailability. Full article
(This article belongs to the Special Issue Hot-Melt Extrusion: Applications in Pharmaceutics)
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17 pages, 4742 KiB  
Article
Vacuum Compression Molding as a Screening Tool to Investigate Carrier Suitability for Hot-Melt Extrusion Formulations
by Gauri Shadambikar, Thomas Kipping, Nicole Di-Gallo, Alessandro-Giuseppe Elia, Anja-Nadine Knüttel, Daniel Treffer and Michael. A Repka
Pharmaceutics 2020, 12(11), 1019; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12111019 - 24 Oct 2020
Cited by 22 | Viewed by 5815
Abstract
Hot-melt extrusion (HME) is the most preferred and effective method for manufacturing amorphous solid dispersions at production scale, but it consumes large amounts of samples when used for formulation development. Herein, we show a novel approach to screen the polymers by overcoming the [...] Read more.
Hot-melt extrusion (HME) is the most preferred and effective method for manufacturing amorphous solid dispersions at production scale, but it consumes large amounts of samples when used for formulation development. Herein, we show a novel approach to screen the polymers by overcoming the disadvantage of conventional HME screening by using a minimum quantity of active pharmaceutical ingredient (API). Vacuum Compression Molding (VCM) is a fusion-based method to form solid specimens starting from powders. This study aimed to investigate the processability of VCM for the creation of amorphous formulations and to compare its results with HME-processed formulations. Mixtures of indomethacin (IND) with drug carriers (Parteck® MXP, Soluplus®, Kollidon® VA 64, Eudragit® EPO) were processed using VCM and extrusion technology. Thermal characterization was performed using differential scanning calorimetry, and the solid-state was analyzed via X-ray powder diffraction. Dissolution studies in the simulated gastric fluid were performed to evaluate the drug release. Both technologies showed similar results proving the effectiveness of VCM as a screening tool for HME-based formulations. Full article
(This article belongs to the Special Issue Hot-Melt Extrusion: Applications in Pharmaceutics)
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20 pages, 9837 KiB  
Article
Hot-Melt Extrusion as an Advantageous Technology to Obtain Effervescent Drug Products
by Ana Luiza Lima, Ludmila A. G. Pinho, Juliano A. Chaker, Livia L. Sa-Barreto, Ricardo Neves Marreto, Tais Gratieri, Guilherme M. Gelfuso and Marcilio Cunha-Filho
Pharmaceutics 2020, 12(8), 779; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12080779 - 17 Aug 2020
Cited by 12 | Viewed by 3976
Abstract
Here, we assessed the feasibility of hot-melt extrusion (HME) to obtain effervescent drug products for the first time. For this, a combined mixture design was employed using paracetamol as a model drug. Extrudates were obtained under reduced torque (up to 0.3 Nm) at [...] Read more.
Here, we assessed the feasibility of hot-melt extrusion (HME) to obtain effervescent drug products for the first time. For this, a combined mixture design was employed using paracetamol as a model drug. Extrudates were obtained under reduced torque (up to 0.3 Nm) at 100 °C to preserve the stability of the effervescent salts. Formulations showed vigorous and rapid effervescent disintegration (<3 min), adequate flow characteristics, and complete solubilization of paracetamol instantly after the effervescent reaction. Formulations containing PVPVA in the concentration range of 15–20% m/m were demonstrated to be sensitive to accelerated aging conditions, undergoing marked microstructural changes, since the capture of water led to the agglomeration and loss of their functional characteristics. HPMC matrices, in contrast, proved to be resistant to storage conditions in high relative humidity, showing superior performance to controls, including the commercial product. Moreover, the combined mixture design allowed us to identify significant interactions between the polymeric materials and the disintegrating agents, showing the formulation regions in which the responses are kept within the required levels. In conclusion, this study demonstrates that HME can bring important benefits to the elaboration of effervescent drug products, simplifying the production process and obtaining formulations with improved characteristics, such as faster disintegration, higher drug solubilization, and better stability. Full article
(This article belongs to the Special Issue Hot-Melt Extrusion: Applications in Pharmaceutics)
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14 pages, 3453 KiB  
Article
Preparation of Hot-Melt Extruded Dosage Form for Enhancing Drugs Absorption Based on Computational Simulation
by Sung-Min Choi, Sung-Hoon Lee, Chin-Yang Kang and Jun-Bom Park
Pharmaceutics 2020, 12(8), 757; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12080757 - 11 Aug 2020
Viewed by 3131
Abstract
The aim of this study was to control the dissolution rate and permeability of cilostazol. To enhance the dissolution rate of the active pharmaceutical ingredient (API), hot-melt extrusion (HME) technology was applied to prepare a solid dispersion (SD). To control permeability in the [...] Read more.
The aim of this study was to control the dissolution rate and permeability of cilostazol. To enhance the dissolution rate of the active pharmaceutical ingredient (API), hot-melt extrusion (HME) technology was applied to prepare a solid dispersion (SD). To control permeability in the gastrointestinal tract regardless of food intake, the HME process was optimized based on physiologically based pharmacokinetic (PBPK) simulation. The extrudates were produced using a laboratory-scale twin-screw hot-melt extruder with co-rotatory screws and a constant feeding rate. Next, for PBPK simulation, parameter-sensitive analysis (PSA) was conducted to determine the optimization approach direction. As demonstrated by the dissolution test, the solubility of extrudate was enhanced comparing cilostazol alone. Based on the PSA analysis, the surfactant induction was a crucial factor in cilostazol absorption; thus, an extrudate with an even distribution of lipids was produced using hot-melt extrusion technology, for inducing the bile salts in the gastrointestinal tract. In vivo experiments with rats demonstrated that the optimized hot-melt extruded formulation was absorbed more rapidly with lower deviation and regardless of the meal consumed when compared to marketed cilostazol formulations. Full article
(This article belongs to the Special Issue Hot-Melt Extrusion: Applications in Pharmaceutics)
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