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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Nanomedicine and Nanotechnology".

Deadline for manuscript submissions: closed (10 November 2021) | Viewed by 24825

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Prof. Dr. Carlotta Marianecci

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Department of Drug Chemistry and Technology, Sapienza University of Rome, 00185 Rome, Italy
Interests: drug delivery; drug targeting; niosomes; liposomes; nanobubbles; nanoemulsions; brain targeting; theranostic
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Prof. Dr. Maria Carafa

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Department of Drug Chemistry and Technology, Sapienza University of Rome, 00185 Rome, Italy
Interests: phospholipid and non-phospholipid vesicles; pH-responsive vesicles; nanobubbles; nanoemulsions; brain delivery
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Dr. Federica Rinaldi

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Department of Drug Chemistry and Technologies, Sapienza University, 00185 Rome, Italy
Interests: phospholipid and non-phospholipid vesicles as drug delivery systems (soft nanocarriers); nanoemulsions; nanobubbles; anticancer drug delivery; anti-infective drug delivery; natural compound and drug delivery; nanomedicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Microemulsions (MEs) and nanoemulsions (NEs) are emulsions of a droplet size in the nanometric scale (generally smaller than 250 nm). Classic MEs and NEs consists of oil, water, and an emulsifier. An emulsifier is essential for the formation of minute-sized droplets, because it reduces the interfacial tension, the surface energy per unit area, among the oil and aqueous phases of the emulsion. Both MEs and NEs have attracted great interest as drug delivery systems, as well as cosmetic and cosmeceutical carriers for skin and hair preparations and also in the food industry. Furthermore, the oil phase can be an essential oil, extracted from various plants, with great potential as a natural source of active agents, such as antimicrobials. These natural antimicrobials in MEs and NEs are increasingly utilized in the food and pharmaceutical industries.

MEs and NEs are characterized by thermodynamic stability, great solubilization potential, clarity, easy preparation, and scale up. Moreover, MEs and NEs can operate through various routes and can be derivatized to provide better targetability. MEs and NEs are biodegradable, biocompatible, easy to prepare, and able to entrap lipophilic drugs stabilizing and protecting them in the oily phase.

This SI focuses on pharmaceutical applications of o/w (oil in water) micro and nanoemulsions, but there is also some current research ongoing with non-aqueous and/or oil in oil emulsions.

The topics to be covered include but are not limited to approaches employed in MEs and NEs for pharmaceutical applications, and MEs and NEs administered by various routes.

Prof. Dr. Carlotta Marianecci
Prof. Dr. Maria Carafa
Dr. Federica Rinaldi
Guest Editors

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Keywords

microemulsions
nanoemulsions
formulation
physical chemical characterization
stability studies
in vitro studies
toxicological evaluation
in vivo applications

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Published Papers (8 papers)

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Research

13 pages, 7458 KiB

Open AccessArticle

Nano-Based Drug Delivery Systems of Potent MmpL3 Inhibitors for Tuberculosis Treatment

by Patrizia Nadia Hanieh, Sara Consalvi, Jacopo Forte, Gianluigi Cabiddu, Alessandro De Logu, Giovanna Poce, Federica Rinaldi, Mariangela Biava, Maria Carafa and Carlotta Marianecci

Pharmaceutics 2022, 14(3), 610; https://doi.org/10.3390/pharmaceutics14030610 - 10 Mar 2022

Cited by 7 | Viewed by 2513

Abstract

Tuberculosis remains one of the world’s deadliest infectious diseases, accounting for nearly 1.3 million deaths every year. Tuberculosis treatment is challenging because of the toxicity, decreased bioavailability at the target site of the conventional drugs and, most importantly, low adherence of patients; this leads to drug resistance. Here, we describe the development of suitable nanocarriers with specific physicochemical properties to efficiently deliver two potent antimycobacterial compounds. We prepared nanoemulsions and niosomes formulations and loaded them with two different MmpL3 inhibitors previously identified (NEs + BM635 and NIs + BM859). NEs + BM635 and NIs + BM859 were deeply characterized for their physicochemical properties and anti-mycobacterial activity. NEs + BM635 and NIs + BM859 showed good hydrodynamic diameter, ζ-Potential, PDI, drug-entrapment efficiency, polarity, and microviscosity and stability. Even though both formulations proved to perform well, only NIs + BM859 showed potent antimycobacterial activity against M. tuberculosis (MIC = 0.6 µM) compared to that of the free compound. This is most probably caused by the fact that BM635, being highly hydrophobic, encounters maximum hindrance in diffusion, whereas BM859, characterized by high solubility in aqueous medium (152 µM), diffuses more easily. The niosomal formulation described in this work may be a useful therapeutic tool for tuberculosis treatment, and further studies will follow to characterize the in vivo behavior of the formulation. Full article

(This article belongs to the Special Issue Up-to-Date Pharmaceutical Applications of Micro/Nanoemulsions)

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23 pages, 8734 KiB

Open AccessArticle

Particle Engineering of Innovative Nanoemulsion Designs to Modify the Accumulation in Female Sex Organs by Particle Size and Surface Charge

by Eike Folker Busmann and Henrike Lucas

Pharmaceutics 2022, 14(2), 301; https://doi.org/10.3390/pharmaceutics14020301 - 27 Jan 2022

Cited by 2 | Viewed by 2743

Abstract

Particle engineering of nanosized drug delivery systems (DDS) can be used as a strategic tool to influence their pharmacokinetics after intravenous (i.v.) application by the targeted adaptation of their particle properties according to the needs at their site of action. This study aimed to investigate particle properties depending on patterns in the biodistribution profile to modify the accumulation in the female sex organs using tailor-made nanoemulsion designs and thereby to either increase therapeutic efficiency for ovarian dysfunctions and diseases or to decrease the side effects caused by unintended accumulation. Through the incorporation of the anionic phospholipid phosphatidylglycerol (PG) into the stabilizing macrogol 15 hydroxystearate (MHS) layer of the nanoemulsions droplets, it was possible to produce tailor-made nanoparticles with tunable particle size between 25 to 150 nm in diameter as well as tunable surface charges between −2 to nearly −30 mV zeta potential using a phase inversion-based process. Three chosen negatively surface-charged nanoemulsions of 50, 100, and 150 nm in diameter showed very low cellular toxicities on 3T3 and NHDF fibroblasts and merely interacted with the blood cells, but instead stayed inert in the plasma. In vivo and ex vivo fluorescence imaging of adult female mice i.v. injected with the negatively surface-charged nanoemulsions revealed a high accumulation depending on their particle size in the reticuloendothelial system (RES), being found in the liver and spleen with a mean portion of the average radiant efficiency (PARE) between 42–52%, or 8–10%, respectively. With increasing particle size, an accumulation in the heart was detected with a mean PARE up to 8%. These three negatively surface-charged nanoemulsions overcame the particle size-dependent accumulation in the female sex organs and accumulated equally with a small mean PARE of 5%, suitable to reduce the side effects caused by unintended accumulation while maintaining different biodistribution profiles. In contrast, previously investigated neutral surface-charged nanoemulsions accumulated with a mean PARE up to 10%, strongly dependent on their particle sizes, which is useful to improve the therapeutic efficacy for ovarian dysfunctions and diseases. Full article

(This article belongs to the Special Issue Up-to-Date Pharmaceutical Applications of Micro/Nanoemulsions)

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22 pages, 2324 KiB

Open AccessArticle

In Vitro Evaluation of Curcumin- and Quercetin-Loaded Nanoemulsions for Intranasal Administration: Effect of Surface Charge and Viscosity

by Gustavo Vaz, Adryana Clementino, Evgenia Mitsou, Elena Ferrari, Francesca Buttini, Cristina Sissa, Aristotelis Xenakis, Fabio Sonvico and Cristiana Lima Dora

Pharmaceutics 2022, 14(1), 194; https://doi.org/10.3390/pharmaceutics14010194 - 14 Jan 2022

Cited by 16 | Viewed by 3320

Abstract

The nose-to-brain delivery of neuroprotective natural compounds is an appealing approach for the treatment of neurodegenerative diseases. Nanoemulsions containing curcumin (CUR) and quercetin (QU) were prepared by high-pressure homogenization and characterized physicochemically and structurally. A negative (CQ_NE−), a positive (CQ_NE+), and a gel (CQ_NEgel) formulation were developed. The mean particle size of the CQ_NE− and CQ_NE+ was below 120 nm, while this increased to 240 nm for the CQ_NEgel. The formulations showed high encapsulation efficiency and protected the CUR/QU from biological/chemical degradation. Electron paramagnetic resonance spectroscopy showed that the CUR/QU were located at the interface of the oil phase in the proximity of the surfactant layer. The cytotoxicity studies showed that the formulations containing CUR/QU protected human nasal cells from the toxicity evidenced for blank NEs. No permeation across an in vitro model nasal epithelium was evidenced for CUR/QU, probably due to their poor water-solubility and instability in physiological buffers. However, the nasal cells’ drug uptake showed that the total amount of CUR/QU in the cells was related to the NE characteristics (CQ_NE− > CQ_NE+ > CQ_NEgel). The method used allowed the obtainment of nanocarriers of an appropriate size for nasal administration. The treatment of the cells showed the protection of cellular viability, holding promise as an anti-inflammatory treatment able to prevent neurodegenerative diseases. Full article

(This article belongs to the Special Issue Up-to-Date Pharmaceutical Applications of Micro/Nanoemulsions)

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43 pages, 7542 KiB

Open AccessEditor’s ChoiceArticle

Insights from a Box–Behnken Optimization Study of Microemulsions with Salicylic Acid for Acne Therapy

by Maria-Cristina Anicescu, Cristina-Elena Dinu-Pîrvu, Marina-Theodora Talianu, Mihaela Violeta Ghica, Valentina Anuța, Răzvan-Mihai Prisada, Anca Cecilia Nicoară and Lăcrămioara Popa

Pharmaceutics 2022, 14(1), 174; https://doi.org/10.3390/pharmaceutics14010174 - 12 Jan 2022

Cited by 8 | Viewed by 3383

Abstract

The present study brings to attention a method to develop salicylic acid-based oil in water (O/W) microemulsions using a tensioactive system based on Tween 80, lecithin, and propylene glycol (PG), enriched with a vegetable oat oil phase and hyaluronic acid. The systems were physically characterized and the Quality by design approach was applied to optimize the attributes of microemulsions using Box–Behnken modeling, combined with response surface methodology. For this purpose, a 3³ fractional factorial design was selected. The effect of independent variables namely X1: Tween 80/PG (%), X2: Lecithin (%), X3: Oil phase (%) was analyzed considering their impact upon the internal structure and evaluated parameters chosen as dependent factors: viscosity, mean droplet size, and work of adhesion. A high viscosity, a low droplet size, an adequate wettability—with a reduced mechanical work—and clarity were considered as desirable for the optimal systems. It was found that the optimal microemulsion which complied with the established conditions was based on: Tween 80/PG 40%, lecithin 0.3%, oat oil 2%, salicylic acid 0.5%, hyaluronic acid 1%, and water 56.2%. The response surface methodology was considered an appropriate tool to explain the impact of formulation factors on the physical properties of microemulsions, offering a complex pattern in the assessment of stability and quality attributes for the optimized formulation. Full article

(This article belongs to the Special Issue Up-to-Date Pharmaceutical Applications of Micro/Nanoemulsions)

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23 pages, 2338 KiB

Open AccessArticle

New, Biocompatible, Chitosan-Gelled Microemulsions Based on Essential Oils and Sucrose Esters as Nanocarriers for Topical Delivery of Fluconazole

by Lavinia Vlaia, Ioana Olariu, Ana Maria Muţ, Georgeta Coneac, Vicenţiu Vlaia, Dan Florin Anghel, Monica Elisabeta Maxim, Gabriela Stângă, Amadeus Dobrescu, Maria Suciu, Zoltan Szabadai and Dumitru Lupuleasa

Pharmaceutics 2022, 14(1), 75; https://doi.org/10.3390/pharmaceutics14010075 - 29 Dec 2021

Cited by 13 | Viewed by 2320

Abstract

Biocompatible gel microemulsions containing natural origin excipients are promising nanocarrier systems for the safe and effective topical application of hydrophobic drugs, including antifungals. Recently, to improve fluconazole skin permeation, tolerability and therapeutic efficacy, we developed topical biocompatible microemulsions based on cinnamon, oregano or clove essential oil (CIN, ORG or CLV) as the oil phase and sucrose laurate (D1216) or sucrose palmitate (D1616) as surfactants, excipients also possessing intrinsic antifungal activity. To follow up this research, this study aimed to improve the adhesiveness of respective fluconazole microemulsions using chitosan (a biopolymer with intrinsic antifungal activity) as gellator and to evaluate the formulation variables’ effect (composition and concentration of essential oil, sucrose ester structure) on the gel microemulsions’ (MEGELs) properties. All MEGELs were evaluated for drug content, pH, rheological behavior, viscosity, spreadability, in vitro drug release and skin permeation and antifungal activity. The results showed that formulation variables determined distinctive changes in the MEGELs’ properties, which were nevertheless in accordance with official requirements for semisolid preparations. The highest flux and release rate values and large diameters of the fungal growth inhibition zone were produced by formulations MEGEL-FZ-D1616-CIN 10%, MEGEL-FZ-D1216-CIN 10% and MEGEL-FZ-D1616-ORG 10%. In conclusion, these MEGELs were demonstrated to be effective platforms for fluconazole topical delivery. Full article

(This article belongs to the Special Issue Up-to-Date Pharmaceutical Applications of Micro/Nanoemulsions)

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15 pages, 2692 KiB

Open AccessArticle

A Squalene-Based Nanoemulsion for Therapeutic Delivery of Resiquimod

by Zhongkun Zhang, Jimmy Chun-Tien Kuo, Chi Zhang, Yirui Huang, Zerui Zhou and Robert J. Lee

Pharmaceutics 2021, 13(12), 2060; https://doi.org/10.3390/pharmaceutics13122060 - 2 Dec 2021

Cited by 9 | Viewed by 3935

Abstract

Agonists for toll-like receptors (TLRs) have shown promising activities against cancer. In the present study, a squalene-based nanoemulsion (NE) was loaded with resiquimod, a TLR7/8 agonist for therapeutic delivery. R848 NE was developed and characterized for long-term stability. In vitro and in vivo antitumor immunity of R848 NE were also evaluated in combination with SD-101, a CpG-containing TLR9 agonist. In vitro studies demonstrated strong long-term stability and immune responses to R848 NE. When combined with SD-101, strong antitumor activity was observed in MC38 murine colon carcinoma model with over 80% tumor growth inhibition. The combination treatment showed a 4-fold increase in systemic TNFa production and a 2.6-fold increase in Cd8a expression in tumor tissues, suggesting strong cell-mediated immune responses against the tumor. The treatment not only demonstrated a strong antitumor immunity by TLR7/8 and TLR9 activations but also induced PD-L1 upregulation in tumors, suggesting a potential therapeutic synergy with immune checkpoint inhibitors. Full article

(This article belongs to the Special Issue Up-to-Date Pharmaceutical Applications of Micro/Nanoemulsions)

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23 pages, 1849 KiB

Open AccessArticle

Active Targeted Nanoemulsions for Repurposing of Tegaserod in Alzheimer’s Disease Treatment

by Line Séguy, Léna Guyon, Manon Maurel, Pascal Verdié, Audrey Davis, Sophie Corvaisier, Vincent Lisowski, Patrick Dallemagne, Anne-Claire Groo and Aurélie Malzert-Fréon

Pharmaceutics 2021, 13(10), 1626; https://doi.org/10.3390/pharmaceutics13101626 - 6 Oct 2021

Cited by 9 | Viewed by 3088

Abstract

Background and Purpose: The activation of 5-HT₄ receptors with agonists has emerged as a valuable therapeutic strategy to treat Alzheimer’s disease (AD) by enhancing the nonamyloidogenic pathway. Here, the potential therapeutic effects of tegaserod, an effective agent for irritable bowel syndrome, were assessed for AD treatment. To envisage its efficient repurposing, tegaserod-loaded nanoemulsions were developed and functionalized by a blood–brain barrier shuttle peptide. Results: The butyrylcholinesterase inhibitory activity of tegaserod and its neuroprotective cellular effects were highlighted, confirming the interest of this pleiotropic drug for AD treatment. In regard to its drugability profile, and in order to limit its peripheral distribution after IV administration, its encapsulation into monodisperse lipid nanoemulsions (Tg-NEs) of about 50 nm, and with neutral zeta potential characteristics, was performed. The stability of the formulation in stock conditions at 4 °C and in blood biomimetic medium was established. The adsorption on Tg-NEs of peptide-22 was realized. The functionalized NEs were characterized by chromatographic methods (SEC and C₁₈/HPLC) and isothermal titration calorimetry, attesting the efficiency of the adsorption. From in vitro assays, these nanocarriers appeared suitable for enabling tegaserod controlled release without hemolytic properties. Conclusion: The developed peptide-22 functionalized Tg-NEs appear as a valuable tool to allow exploration of the repurposed tegaserod in AD treatment in further preclinical studies. Full article

(This article belongs to the Special Issue Up-to-Date Pharmaceutical Applications of Micro/Nanoemulsions)

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20 pages, 1470 KiB

Open AccessArticle

Assessment of In-Situ Gelling Microemulsion Systems upon Temperature and Dilution Condition for Corneal Delivery of Bevacizumab

by Elena Peira, Giulia Chindamo, Daniela Chirio, Simona Sapino, Simonetta Oliaro-Bosso, Erica Rebba, Pavlo Ivanchenko and Marina Gallarate

Pharmaceutics 2021, 13(2), 258; https://doi.org/10.3390/pharmaceutics13020258 - 13 Feb 2021

Cited by 8 | Viewed by 2022

Abstract

Bevacizumab (BVZ), a recombinant humanized monoclonal antibody, has recently been proposed as a topical application in the treatment of anterior segment neovascularization; however, as there are some disadvantages in the administration of common eye-drops, ophthalmic topical drug delivery systems are under study to improve the precorneal residence time, reducing the frequency of administration. In this work, oil-in-water and water-in-oil BVZ-loaded microemulsions are developed, able to increase their viscosity, either by the formation of a liquid-crystalline structure upon aqueous dilution, thanks to the presence of Epikuron^® 200 and polysorbate 80, or by body-temperature-induced jellification for the presence of Pluronic^® F127 aqueous solution as an external phase. In oil-in-water microemulsion, hydrophobic ion pairs of BVZ were also prepared, and their incorporation was determined by release studies. Microemulsions were characterized for rheological behavior, corneal opacity, in vitro corneal permeation, and adhesion properties. The studied microemulsions were able to incorporate BVZ (from 1.25 to 1.6 mg/mL), which maintained dose-dependent activity on retinal pigment epithelial ARPE-19 cell lines. BVZ loaded in microemulsions permeated the excised cornea easier (0.76–1.56% BVZ diffused, 4–20% BVZ accumulated) than BVZ commercial solution (0.4% BVZ diffused, 5% accumulated) and only a mild irritation effect on the excised cornea was observed. The good adhesion properties as well the increased viscosity after application, under conditions that mimic the corneal environment (from 1 × 10³ to more than 100 × 10³ mPa·s), might prolong precorneal residence time, proving these systems could be excellent topical BVZ release systems. Full article

(This article belongs to the Special Issue Up-to-Date Pharmaceutical Applications of Micro/Nanoemulsions)

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