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Open AccessEditor’s ChoiceArticle

Targeted Self-Emulsifying Drug Delivery Systems to Restore Docetaxel Sensitivity in Resistant Tumors

by Virginia Campani, Iris Chiara Salaroglio, Valeria Nele, Joanna Kopecka, Andreas Bernkop-Schnürch, Chiara Riganti and Giuseppe De Rosa

Pharmaceutics 2022, 14(2), 292; https://doi.org/10.3390/pharmaceutics14020292 - 26 Jan 2022

Cited by 8 | Viewed by 3548

Abstract

The use of chemotherapeutic agents such as docetaxel (DTX) in anticancer therapy is often correlated to side effects and the occurrence of drug resistance, which substantially impair the efficacy of the drug. Here, we demonstrate that self-emulsifying drug delivery systems (SEDDS) coated with [...] Read more.

The use of chemotherapeutic agents such as docetaxel (DTX) in anticancer therapy is often correlated to side effects and the occurrence of drug resistance, which substantially impair the efficacy of the drug. Here, we demonstrate that self-emulsifying drug delivery systems (SEDDS) coated with enoxaparin (Enox) are a promising strategy to deliver DTX in resistant tumors. DTX partition studies between the SEDDS pre-concentrate and the release medium (water) suggest that the drug is well retained within the SEDDS upon dilution in the release medium. All SEDDS formulations show droplets with a mean diameter between 110 and 145 nm following dilution in saline and negligible hemolytic activity; the droplet size remains unchanged upon sterilization. Enox-coated SEDDS containing DTX exhibit an enhanced inhibition of cell growth compared to the control on cells of different solid tumors characterized by high levels of FGFR, which is due to an increased DTX internalization mediated by Enox. Moreover, only Enox-coated SEDDS are able to restore the sensitivity to DTX in resistant cells expressing MRP1 and BCRP by inhibiting the activity of these two main efflux transporters for DTX. The efficacy and safety of these formulations is also confirmed in vivo in resistant non-small cell lung cancer xenografts. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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16 pages, 1741 KiB

Open AccessArticle

Microfluidic Technology for the Production of Hybrid Nanomedicines

by Ilaria Ottonelli, Jason Thomas Duskey, Arianna Rinaldi, Maria Vittoria Grazioli, Irene Parmeggiani, Maria Angela Vandelli, Leon Z. Wang, Robert K. Prud’homme, Giovanni Tosi and Barbara Ruozi

Pharmaceutics 2021, 13(9), 1495; https://doi.org/10.3390/pharmaceutics13091495 - 17 Sep 2021

Cited by 14 | Viewed by 3433

Abstract

Microfluidic technologies have recently been applied as innovative methods for the production of a variety of nanomedicines (NMeds), demonstrating their potential on a global scale. The capacity to precisely control variables, such as the flow rate ratio, temperature, total flow rate, etc., allows [...] Read more.

Microfluidic technologies have recently been applied as innovative methods for the production of a variety of nanomedicines (NMeds), demonstrating their potential on a global scale. The capacity to precisely control variables, such as the flow rate ratio, temperature, total flow rate, etc., allows for greater tunability of the NMed systems that are more standardized and automated than the ones obtained by well-known benchtop protocols. However, it is a crucial aspect to be able to obtain NMeds with the same characteristics of the previously optimized ones. In this study, we focused on the transfer of a production protocol for hybrid NMeds (H-NMeds) consisting of PLGA, Cholesterol, and Pluronic^® F68 from a benchtop nanoprecipitation method to a microfluidic device. For this aim, we modified parameters such as the flow rate ratio, the concentration of core materials in the organic phase, and the ratio between PLGA and Cholesterol in the feeding organic phase. Outputs analysed were the chemico–physical properties, such as size, PDI, and surface charge, the composition in terms of %Cholesterol and residual %Pluronic^® F68, their stability to lyophilization, and the morphology via atomic force and electron microscopy. On the basis of the results, even if microfluidic technology is one of the unique procedures to obtain industrial production of NMeds, we demonstrated that the translation from a benchtop method to a microfluidic one is not a simple transfer of already established parameters, with several variables to be taken into account and to be optimized. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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14 pages, 1663 KiB

Open AccessArticle

Pulmonary Delivery of Curcumin and Beclomethasone Dipropionate in a Multicomponent Nanosuspension for the Treatment of Bronchial Asthma

by Luca Casula, Francesco Lai, Elena Pini, Donatella Valenti, Chiara Sinico, Maria Cristina Cardia, Salvatore Marceddu, Giorgia Ailuno and Anna Maria Fadda

Pharmaceutics 2021, 13(8), 1300; https://doi.org/10.3390/pharmaceutics13081300 - 20 Aug 2021

Cited by 23 | Viewed by 3396

Abstract

Curcumin has shown a potential extraordinary activity as an add-on ingredient in asthma treatment, due to its immunomodulatory and anti-inflammatory mechanism of action. However, its low water solubility and bioavailability lead to a poor therapeutic effect, which can be overcome by its formulation [...] Read more.

Curcumin has shown a potential extraordinary activity as an add-on ingredient in asthma treatment, due to its immunomodulatory and anti-inflammatory mechanism of action. However, its low water solubility and bioavailability lead to a poor therapeutic effect, which can be overcome by its formulation as nanocrystals. The aim of this study was to prepare a multicomponent formulation for the delivery of curcumin (CUR) and beclomethasone dipropionate (BDP) into the lungs as water-based nanosuspensions (NS). Single component formulations (CUR-NS, BDP-NS) and a multicomponent formulation (CUR+BDP-NS) were prepared through a wet ball media milling technique, using P188 as a non-toxic stabilizer. Characterization was carried out in terms of size, size distribution, zeta potential, nanocrystals morphology, and solid-state properties. Moreover, the inhalation delivery efficiency was studied with Next Generation Impactor (NGI, Apparatus E Ph. Eu). CUR-NS was optimized and showed a long-term stability and improved nanocrystals apparent solubility. The three formulations exhibited a nanocrystal mean diameter in the range of 200–240 nm and a homogenous particle size distribution. Aggregation or sedimentation phenomena were not observed in the multicomponent formulation on 90 days storage at room temperature. Finally, the nebulization tests of the three samples showed optimal aerodynamic parameters and MMAD < 5 µm. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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15 pages, 3073 KiB

Open AccessArticle

The Anti-Arthritic Efficacy of Khellin Loaded in Ascorbyl Decanoate Nanovesicles after an Intra-Articular Administration

by Giulia Vanti, Lorenzo Di Cesare Mannelli, Laura Micheli, Lorenzo Cinci, Lucia Grifoni, Maria Camilla Bergonzi, Carla Ghelardini and Anna Rita Bilia

Pharmaceutics 2021, 13(8), 1275; https://doi.org/10.3390/pharmaceutics13081275 - 17 Aug 2021

Cited by 8 | Viewed by 2220

Abstract

Osteoarthritis is the most widespread joint-affecting disease. The management of persistent pain remains inadequate and demands new therapeutic strategies. In this study, we explored the pain relieving and protective properties of a single intra-articular (i.a.) injection of khellin loaded in nanovesicles (K-Ves) based [...] Read more.

Osteoarthritis is the most widespread joint-affecting disease. The management of persistent pain remains inadequate and demands new therapeutic strategies. In this study, we explored the pain relieving and protective properties of a single intra-articular (i.a.) injection of khellin loaded in nanovesicles (K-Ves) based on ascorbyl decanoate plus phosphatidylcholine in a rat model of osteoarthritis (OA) induced by monosodium iodoacetate (MIA) treatment. The developed nanovesicles (approximately 136 nm) had a narrow size distribution (PdI 0.26), a good recovery (about 80%) and a worthy encapsulation efficiency (about 70%) with a ζ-potential of about −40 mV. The stability of K-Ves was assessed in simulated synovial fluid. Seven days after the articular damage with MIA, both K-Ves and a suspension of khellin (K, 50 μL) were i.a. injected. K-Ves significantly counteracted MIA-induced hypersensitivity to mechanical noxious (paw pressure test) and non-noxious stimuli (von Frey test) and significantly reduced the postural unbalance related to spontaneous pain (incapacitance test) and the motor alterations (beam balance test) 7 and 14 days after the i.a. injection. K was partially active only on day 7 after the treatment. The histology emphasized the improvement of several morphological factors in MIA plus K-Ves-treated animals. In conclusion, K-Ves could be successfully used for the local treatment of osteoarthritis. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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21 pages, 3912 KiB

Open AccessArticle

Essential Oil-Loaded NLC for Potential Intranasal Administration

by Angela Bonaccorso, Cinzia Cimino, Daniela Erminia Manno, Barbara Tomasello, Antonio Serra, Teresa Musumeci, Giovanni Puglisi, Rosario Pignatello and Claudia Carbone

Pharmaceutics 2021, 13(8), 1166; https://doi.org/10.3390/pharmaceutics13081166 - 28 Jul 2021

Cited by 18 | Viewed by 3204

Abstract

Complementary and alternative medicines represent an interesting field of research on which worldwide academics are focusing many efforts. In particular, the possibility to exploit pharmaceutical technology strategies, such as the nanoencapsulation, for the delivery of essential oils is emerging as a promising strategy [...] Read more.

Complementary and alternative medicines represent an interesting field of research on which worldwide academics are focusing many efforts. In particular, the possibility to exploit pharmaceutical technology strategies, such as the nanoencapsulation, for the delivery of essential oils is emerging as a promising strategy not only in Italy but also all over the world. The aim of this work was the development of nanostructured lipid carriers (NLC) for the delivery of essential oils (Lavandula, Mentha, and Rosmarinus) by intranasal administration, an interesting topic in which Italian contributions have recently increased. Essential oil-loaded NLC, projected as a possible add-on strategy in the treatment of neurodegenerative diseases, were characterized in comparison to control formulations prepared with Tegosoft CT and Neem oil. Homogeneous (polydispersity index, PDI < 0.2) nanoparticles with a small size (<200 nm) and good stability were obtained. Morphological and physical-chemical studies showed the formation of different structures depending on the nature of the liquid oil component. In particular, NLC prepared with Lavandula or Rosmarinus showed the formation of a more ordered structure with higher cytocompatibility on two cell lines, murine and human fibroblasts. Taken together, our preliminary results show that optimized positively charged NLC containing Lavandula or Rosmarinus can be proposed as a potential add-on strategy in the treatment of neurodegenerative diseases through intranasal administration, due to the well-known beneficial effects of essential oils and the mucoadhesive properties of NLC. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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13 pages, 3984 KiB

Open AccessArticle

In Vitro Wound-Healing Properties of Water-Soluble Terpenoids Loaded on Halloysite Clay

by Lisa Marinelli, Ivana Cacciatore, Piera Eusepi, Marilisa Pia Dimmito, Annalisa Di Rienzo, Marcella Reale, Erica Costantini, Ana Borrego-Sánchez, Fátima García-Villén, César Viseras, Gianluca Morroni, Simona Fioriti, Lucia Brescini and Antonio Di Stefano

Pharmaceutics 2021, 13(8), 1117; https://doi.org/10.3390/pharmaceutics13081117 - 22 Jul 2021

Cited by 13 | Viewed by 2994

Abstract

Recently, mineral healing clays have gained much attention for wound-dressing applications. Here, we selected halloysite (HAL) clay as a biocompatible, non-toxic material that is useful as a drug delivery system to enhance the healing properties of water-soluble terpenoids 1-3 (T1-3). Terpenoids-loaded [...] Read more.

Recently, mineral healing clays have gained much attention for wound-dressing applications. Here, we selected halloysite (HAL) clay as a biocompatible, non-toxic material that is useful as a drug delivery system to enhance the healing properties of water-soluble terpenoids 1-3 (T1-3). Terpenoids-loaded HAL clay (TH1-3) was prepared and characterized by adsorption equilibrium studies, X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy, and release studies. The results reveal that T1-3 were adsorbed at the HAL surface with good efficiency. The prevalent mechanism of drug retention is due to the adsorption via electrostatic interactions between the cationic groups of the T1-3 and the HAL’s external surface. Release studies demonstrated that T3 was released in a higher percentage (>60%) compared to T1-2 (≈50%). Additionally, TH1-3 were assessed for their antimicrobial activity and capability to promote the re-epithelialization of scratched HaCat monolayers, through the time-kill test and the wound-healing assays, respectively. The results reveal that all the tested formulations were able to reduce the microbial growth after 1 h of incubation and that they ensured complete wound closure after 48 h. Furthermore, at the concentration of 1 µg/mL, TH3 exhibited 45% wound closure at 24 h, compared to TH1 (27%) and TH2 (30%), proving to be the best candidate in making the tissue-repair process easier and faster. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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21 pages, 15816 KiB

Open AccessArticle

Mannitol Polymorphs as Carrier in DPIs Formulations: Isolation Characterization and Performance

by Ayça Altay Benetti, Annalisa Bianchera, Francesca Buttini, Laura Bertocchi and Ruggero Bettini

Pharmaceutics 2021, 13(8), 1113; https://doi.org/10.3390/pharmaceutics13081113 - 21 Jul 2021

Cited by 16 | Viewed by 3553

Abstract

The search for best performing carriers for dry powder inhalers is getting a great deal of interest to overcome the limitations posed by lactose. The aerosolization of adhesive mixtures between a carrier and a micronized drug is strongly influenced by the carrier solid-state [...] Read more.

The search for best performing carriers for dry powder inhalers is getting a great deal of interest to overcome the limitations posed by lactose. The aerosolization of adhesive mixtures between a carrier and a micronized drug is strongly influenced by the carrier solid-state properties. This work aimed at crystallizing kinetically stable D-mannitol polymorphs and at investigating their aerosolization performance when used in adhesive mixtures with two model drugs (salbutamol sulphate, SS, and budesonide, BUD) using a median and median/high resistance inhaler. A further goal was to assess in vitro the cytocompatibility of the produced polymer-doped mannitol polymorphs toward two lung epithelial cell lines. Kinetically stable (up to 12 months under accelerate conditions) α, and δ mannitol forms were crystallized in the presence of 2% w/w PVA and 1% w/w PVP respectively. These solid phases were compared with the β form and lactose as references. The solid-state properties of crystallized mannitol significantly affected aerosolization behavior, with the δ form affording the worst fine particle fraction with both the hydrophilic (9.3 and 6.5%) and the lipophilic (19.6 and 32%) model drugs, while α and β forms behaved in the same manner (11–13% for SS; 53–58% for BUD) and better than lactose (8 and 13% for SS; 26 and 39% for BUD). Recrystallized mannitol, but also PVA and PVP, proved to be safe excipients toward lung cell lines. We concluded that, also for mannitol, the physicochemical properties stemming from different crystal structures represent a tool for modulating carrier-drug interaction and, in turn, aerosolization performance. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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21 pages, 6491 KiB

Open AccessArticle

Emulgel Loaded with Flaxseed Extracts as New Therapeutic Approach in Wound Treatment

by Cinzia Pagano, Claudio Baiocchi, Tommaso Beccari, Francesca Blasi, Lina Cossignani, Maria Rachele Ceccarini, Ciriana Orabona, Elena Orecchini, Enrico Di Raimo, Sara Primavilla, Laura Salvini, Alessandro Di Michele, Luana Perioli and Maurizio Ricci

Pharmaceutics 2021, 13(8), 1107; https://doi.org/10.3390/pharmaceutics13081107 - 21 Jul 2021

Cited by 14 | Viewed by 3175

Abstract

Dry (D.E.) and liquid (L.E.) extracts were prepared from flaxseeds and their application in health field was evaluated. The chemical analysis showed that D.E. is rich in the lignan secoisolariciresinol diglucoside and L.E. in unsaturated triglycerides containing linolenic acid. Mainly, D.E. showed reducing [...] Read more.

Dry (D.E.) and liquid (L.E.) extracts were prepared from flaxseeds and their application in health field was evaluated. The chemical analysis showed that D.E. is rich in the lignan secoisolariciresinol diglucoside and L.E. in unsaturated triglycerides containing linolenic acid. Mainly, D.E. showed reducing (15.73 μmol Fe²⁺/g) and radical scavenging capacities (5.25 mg TE/g) and ability to down-regulate the expression of the pro-inflammatory cytokines NO (IC₅₀ = 0.136 ± 0.009 mg/mL) and IL-6 (IC₅₀ = 0.308 ± 0.103 mg/mL), suggesting its use in wound treatment. D.E. and L.E. were active against S. pyogenes and D.E. also against S. aureus. The two extracts were combined in a novel O/W emulgel in which the water phase was viscosized using a low molecular weight and highly deacetylated chitosan (1% wt./v). The presence of this polymer in the emulgel decreased the MIC values of the extracts. In fact, MIC shifted from 0.59 mg/mL to 0.052 mg/mL for D.E. and from 0.22 mg/mL to 0.036 mg/mL for L.E., concentrations safe both for keratinocytes and macrophages. Moreover, the emulgel demonstrated to inhibit S. aureus, P. aeruginosa, S. pyogenes, E. coli, and K. pneumoniae growth (inhibition halos 24–36 mm), strains often responsible for diabetic foot ulcer infection. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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24 pages, 8850 KiB

Open AccessArticle

Liquid Lipids Act as Polymorphic Modifiers of Tristearin-Based Formulations Produced by Melting Technologies

by Serena Bertoni, Nadia Passerini and Beatrice Albertini

Pharmaceutics 2021, 13(7), 1089; https://doi.org/10.3390/pharmaceutics13071089 - 16 Jul 2021

Cited by 17 | Viewed by 3618

Abstract

Despite the growing interest in lipid-based formulations, their polymorphism is still a challenge in the pharmaceutical industry. Understanding and controlling the polymorphic behavior of lipids is a key element for achieving the quality and preventing stability issues. This study aims to evaluate the [...] Read more.

Despite the growing interest in lipid-based formulations, their polymorphism is still a challenge in the pharmaceutical industry. Understanding and controlling the polymorphic behavior of lipids is a key element for achieving the quality and preventing stability issues. This study aims to evaluate the impact of different oral-approved liquid lipids (LL) on the polymorphism, phase transitions and structure of solid lipid-based formulations and explore their influence on drug release. The LL investigated were isopropyl myristate, ethyl oleate, oleic acid, medium chain trigycerides, vitamin E acetate, glyceryl monooleate, lecithin and sorbitane monooleate. Spray-congealing was selected as an example of a melting-based solvent-free manufacturing method to produce microparticles (MPs) of tristearin (Dynasan^®118). During the production process, tristearin MPs crystallized in the metastable α-form. Stability studied evidenced a slow phase transition to the stable β-polymorph overtime, with the presence of the α-form still detected after 60 days of storage at 25 °C. The addition of 10% w/w of LL promoted the transition of tristearin from the α-form to the stable β-form with a kinetic varying from few minutes to days, depending on the specific LL. The combination of various techniques (DSC, X-ray diffraction analysis, Hot-stage polarized light microscopy, SEM) showed that the addition of LL significantly modified the crystal structure of tristearin-based formulations at different length scales. Both the polymorphic form and the LL addition had a strong influence on the release behavior of a model hydrophilic drug (caffeine). Overall, the addition of LL can be considered an interesting approach to control triglyceride crystallization in the β-form. From the industrial viewpoint, this approach might be advantageous as any polymorphic change will be complete before storage, hence enabling the production of stable lipid formulations. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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13 pages, 3099 KiB

Open AccessArticle

Rifampicin–Liposomes for Mycobacterium abscessus Infection Treatment: Intracellular Uptake and Antibacterial Activity Evaluation

by Federica Rinaldi, Patrizia Nadia Hanieh, Simona Sennato, Federica De Santis, Jacopo Forte, Maurizio Fraziano, Stefano Casciardi, Carlotta Marianecci, Federico Bordi and Maria Carafa

Pharmaceutics 2021, 13(7), 1070; https://doi.org/10.3390/pharmaceutics13071070 - 13 Jul 2021

Cited by 17 | Viewed by 3548

Abstract

Treatment of pulmonary infections caused by Mycobacterium abscessus are extremely difficult to treat, as this species is naturally resistant to many common antibiotics. Liposomes are vesicular nanocarriers suitable for hydrophilic and lipophilic drug loading, able to deliver drugs to the target site, and [...] Read more.

Treatment of pulmonary infections caused by Mycobacterium abscessus are extremely difficult to treat, as this species is naturally resistant to many common antibiotics. Liposomes are vesicular nanocarriers suitable for hydrophilic and lipophilic drug loading, able to deliver drugs to the target site, and successfully used in different pharmaceutical applications. Moreover, liposomes are biocompatible, biodegradable and nontoxic vesicles and nebulized liposomes are efficient in targeting antibacterial agents to macrophages. The present aim was to formulate rifampicin-loaded liposomes (RIF–Lipo) for lung delivery, in order to increase the local concentration of the antibiotic. Unilamellar liposomal vesicles composed of anionic DPPG mixed with HSPC for rifampicin delivery were designed, prepared, and characterized. Samples were prepared by using the thin-film hydration method. RIF–Lipo and unloaded liposomes were characterized in terms of size, ζ-potential, bilayer features, stability and in different biological media. Rifampicin’s entrapment efficiency and release were also evaluated. Finally, biological activity of RIF-loaded liposomes in Mycobacterium abscessus-infected macrophages was investigated. The results show that RIF-lipo induce a significantly better reduction of intracellular Mycobacterium abscessus viability than the treatment with free drug. Liposome formulation of rifampicin may represent a valuable strategy to enhance the biological activity of the drug against intracellular mycobacteria. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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14 pages, 2315 KiB

Open AccessArticle

In Vitro Skin Permeation of Idebenone from Lipid Nanoparticles Containing Chemical Penetration Enhancers

by Lucia Montenegro, Ludovica Maria Santagati, Maria Grazia Sarpietro, Francesco Castelli, Annamaria Panico, Edy Angela Siciliano, Francesco Lai, Donatella Valenti and Chiara Sinico

Pharmaceutics 2021, 13(7), 1027; https://doi.org/10.3390/pharmaceutics13071027 - 6 Jul 2021

Cited by 5 | Viewed by 2729

Abstract

Lipid nanoparticles (LNPs) have been proposed as carriers for drug skin delivery and targeting. As LNPs effectiveness could be increased by the addition of chemical penetration enhancers (PE), in this work, the feasibility of incorporating PE into LNPs to improve idebenone (IDE) targeting [...] Read more.

Lipid nanoparticles (LNPs) have been proposed as carriers for drug skin delivery and targeting. As LNPs effectiveness could be increased by the addition of chemical penetration enhancers (PE), in this work, the feasibility of incorporating PE into LNPs to improve idebenone (IDE) targeting to the skin was investigated. LNPs loading IDE 0.7% w/w were prepared using hydrophilic (propylene glycol, PG, 10% w/w or N-methylpyrrolidone, NMP, 10% w/w) and/or lipophilic PE (oleic acid, OA, 1% w/w; isopropyl myristate, IPM, 3.5% w/w; a mixture of 0.5% w/w OA and 2.5% w/w IPM). All LNPs showed small sizes (<60 nm), low polydispersity index and good stability. According to the obtained results, IDE release from LNPs was not the rate-limiting step in IDE skin penetration. No IDE permeation was observed through excised pigskin from all LNPs, while the greatest increase of IDE penetration into the different skin layers was obtained using the mixture OA/IPM. The antioxidant activity of IDE-loaded LNPs, determined by the oxygen radical absorbance capacity assay, was greater than that of free IDE. These results suggest that the use of suitable PE as LNPs components could be regarded as a promising strategy to improve drug targeting to the skin. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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18 pages, 2545 KiB

Open AccessArticle

Development of a Cyclodextrin-Based Mucoadhesive-Thermosensitive In Situ Gel for Clonazepam Intranasal Delivery

by Marzia Cirri, Francesca Maestrelli, Giulia Nerli, Natascia Mennini, Mario D’Ambrosio, Cristina Luceri and Paola Angela Mura

Pharmaceutics 2021, 13(7), 969; https://doi.org/10.3390/pharmaceutics13070969 - 26 Jun 2021

Cited by 21 | Viewed by 3447

Abstract

A thermosensitive, mucoadhesive in-situ gel for clonazepam (CLZ) intranasal delivery was developed, which aimed to achieve prolonged in-situ residence and controlled drug release, overcoming problems associated with its oral or parenteral administration. Poloxamer was selected as a thermosensitive polymer and chitosan glutamate and [...] Read more.

A thermosensitive, mucoadhesive in-situ gel for clonazepam (CLZ) intranasal delivery was developed, which aimed to achieve prolonged in-situ residence and controlled drug release, overcoming problems associated with its oral or parenteral administration. Poloxamer was selected as a thermosensitive polymer and chitosan glutamate and sodium hyaluronate as mucoadhesive and permeation enhancer. Moreover, randomly methylated β-Cyclodextrin (RAMEB) was used to improve the low drug solubility. A screening DoE was applied for a systematic examination of the effect of varying the formulation components proportions on gelation temperature, gelation time and pH. Drug-loaded gels at different clonazepam-RAMEB concentrations were then prepared and characterized for gelation temperature, gelation time, gel strength, mucoadhesive strength, mucoadhesion time, and drug release properties. All formulations showed suitable gelation temperature (29–30.5 °C) and time (50–65 s), but the one with the highest drug-RAMEB concentration showed the best mucoadhesive strength, longest mucoadhesion time (6 h), and greatest release rate. Therefore, it was selected for cytotoxicity and permeation studies through Caco-2 cells, compared with an analogous formulation without RAMEB and a drug solution. Both gels were significantly more effective than the solution. However, RAMEB was essential not only to promote drug release, but also to reduce drug cytotoxicity and further improve its permeability. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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20 pages, 2339 KiB

Open AccessArticle

Polymer Coated Oncolytic Adenovirus to Selectively Target Hepatocellular Carcinoma Cells

by Mariangela Garofalo, Federica Bellato, Salvatore Magliocca, Alessio Malfanti, Lukasz Kuryk, Beate Rinner, Samuele Negro, Stefano Salmaso, Paolo Caliceti and Francesca Mastrotto

Pharmaceutics 2021, 13(7), 949; https://doi.org/10.3390/pharmaceutics13070949 - 24 Jun 2021

Cited by 23 | Viewed by 4066

Abstract

Despite significant advances in chemotherapy, the overall prognosis of hepatocellular carcinoma (HCC) remains extremely poor. HCC targeting strategies were combined with the tumor cell cytotoxicity of oncolytic viruses (OVs) to develop a more efficient and selective therapeutic system. OVs were coated with a [...] Read more.

Despite significant advances in chemotherapy, the overall prognosis of hepatocellular carcinoma (HCC) remains extremely poor. HCC targeting strategies were combined with the tumor cell cytotoxicity of oncolytic viruses (OVs) to develop a more efficient and selective therapeutic system. OVs were coated with a polygalactosyl-b-agmatyl diblock copolymer (Gal₃₂-b-Agm₂₉), with high affinity for the asialoglycoprotein receptor (ASGPR) expressed on the liver cell surface, exploiting the electrostatic interaction of the positively charged agmatine block with the negatively charged adenoviral capsid surface. The polymer coating altered the viral particle diameter (from 192 to 287 nm) and zeta-potential (from –24.7 to 23.3 mV) while hiding the peculiar icosahedral symmetrical OV structure, as observed by TEM. Coated OVs showed high potential therapeutic value on the human hepatoma cell line HepG2 (cytotoxicity of 72.4% ± 4.96), expressing a high level of ASGPRs, while a lower effect was attained with ASPGR-negative A549 cell line (cytotoxicity of 54.4% ± 1.59). Conversely, naked OVs showed very similar effects in both tested cell lines. Gal₃₂-b-Agm₂₉ OV coating enhanced the infectivity and immunogenic cell death program in HepG2 cells as compared to the naked OV. This strategy provides a rationale for future studies utilizing oncolytic viruses complexed with polymers toward effective treatment of hepatocellular carcinoma. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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17 pages, 4638 KiB

Open AccessArticle

Folic Acid-Targeted Paclitaxel-Polymer Conjugates Exert Selective Cytotoxicity and Modulate Invasiveness of Colon Cancer Cells

by Antonella Grigoletto, Gabriele Martinez, Daniela Gabbia, Tommaso Tedeschini, Michela Scaffidi, Sara De Martin and Gianfranco Pasut

Pharmaceutics 2021, 13(7), 929; https://doi.org/10.3390/pharmaceutics13070929 - 23 Jun 2021

Cited by 14 | Viewed by 3171

Abstract

Although selective tumor delivery of anticancer drugs has been sought by exploiting either passive targeting or by ligand-mediated targeting, a selective anticancer therapy remains an unmet medical need. Despite the advances which have been achieved by nanomedicines, nanosystems such as polymer-drug conjugates still [...] Read more.

Although selective tumor delivery of anticancer drugs has been sought by exploiting either passive targeting or by ligand-mediated targeting, a selective anticancer therapy remains an unmet medical need. Despite the advances which have been achieved by nanomedicines, nanosystems such as polymer-drug conjugates still miss the goal of clinical efficacy. In this study, we demonstrated that polymer-drug conjugates require a thoroughly chemical design and the right targeting agent/polymer ratio to be selective and effective towards cancer cells. In particular, two PEG conjugates carrying paclitaxel and targeted with different folic acid (FA)/PEG ratios (one or three) were investigated. The cytotoxicity study in positive (HT-29) and negative (HCT-15) FA receptor (FR)-cell lines demonstrated that the conjugates with one or three FAs were 4- or 28-fold more active in HT-29 cells, respectively. The higher activity of the 3-FA conjugate was confirmed by its strong impact on cell cycle arrest. Furthermore, FA targeting had a clear effect on migration and invasiveness of HT-29 cells, which were significantly reduced by both conjugates. Interestingly, the 3-FA conjugate showed also an improved pharmacokinetic profile in mice. The results of this study indicate that thorough investigations are needed to optimize and tune drug delivery and achieve the desired selectivity and activity towards cancer cells. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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18 pages, 2143 KiB

Open AccessArticle

The Chronotopic™ System for Pulsatile and Colonic Delivery of Active Molecules in the Era of Precision Medicine: Feasibility by 3D Printing via Fused Deposition Modeling (FDM)

by Alice Melocchi, Marco Uboldi, Francesco Briatico-Vangosa, Saliha Moutaharrik, Matteo Cerea, Anastasia Foppoli, Alessandra Maroni, Luca Palugan, Lucia Zema and Andrea Gazzaniga

Pharmaceutics 2021, 13(5), 759; https://doi.org/10.3390/pharmaceutics13050759 - 20 May 2021

Cited by 37 | Viewed by 4566

Abstract

The pulsatile-release Chronotopic™ system was conceived of as a drug-containing core surrounded by a coat made of swellable/soluble hydrophilic polymers, the latter being able to provide a programmable lag phase prior to drug liberation. This system was also proposed in a colon-targeting configuration, [...] Read more.

The pulsatile-release Chronotopic™ system was conceived of as a drug-containing core surrounded by a coat made of swellable/soluble hydrophilic polymers, the latter being able to provide a programmable lag phase prior to drug liberation. This system was also proposed in a colon-targeting configuration, entailing a gastroresistant film to prevent early interaction of the inner coat with gastric fluids and enabling the attainment of a lag phase matching the small intestinal transit time. Over the years, various multiple-step manufacturing processes have been tested for the fabrication of the Chronotopic™ system in both its configurations. This work focused on the evaluation of 3D printing by fused deposition modeling in view of its potential towards product personalization, on demand one-step manufacturing and efficient scale down of batches. The feasibility of each part of the Chronotopic™ system was independently investigated starting from in-house made filaments, characterizing the resulting specimens for physico-technological and performance characteristics. The printing parameters identified as suitable during the set-up phase were then used to fabricate prototypes either in a single step for the pulsatile configuration or following two different fabrication approaches for the colon-targeting one. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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33 pages, 2706 KiB

Open AccessReview

Nanotechnology Addressing Cutaneous Melanoma: The Italian Landscape

by Luigi Battaglia, Anna Scomparin, Chiara Dianzani, Paola Milla, Elisabetta Muntoni, Silvia Arpicco and Roberta Cavalli

Pharmaceutics 2021, 13(10), 1617; https://doi.org/10.3390/pharmaceutics13101617 - 4 Oct 2021

Cited by 12 | Viewed by 2982

Abstract

Cutaneous melanoma is one of the most aggressive solid tumors, with a low survival for the metastatic stage. Currently, clinical melanoma treatments include surgery, chemotherapy, targeted therapy, immunotherapy and radiotherapy. Of note, innovative therapeutic regimens concern the administration of multitarget drugs in tandem, [...] Read more.

Cutaneous melanoma is one of the most aggressive solid tumors, with a low survival for the metastatic stage. Currently, clinical melanoma treatments include surgery, chemotherapy, targeted therapy, immunotherapy and radiotherapy. Of note, innovative therapeutic regimens concern the administration of multitarget drugs in tandem, in order to improve therapeutic efficacy. However, also, if this drug combination is clinically relevant, the patient’s response is not yet optimal. In this scenario, nanotechnology-based delivery systems can play a crucial role in the clinical treatment of advanced melanoma. In fact, their nano-features enable targeted drug delivery at a cellular level by overcoming biological barriers. Various nanomedicines have been proposed for the treatment of cutaneous melanoma, and a relevant number of them are undergoing clinical trials. In Italy, researchers are focusing on the pharmaceutical development of nanoformulations for malignant melanoma therapy. The present review reports an overview of the main melanoma-addressed nanomedicines currently under study in Italy, alongside the state of the art of melanoma therapy. Moreover, the latest Italian advances concerning the pre-clinical evaluation of nanomedicines for melanoma are described. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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30 pages, 1895 KiB

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Developing Actively Targeted Nanoparticles to Fight Cancer: Focus on Italian Research

by Monica Argenziano, Silvia Arpicco, Paola Brusa, Roberta Cavalli, Daniela Chirio, Franco Dosio, Marina Gallarate, Elena Peira, Barbara Stella and Elena Ugazio

Pharmaceutics 2021, 13(10), 1538; https://doi.org/10.3390/pharmaceutics13101538 - 22 Sep 2021

Cited by 13 | Viewed by 3733

Abstract

Active targeting is a valuable and promising approach with which to enhance the therapeutic efficacy of nanodelivery systems, and the development of tumor-targeted nanoparticles has therefore attracted much research attention. In this field, the research carried out in Italian Pharmaceutical Technology academic groups [...] Read more.

Active targeting is a valuable and promising approach with which to enhance the therapeutic efficacy of nanodelivery systems, and the development of tumor-targeted nanoparticles has therefore attracted much research attention. In this field, the research carried out in Italian Pharmaceutical Technology academic groups has been focused on the development of actively targeted nanosystems using a multidisciplinary approach. To highlight these efforts, this review reports a thorough description of the last 10 years of Italian research results on the development of actively targeted nanoparticles to direct drugs towards different receptors that are overexpressed on cancer cells or in the tumor microenvironment. In particular, the review discusses polymeric nanocarriers, liposomes, lipoplexes, niosomes, solid lipid nanoparticles, squalene nanoassemblies and nanobubbles. For each nanocarrier, the main ligands, conjugation strategies and target receptors are described. The literature indicates that polymeric nanoparticles and liposomes stand out as key tools for improving specific drug delivery to the site of action. In addition, solid lipid nanoparticles, squalene nanoparticles and nanobubbles have also been successfully proposed. Taken together, these strategies all offer many platforms for the design of nanocarriers that are suitable for future clinical translation. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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39 pages, 834 KiB

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Biomaterials for Soft Tissue Repair and Regeneration: A Focus on Italian Research in the Field

by Maria Cristina Bonferoni, Carla Caramella, Laura Catenacci, Bice Conti, Rossella Dorati, Franca Ferrari, Ida Genta, Tiziana Modena, Sara Perteghella, Silvia Rossi, Giuseppina Sandri, Milena Sorrenti, Maria Luisa Torre and Giuseppe Tripodo

Pharmaceutics 2021, 13(9), 1341; https://doi.org/10.3390/pharmaceutics13091341 - 26 Aug 2021

Cited by 31 | Viewed by 4455

Abstract

Tissue repair and regeneration is an interdisciplinary field focusing on developing bioactive substitutes aimed at restoring pristine functions of damaged, diseased tissues. Biomaterials, intended as those materials compatible with living tissues after in vivo administration, play a pivotal role in this area and [...] Read more.

Tissue repair and regeneration is an interdisciplinary field focusing on developing bioactive substitutes aimed at restoring pristine functions of damaged, diseased tissues. Biomaterials, intended as those materials compatible with living tissues after in vivo administration, play a pivotal role in this area and they have been successfully studied and developed for several years. Namely, the researches focus on improving bio-inert biomaterials that well integrate in living tissues with no or minimal tissue response, or bioactive materials that influence biological response, stimulating new tissue re-growth. This review aims to gather and introduce, in the context of Italian scientific community, cutting-edge advancements in biomaterial science applied to tissue repair and regeneration. After introducing tissue repair and regeneration, the review focuses on biodegradable and biocompatible biomaterials such as collagen, polysaccharides, silk proteins, polyesters and their derivatives, characterized by the most promising outputs in biomedical science. Attention is pointed out also to those biomaterials exerting peculiar activities, e.g., antibacterial. The regulatory frame applied to pre-clinical and early clinical studies is also outlined by distinguishing between Advanced Therapy Medicinal Products and Medical Devices. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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31 pages, 3848 KiB

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The Pharmaceutical Technology Approach on Imaging Innovations from Italian Research

by Giorgia Ailuno, Rosa Maria Iacobazzi, Antonio Lopalco, Sara Baldassari, Ilaria Arduino, Amalia Azzariti, Sara Pastorino, Gabriele Caviglioli and Nunzio Denora

Pharmaceutics 2021, 13(8), 1214; https://doi.org/10.3390/pharmaceutics13081214 - 6 Aug 2021

Cited by 5 | Viewed by 2970

Abstract

Many modern therapeutic approaches are based on precise diagnostic evidence, where imaging procedures play an essential role. To date, in the diagnostic field, a plethora of agents have been investigated to increase the selectivity and sensitivity of diagnosis. However, the most common drawbacks [...] Read more.

Many modern therapeutic approaches are based on precise diagnostic evidence, where imaging procedures play an essential role. To date, in the diagnostic field, a plethora of agents have been investigated to increase the selectivity and sensitivity of diagnosis. However, the most common drawbacks of conventional imaging agents reside in their non-specificity, short imaging time, instability, and toxicity. Moreover, routinely used diagnostic agents have low molecular weights and consequently a rapid clearance and renal excretion, and this represents a limitation if long-lasting imaging analyses are to be conducted. Thus, the development of new agents for in vivo diagnostics requires not only a deep knowledge of the physical principles of the imaging techniques and of the physiopathological aspects of the disease but also of the relative pharmaceutical and biopharmaceutical requirements. In this scenario, skills in pharmaceutical technology have become highly indispensable in order to respond to these needs. This review specifically aims to collect examples of newly developed diagnostic agents connoting the importance of an appropriate formulation study for the realization of effective products. Within the context of pharmaceutical technology research in Italy, several groups have developed and patented promising agents for fluorescence and radioactive imaging, the most relevant of which are described hereafter. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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21 pages, 496 KiB

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Versatile Nasal Application of Cyclodextrins: Excipients and/or Actives?

by Giovanna Rassu, Milena Sorrenti, Laura Catenacci, Barbara Pavan, Luca Ferraro, Elisabetta Gavini, Maria Cristina Bonferoni, Paolo Giunchedi and Alessandro Dalpiaz

Pharmaceutics 2021, 13(8), 1180; https://doi.org/10.3390/pharmaceutics13081180 - 30 Jul 2021

Cited by 22 | Viewed by 3501

Abstract

Cyclodextrins (CDs) are oligosaccharides widely used in the pharmaceutical field. In this review, a detailed examination of the literature of the last two decades has been made to understand the role of CDs in nasal drug delivery systems. In nasal formulations, CDs are [...] Read more.

Cyclodextrins (CDs) are oligosaccharides widely used in the pharmaceutical field. In this review, a detailed examination of the literature of the last two decades has been made to understand the role of CDs in nasal drug delivery systems. In nasal formulations, CDs are used as pharmaceutical excipients, as solubilizers and absorption promoters, and as active ingredients due to their several biological activities (antiviral, antiparasitic, anti-atherosclerotic, and neuroprotective). The use of CDs in nasal formulations allowed obtaining versatile drug delivery systems intended for local and systemic effects, as well as for nose-to-brain transport of drugs. In vitro and in vivo models currently employed are suitable to analyze the effects of CDs in nasal formulations. Therefore, CDs are versatile pharmaceutical materials, and due to the continual synthesis of new CDs derivatives, the research on the new nasal applications is an interesting field evolving in the coming years, to which Italian research will still contribute. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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24 pages, 13173 KiB

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Polymeric Biomaterials for the Treatment of Cardiac Post-Infarction Injuries

by Sonia Trombino, Federica Curcio, Roberta Cassano, Manuela Curcio, Giuseppe Cirillo and Francesca Iemma

Pharmaceutics 2021, 13(7), 1038; https://doi.org/10.3390/pharmaceutics13071038 - 7 Jul 2021

Cited by 21 | Viewed by 3482

Abstract

Cardiac regeneration aims to reconstruct the heart contractile mass, preventing the organ from a progressive functional deterioration, by delivering pro-regenerative cells, drugs, or growth factors to the site of injury. In recent years, scientific research focused the attention on tissue engineering for the [...] Read more.

Cardiac regeneration aims to reconstruct the heart contractile mass, preventing the organ from a progressive functional deterioration, by delivering pro-regenerative cells, drugs, or growth factors to the site of injury. In recent years, scientific research focused the attention on tissue engineering for the regeneration of cardiac infarct tissue, and biomaterials able to anatomically and physiologically adapt to the heart muscle have been proposed as valuable tools for this purpose, providing the cells with the stimuli necessary to initiate a complete regenerative process. An ideal biomaterial for cardiac tissue regeneration should have a positive influence on the biomechanical, biochemical, and biological properties of tissues and cells; perfectly reflect the morphology and functionality of the native myocardium; and be mechanically stable, with a suitable thickness. Among others, engineered hydrogels, three-dimensional polymeric systems made from synthetic and natural biomaterials, have attracted much interest for cardiac post-infarction therapy. In addition, biocompatible nanosystems, and polymeric nanoparticles in particular, have been explored in preclinical studies as drug delivery and tissue engineering platforms for the treatment of cardiovascular diseases. This review focused on the most employed natural and synthetic biomaterials in cardiac regeneration, paying particular attention to the contribution of Italian research groups in this field, the fabrication techniques, and the current status of the clinical trials. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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