Special Issue "Nanosuspensions for the Improvement of Drug Bioavailability"

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: 28 February 2022.

Special Issue Editors

Prof. Dr. Francesco Lai
E-Mail Website
Guest Editor
Università degli Studi di Cagliari, Cagliari, Italy
Interests: nanocrystals; lipid nanoparticles; dermal delivery
Dr. Michele Schlich
E-Mail Website
Guest Editor
Università degli Studi di Cagliari, Cagliari, Italy and Istituto Italiano di Tecnologia, Genova, Italy
Interests: nucleic acid delivery; lipid nanoparticles; nanocrystals for topical application
Dr. Rosa Pireddu
E-Mail
Guest Editor
Università degli Studi di Cagliari, Cagliari, Italy
Interests: liposomes; nanocrystals; lipid nanoparticles; dermal delivery

Special Issue Information

Dear Colleagues,

Solubility is a critical property of any drug, which need to be dissolved in biological fluids to be absorbed and interact with their molecular target(s). The majority of new chemical entities in discovery and development, and a number of approved compounds listed in classes II and IV of the Biopharmaceutical Classification System, are characterized by poor water solubility. The same issue is shared by a number of natural molecules. Low solubility often results in limited or erratic bioavailability, which might impose higher doses to achieve a pharmacological effect, increasing the risk of toxicity and the waste of material. The reduction of drug particle size below 1 µm generates nanocrystals, which in the last several decades delivered the promise of increasing drug solubility and improving bioavailability. Nanocrystals can be dispersed in aqueous or non-aqueous media to produce nanosuspensions, stabilized by surfactants or polymers if necessary. Nanosuspensions, in addition to allowing high drug concentrations, have proved to be efficient in crossing a number of biological barriers, including the skin, the pulmonary epithelium, and the intestinal wall.

This Special Issue on Nanosuspensions for the Improvement of Drug Bioavailability will include original research and thematic reviews on any aspects related to the development of nanosuspensions.

Specifically, the Guest Editors welcome contributions focused on production processes and characterization methods, on the development of novel nanosuspensions, and on their assay in relevant in vitro/in vivo models. Expert opinions on clinical translation and speculative hypotheses on debated topics are also invited.

Prof. Dr. Francesco Lai
Dr. Michele Schlich
Dr. Rosa Pireddu
Guest Editors

Manuscript Submission Information

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Keywords

  • nanosuspensions
  • nanocrystals
  • solubility
  • dissolution
  • bioavailability
  • nano-sizing
  • stabilizers

Published Papers (4 papers)

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Research

Article
Integrating Elastic Tensor and PC-SAFT Modeling with Systems-Based Pharma 4.0 Simulation, to Predict Process Operations and Product Specifications of Ternary Nanocrystalline Suspensions
Pharmaceutics 2021, 13(11), 1771; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13111771 - 22 Oct 2021
Cited by 1 | Viewed by 518
Abstract
Comminution of BCS II APIs below the 1 μm threshold followed by solidification of the obtained nanosuspensions improves their dissolution properties. The breakage process reveals new crystal faces, thus creating altered crystal habits of improved wettability, facilitated by the adsorption of stabilizing polymers. [...] Read more.
Comminution of BCS II APIs below the 1 μm threshold followed by solidification of the obtained nanosuspensions improves their dissolution properties. The breakage process reveals new crystal faces, thus creating altered crystal habits of improved wettability, facilitated by the adsorption of stabilizing polymers. However, process-induced transformations remain unpredictable, mirroring the current limitations of our atomistic level of understanding. Moreover, conventional equations of estimating dissolution, such as Noyes–Whitney and Nernst–Brunner, are not suitable to quantify the solubility enhancement due to the nanoparticle formation; hence, neither the complex stabilizer contribution nor the adsorption influence on the interfacial tension occurring between the water and APIs is accounted for. For such ternary mixtures, no numeric method exists to correlate the mechanical properties with the interfacial energy, capable of informing the key process parameters and the thermodynamic stability assessment of nanosuspensions. In this work, an elastic tensor analysis was performed to quantify the API stability during process implementation. Moreover, a novel thermodynamic model, described by the stabilizer-coated nanoparticle Gibbs energy anisotropic minimization, was structured to predict the material’s system solubility quantified by the application of PC-SAFT modeling. Comprehensively merging elastic tensor and PC-SAFT analysis into the systems-based Pharma 4.0 algorithm provided a validated, multi-level, built-in method capable of predicting the critical material quality attributes and corresponding key process parameters. Full article
(This article belongs to the Special Issue Nanosuspensions for the Improvement of Drug Bioavailability)
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Article
Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based Approach
Pharmaceutics 2021, 13(8), 1188; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13081188 - 31 Jul 2021
Cited by 1 | Viewed by 714
Abstract
Poor water solubility of new chemical entities is considered as one of the main obstacles in drug development, as it usually leads to low bioavailability after administration. To overcome these problems, the selection of the appropriate formulation technology needs to be based on [...] Read more.
Poor water solubility of new chemical entities is considered as one of the main obstacles in drug development, as it usually leads to low bioavailability after administration. To overcome these problems, the selection of the appropriate formulation technology needs to be based on the physicochemical properties of the drug and introduced in the early stages of drug research. One example of the new potential drug substance with poor solubility is DK-I-60-3, deuterated pyrazoloquinolinone, designed for the treatment of various neuropsychiatric disorders. In this research, based on preformulation studies, nanocrystal technology was chosen to improve the oral bioavailability of DK-I-60-3. Nanocrystal dispersions stabilized by sodium lauryl sulfate and polyvinylpyrrolidone were prepared by modified wet media milling technique, with the selection of appropriate process and formulation parameters. The nanoparticles characterization included particle size and zeta potential measurements, differential scanning calorimetry, X-ray powder diffraction, dissolution and solubility study, and in vivo pharmacokinetic experiments. Developed formulations had small uniform particle sizes and were stable for three months. Nanonization caused decreased crystallite size and induced crystal defects formation, as well as a DK-I-60-3 solubility increase. Furthermore, after oral administration of the developed formulations in rats, two to three-fold bioavailability enhancement was observed in plasma and investigated organs, including the brain. Full article
(This article belongs to the Special Issue Nanosuspensions for the Improvement of Drug Bioavailability)
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Article
Nano Co-Crystal Embedded Stimuli-Responsive Hydrogels: A Potential Approach to Treat HIV/AIDS
Pharmaceutics 2021, 13(2), 127; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13020127 - 20 Jan 2021
Cited by 3 | Viewed by 971
Abstract
Currently, the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS) can only be treated successfully, using combination antiretroviral (ARV) therapy. Lamivudine (3TC) and zidovudine (AZT), two compounds used for the treatment of HIV and prevention of disease progression to AIDS are [...] Read more.
Currently, the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS) can only be treated successfully, using combination antiretroviral (ARV) therapy. Lamivudine (3TC) and zidovudine (AZT), two compounds used for the treatment of HIV and prevention of disease progression to AIDS are used in such combinations. Successful therapy with 3TC and AZT requires frequent dosing that may lead to reduced adherence, resistance and consequently treatment failure. Improved toxicity profiles of 3TC and AZT were observed when combined as a nano co-crystal (NCC). The use of stimuli-responsive delivery systems provides an opportunity to overcome the challenge of frequent dosing, by controlling and/or sustaining delivery of drugs. Preliminary studies undertaken to identify a suitable composition for a stimulus-responsive in situ forming hydrogel carrier for 3TC-AZT NCC were conducted, and the gelation and erosion time were determined. A 25% w/w Pluronic® F-127 thermoresponsive hydrogel was identified as a suitable carrier as it exhibited a gelation time of 5 min and an erosion time of 7 days. NCC-loaded hydrogels were evaluated using in vitro dissolution and cytotoxicity assays. In vitro dissolution undertaken using membrane-less diffusion over 168 h revealed that 3TC and AZT release from NCC-loaded hydrogels was complete and followed zero-order kinetic processes, whereas those loaded with the micro co-crystal and physical mixture were incomplete and best described using the Korsmeyer–Peppas kinetic model. The release of AZT and 3TC from the physical mixture and MCC-loaded gel exhibited a value for n of 0.595 for AZT release from the physical mixture and 0.540 for the MCC technology, whereas the release exponent for 3TC was 0.513 for the physical mixture and 0.557 for the MCC technology indicating that diffusion and erosion controlled 3TC and AZT release. In vitro cytotoxicity assay data revealed that the addition of NCC to the thermoresponsive hydrogel resulted in an improved cell viability of 88.0% ± 5.0% when compared to the cell viability of the NCC of 76.9% ± 5.0%. The results suggest that the use of a thermoresponsive nanosuspension may have the potential to be delivered as an intramuscular injection that can subsequently increase bioavailability and permit dose reduction and/or permit use of a longer dosing frequency. Full article
(This article belongs to the Special Issue Nanosuspensions for the Improvement of Drug Bioavailability)
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Article
Nanosuspensions and Microneedles Roller as a Combined Approach to Enhance Diclofenac Topical Bioavailability
Pharmaceutics 2020, 12(12), 1140; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12121140 - 25 Nov 2020
Cited by 6 | Viewed by 807
Abstract
Topical application of the anti-inflammatory drug diclofenac (DCF) reduces the severity of systemic unwanted effects compared to its oral administration. A number of transdermal formulations are available on the market and routinely used in clinical and home-care settings. However, the amount of DCF [...] Read more.
Topical application of the anti-inflammatory drug diclofenac (DCF) reduces the severity of systemic unwanted effects compared to its oral administration. A number of transdermal formulations are available on the market and routinely used in clinical and home-care settings. However, the amount of DCF delivered across the skin remains limited and often insufficient, thus making the oral route still necessary for achieving sufficient drug concentration at the inflamed site. In attempting to improve the transdermal penetration, we explored the combined use of DCF nanosuspensions with a microneedle roller. Firstly, DCF nanosuspensions were prepared by a top-down media milling method and characterized by spectroscopic, thermal and electron microscopy analyses. Secondly, the pore-forming action of microneedle rollers on skin specimens (ex vivo) was described by imaging at different scales. Finally, DCF nanosuspensions were applied on newborn pig skin (in vitro) in combination with microneedles roller treatment, assessing the DCF penetration and distribution in the different skin layers. The relative contribution of microneedle length, nanosuspension stabilizer and application sequence could be identified by systemically varying these parameters. Full article
(This article belongs to the Special Issue Nanosuspensions for the Improvement of Drug Bioavailability)
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