Publications by authors named "Fabio Sonvico"

79 Publications

Orphan Designation and Cisplatin/Hyaluronan Complex in an Intracavitary Film for Malignant Mesothelioma.

Pharmaceutics 2021 Mar 9;13(3). Epub 2021 Mar 9.

Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy.

Pleural mesothelioma is a lung diffuse tumor, whose complete resection is unlikely. Consequently, metastases reappear where the primary tumor was removed. This paper illustrates the orphan medicine designation procedure of an intracavitary cisplatin film and related pharmaceutical development aspects requested by the European Medicines Agency (EMA) in its Scientific Advice. Since cisplatin pharmacokinetics from the implanted film in sheep resulted substantially modified compared to intravenous administration, the formation of a cisplatin/hyaluronan complex had been hypothesized. Here, the interaction between sodium hyaluronate (NaHA) and cisplatin (CisPt) was demonstrated. Size exclusion chromatography qualitatively evidenced the complex in the film-forming mixture, only showing the NaHA peak. Atomic absorption spectroscopy of the corresponding fraction revealed platinum, confirming the interaction. Reverse phase HPLC quantified about 5% free cisplatin in the film-forming mixture, indirectly meaning that 95% was complexed. Finally, a study of CisPt release from the film assessed how CisPt/NaHA complex affected drug availability. In water, a medium without chloride ions, there was no release and the film remained intact for 48 h and longer, whereas the placebo film dissolved in 15 min. In 0.9% NaCl medium, the film became more soluble, dissolving within 3-4 h. However, cisplatin release was still controlled by the existing complex in solution until chloride ions displaced it. While the film modified its dissolution with aging, CisPt release remained unaffected (90% released in 48 h).
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http://dx.doi.org/10.3390/pharmaceutics13030362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000699PMC
March 2021

Docetaxel-Loaded Poly(3HB--4HB) Biodegradable Nanoparticles: Impact of Copolymer Composition.

Nanomaterials (Basel) 2020 Oct 26;10(11). Epub 2020 Oct 26.

Malaysian Institute of Pharmaceuticals and Nutraceuticals (IPharm), National Institute of Biotechnology Malaysia (NIBM), Ministry of Science, Technology and Innovation (MOSTI), Penang 11800, Malaysia.

Polyhydroxyalkanoate (PHA) copolymers show a relatively higher in vivo degradation rate compared to other PHAs, thus, they receive a great deal of attention for a wide range of medical applications. Nanoparticles (NPs) loaded with poorly water-soluble anticancer drug docetaxel (DCX) were produced using poly(3-hydroxybutyrate--4-hydroxybutyrate), P(3HB--4HB), copolymers biosynthesised from USMAA1020 isolated from the Malaysian environment. Three copolymers with different molar proportions of 4-hydroxybutirate (4HB) were used: 16% (PHB16), 30% (PHB30) and 70% (PHB70) 4HB-containing P(3HB--4HB). Blank and DCX-loaded nanoparticles were then characterized for their size and size distribution, surface charge, encapsulation efficiency and drug release. Preformulation studies showed that an optimised formulation could be achieved through the emulsification/solvent evaporation method using PHB70 with the addition of 1.0% PVA, as stabilizer and 0.03% VitE-TPGS, as surfactant. DCX-loaded PHB70 nanoparticles (DCX-PHB70) gave the desired particle size distribution in terms of average particle size around 150 nm and narrow particle size distribution (polydispersity index (PDI) below 0.100). The encapsulation efficiency result showed that at 30% w/w drug-to-polymer ratio: DCX- PHB16 NPs were able to encapsulate up to 42% of DCX; DCX-PHB30 NPs encapsulated up to 46% of DCX and DCX-PHB70 NPs encapsulated up to 50% of DCX within the nanoparticle system. Approximately 60% of DCX was released from the DCX-PHB70 NPs within 7 days for 5%, 10% and 20% of drug-to-polymer ratio while for the 30% and 40% drug-to-polymer ratios, an almost complete drug release (98%) after 7 days of incubation was observed.
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http://dx.doi.org/10.3390/nano10112123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716210PMC
October 2020

Curcumin and Quercetin-Loaded Nanoemulsions: Physicochemical Compatibility Study and Validation of a Simultaneous Quantification Method.

Nanomaterials (Basel) 2020 Aug 22;10(9). Epub 2020 Aug 22.

Laboratório de Nanotecnologia Aplicada à Saúde, Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Rio Grande, Rio Grande 96210-900 (RS), Brazil.

Biphasic oil/water nanoemulsions have been proposed as delivery systems for the intranasal administration of curcumin (CUR) and quercetin (QU), due to their high drug entrapment efficiency, the possibility of simultaneous drug administration and protection of the encapsulated compounds from degradation. To better understand the physicochemical and biological performance of the selected formulation simultaneously co-encapsulating CUR and QU, a stability test of the compound mixture was firstly carried out using X-ray powder diffraction and thermal analyses, such as differential scanning calorimetry (DSC) and thermogravimetric analyses (TGA). The determination and quantification of the encapsulated active compounds were then carried out being an essential parameter for the development of innovative nanomedicines. Thus, a new HPLC-UV/Vis method for the simultaneous determination of CUR and QU in the nanoemulsions was developed and validated. The X-ray diffraction analyses demonstrated that no interaction between the mixture of active ingredients, if any, is strong enough to take place in the solid state. Moreover, the thermal analysis demonstrated that the CUR and QU are stable in the nanoemulsion production temperature range. The proposed analytical method for the simultaneous quantification of the two actives was selective and linear for both compounds in the range of 0.5-12.5 µg/mL (R > 0.9997), precise (RSD below 3%), robust and accurate (recovery 100 ± 5 %). The method was validated in accordance with ICH Q2 R1 "Validation of Analytical Procedures" and CDER-FDA "Validation of chromatographic methods" guideline. Furthermore, the low limit of detection (LOD 0.005 µg/mL for CUR and 0.14 µg/mL for QU) and the low limit of quantification (LOQ 0.017 µg/mL for CUR and 0.48 µg/mL for QU) of the method were suitable for the application to drug release and permeation studies planned for the development of the nanoemulsions. The method was then applied for the determination of nanoemulsions CUR and QU encapsulation efficiencies (> 99%), as well as for the stability studies of the two compounds in simulated biological fluids over time. The proposed method represents, to our knowledge, the only method for the simultaneous quantification of CUR and QU in nanoemulsions.
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http://dx.doi.org/10.3390/nano10091650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558409PMC
August 2020

Intranasal administration of budesonide-loaded nanocapsule microagglomerates as an innovative strategy for asthma treatment.

Drug Deliv Transl Res 2020 12;10(6):1700-1715

Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av. Ipiranga 2752, Porto Alegre, 90610-000, Brazil.

The co-existence with rhinitis limits the control of asthma. Compared with oral H receptor antagonists, intranasal corticosteroids have been demonstrated to provide greater relief of all symptoms of rhinitis and are recommended as first-line treatment for allergic rhinitis. Intrinsic limitations of nasal delivery, such as the presence of the protective mucous layer, the relentless mucociliary clearance, and the consequent reduced residence time of the formulation in the nasal cavity, limit budesonide efficacy to the treatment of local nasal symptoms. To overcome these limitations and to enable the treatment of asthma via nasal administration, we developed a budesonide-loaded lipid-core nanocapsule (BudNC) microagglomerate powder by spray-drying using a one-step innovative approach. BudNC was obtained, as a white powder, using L-leucine as adjuvant with 75 ± 6% yield. The powder showed a bimodal size distribution curve by laser diffraction with a principal peak just above 3 μm and a second one around 0.45 μm and a drug content determined by HPLC of 8.7 mg of budesonide per gram. In vivo after nasal administration, BudNC showed an improved efficacy in terms of reduction of immune cell influx; production of eotaxin-1, the main inflammatory chemokine; and arrest of airways remodeling when compared with a commercial budesonide product in both short- and long-term asthma models. In addition, data showed that the results in the long-term asthma model were more compelling than the results obtained in the short-term model. Graphical abstract.
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http://dx.doi.org/10.1007/s13346-020-00813-5DOI Listing
December 2020

A liposome-micelle-hybrid (LMH) oral delivery system for poorly water-soluble drugs: Enhancing solubilisation and intestinal transport.

Eur J Pharm Biopharm 2020 Sep 31;154:338-347. Epub 2020 Jul 31.

University of South Australia, Clinical and Health Sciences, Adelaide, South Australia 5000, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, University of South Australia, Mawson Lakes Campus, Mawson Lakes 5095, Australia. Electronic address:

A novel liposome-micelle-hybrid (LMH) carrier system was developed as a superior oral drug delivery platform compared to conventional liposome or micelle formulations. The optimal LMH system was engineered by encapsulating TPGS micelles in the aqueous core of liposomes and its efficacy for oral delivery was demonstrated using lovastatin (LOV) as a model poorly soluble drug with P-gp (permeability glycoprotein) limited intestinal absorption. LOV-LMH was characterised as unilamellar, spherical vesicles encapsulating micellar structures within the interior aqueous core and showing an average diameter below 200 nm. LMH demonstrated enhanced drug loading, water apparent solubility and extended/controlled release of LOV compared to conventional liposomes and micelles. LMH exhibited enhanced LOV absorption and transportation in a Caco-2 cell monolayer model of the intestine by inhibiting the P-gp transporter system compared to free LOV. The LMH system is a promising novel oral delivery approach for enhancing bioavailability of poorly water-soluble drugs, especially those presenting P-gp effluxes limited absorption.
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http://dx.doi.org/10.1016/j.ejpb.2020.07.022DOI Listing
September 2020

The Vaginal-PVPA: A Vaginal Mucosa-Mimicking In Vitro Permeation Tool for Evaluation of Mucoadhesive Formulations.

Pharmaceutics 2020 Jun 19;12(6). Epub 2020 Jun 19.

Drug Transport and Delivery Research Group, Department of Pharmacy, UiT The Arctic University of Norway, Universitetsvegen 57, 9037 Tromsø, Norway.

Drug administration to the vaginal site has gained increasing attention in past decades, highlighting the need for reliable in vitro methods to assess the performance of novel formulations. To optimize formulations destined for the vaginal site, it is important to evaluate the drug retention within the vagina as well as its permeation across the mucosa, particularly in the presence of vaginal fluids. Herewith, the vaginal-PVPA (Phospholipid Vesicle-based Permeation Assay) in vitro permeability model was validated as a tool to evaluate the permeation of the anti-inflammatory drug ibuprofen from liposomal formulations (i.e., plain and chitosan-coated liposomes). Drug permeation was assessed in the presence and absence of mucus and simulated vaginal fluid (SVF) at pH conditions mimicking both the healthy vaginal premenopausal conditions and vaginal infection/pre-puberty/post-menopause state. The permeation of ibuprofen proved to depend on the type of formulation (i.e., chitosan-coated liposomes exhibited lower drug permeation), the mucoadhesive formulation properties and pH condition. This study highlights both the importance of mucus and SVF in the vaginal model to better understand and predict the in vivo performance of formulations destined for vaginal administration, and the suitability of the vaginal-PVPA model for such investigations.
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http://dx.doi.org/10.3390/pharmaceutics12060568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355897PMC
June 2020

Consequences of not-shaking and shake-fire delays on the emitted dose of some commercial solution and suspension pressurized metered dose inhalers.

Expert Opin Drug Deliv 2020 07 19;17(7):1025-1039. Epub 2020 Jun 19.

Food and Drug Department, University of Parma , Parma, Italy.

Background: Pressurized metered-dose inhalers (pMDIs) include hydrofluoroalkane (HFA) propellant to generate a drug aerosol upon actuation and drugs can be formulated as solution or suspension. Suspended particles can cream or sediment depending on density differences between drug and propellant and shaking the pMDI is an essential step to ensure a uniform drug dose release.

Research Design And Methods: The effect of the delay (0, 10, 30, 60 seconds) in pMDI actuation after shaking and the effect of no-shaking during the canister life on the emitted dose (ED) for commercial solution and suspension pMDIs was investigated.

Results: The ED for solutions was unaffected by no-shaking or by the progressive increasing delay in actuation after shaking (between 77% and 97%). For all the suspension products, shaking was demonstrated to be critical to assure the close to nominal drug delivery. In detail, the actuation delay after shaking led to an increase up to 380% or a drop to 32% of ED in relation to the label claim with high variability.

Conclusion: The drug delivered can vary widely for no-shaking and over different shake-fire delays with suspension pMDIs while solution formulations appear to remain stable.
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http://dx.doi.org/10.1080/17425247.2020.1767066DOI Listing
July 2020

Evaluation of the Drug Release Kinetics in Assembled Modular Systems Based on the Dome Matrix Technology.

J Pharm Sci 2020 09 11;109(9):2819-2826. Epub 2020 Jun 11.

Instituto de Investigaciones para la Industria Química, CONICET-Universidad Nacional de Salta, Salta, Argentina. Electronic address:

Mathematical models are an important tool in pharmaceutical formulations development, to evaluate in vitro and in vivo drug release processes and to optimize the design of new systems. Dome Matrix technology allows the combination of modules with different types of drugs, doses, and releases kinetics. This work aimed to design drug release systems based on Dome Matrix technology, with different swelling and erosion properties, to obtain complex drug release profiles and analyze them with simple mathematical models. Most of the release profiles followed a sigmoid curve, with an inflection point corresponding to a change in the release rate behavior. The experimental data were fitted with a simple model recently developed, named the Dual Release model, which consists in the combination of a modified Korsmayer-Peppas model from the beginning to the inflection point and the Lumped model from there until the end. This approach allowed determining relevant pharmaceutical parameters, such as the maximum release rate and the dissolution efficiency, among others. The use of the Dual Release model and the pharmaceutical parameters that characterize the different Dome Matrix modules allows optimizing the choice of the composition and the configuration during the development of a drug delivery system.
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http://dx.doi.org/10.1016/j.xphs.2020.06.006DOI Listing
September 2020

Excipient-free pulmonary insulin dry powder: Pharmacokinetic and pharmacodynamics profiles in rats.

J Control Release 2020 07 21;323:412-420. Epub 2020 Apr 21.

Food and Drug Department, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy. Electronic address:

A novel pure insulin spray-dried powder for DPI product (Ins_SD) was studied with respect to physico-chemical stability, in vitro respirability, bioavailability, activity and tolerability. Ins_SD powder exhibited a very high in vitro respirability, independently of the DPI product preparation (manual or semi-automatic). Physico-chemical characteristics of Ins_SD powder remained within the pharmacopoeia limits during 6 months of storage at room temperature. PK/PD profiles were measured in rats that received the pulmonary powders by intratracheal insufflation and compared with Afrezza inhalation insulin. Due to the low drug powder mass to deliver, both insulin powders were diluted with mannitol. Insulin from Ins_SD was promptly absorbed (t 15 min and C4.9 ± 1.5 mU/ml). Afrezza had a slower absorption (t 30 min and C of 1.8 ± 0.37 mU/ml). After glucose injection, Ins_SD determined a rapid reduction of glucose level, similar to Afrezza. As reference, insulin subcutaneous injection showed a long-lasting hypoglycemic effect due to the slow absorption that prolonged insulin plasma level. In summary, Ins_SD product is suitable for post-prandial glucose control, providing a convenient and compliant product, in particular in the event of using a disposable device. Albeit the product has to be stored in fridge, its stability at room temperature allows the diabetic individual to carry the daily dose in normal conditions.
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http://dx.doi.org/10.1016/j.jconrel.2020.04.015DOI Listing
July 2020

Pulmonary delivery of a p38 α/β MAP kinase inhibitor: bioanalytical method validation and biodistribution in rat plasma and respiratory tissues.

Eur J Pharm Sci 2020 Apr 17;149:105341. Epub 2020 Apr 17.

Food and Drug Department, University of Parma, Parma, Italy; Biopharmanet-TEC, University of Parma, Parma, Italy. Electronic address:

PF-03715455, an inhaled p38 α/β mitogen-activated protein (MAP) kinase inhibitor (MAPK), has being identified as an agent with potential therapeutic action on lung diseases such as COPD and severe asthma. However, little is known about this MAPKs local and systemic pharmacokinetics after pulmonary delivery. Consequently, the aim of the present work was to develop and validate a method of extraction and quantification of PF-03715455 in rat plasma and lung tissues and to determine the drug biodistribution in plasma and respiratory tissues after intratracheal administration of the drug solution in rats. The method was validated in rat plasma samples and resulted selective and linear in the concentration range of 0.08-100 ng/ml. Then a partial validation was carried out on samples obtained by the extraction and quantification of PF-03715455 from rat lung homogenate in order to ascertain method applicability on lung tissue samples. The intratracheal administration of drug in solution to rats evidenced a rapid elimination from the plasma, while on the contrary a prolonged residence time in lung tissue was evidenced. In conclusion, a linear, accurate, precise and reproducible method has been developed and validated according to FDA and EMA guidelines to quantify plasmatic and tissue-associated concentrations of PF-03715455 in order to investigate this compound in pharmacokinetics pre-clinical studies in rats. The administration of drug solution evidenced a prolonged permanence of the drug in the lungs that could be related to a slow absorption/poor permeability of the drug across airways epithelia.
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http://dx.doi.org/10.1016/j.ejps.2020.105341DOI Listing
April 2020

A consensus research agenda for optimising nasal drug delivery.

Expert Opin Drug Deliv 2020 02 30;17(2):127-132. Epub 2020 Jan 30.

Department of Pharmaceutics and Biopharmaceutics, Kiel University, Kiel, Germany.

Nasal drug delivery has specific challenges which are distinct from oral inhalation, alongside which it is often considered. The next generation of nasal products will be required to deliver new classes of molecule, e.g. vaccines, biologics and drugs with action in the brain or sinuses, to local and systemic therapeutic targets. Innovations and new tools/knowledge are required to design products to deliver these therapeutic agents to the right target at the right time in the right patients. We report the outcomes of an expert meeting convened to consider gaps in knowledge and unmet research needs in terms of (i) formulation and devices, (ii) meaningful product characterization and modeling, (iii) opportunities to modify absorption and clearance. Important research questions were identified in the areas of device and formulation innovation, critical quality attributes for different nasal products, development of nasal casts for drug deposition studies, improved experimental models, the use of simulations and nasal delivery in special populations. We offer these questions as a stimulus to research and suggest that they might be addressed most effectively by collaborative research endeavors.
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http://dx.doi.org/10.1080/17425247.2020.1714589DOI Listing
February 2020

Nasal Drug Delivery of Anticancer Drugs for the Treatment of Glioblastoma: Preclinical and Clinical Trials.

Molecules 2019 Nov 26;24(23). Epub 2019 Nov 26.

Food and Drug Department, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.

Glioblastoma (GBM) is the most lethal form of brain tumor, being characterized by the rapid growth and invasion of the surrounding tissue. The current standard treatment for glioblastoma is surgery, followed by radiotherapy and concurrent chemotherapy, typically with temozolomide. Although extensive research has been carried out over the past years to develop a more effective therapeutic strategy for the treatment of GBM, efforts have not provided major improvements in terms of the overall survival of patients. Consequently, new therapeutic approaches are urgently needed. Overcoming the blood-brain barrier (BBB) is a major challenge in the development of therapies for central nervous system (CNS) disorders. In this context, the intranasal route of drug administration has been proposed as a non-invasive alternative route for directly targeting the CNS. This route of drug administration bypasses the BBB and reduces the systemic side effects. Recently, several formulations have been developed for further enhancing nose-to-brain transport, mainly with the use of nano-sized and nanostructured drug delivery systems. The focus of this review is to provide an overview of the strategies that have been developed for delivering anticancer compounds for the treatment of GBM while using nasal administration. In particular, the specific properties of nanomedicines proposed for nose-to-brain delivery will be critically evaluated. The preclinical and clinical data considered supporting the idea that nasal delivery of anticancer drugs may represent a breakthrough advancement in the fight against GBM.
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http://dx.doi.org/10.3390/molecules24234312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930669PMC
November 2019

Novel O/W nanoemulsions for nasal administration: Structural hints in the selection of performing vehicles with enhanced mucopenetration.

Colloids Surf B Biointerfaces 2019 Nov 15;183:110439. Epub 2019 Aug 15.

Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, via fratelli Cervi 93, 20900 Segrate (Mi), Italy. Electronic address:

We propose novel oil-in-water nanoemulsions (O/W NEs) including PEGylated surfactants and chitosan, showing good biocompatibility and optimization for nasal administration of drugs or vaccines. The transmucosal route has been shown to be ideal for a fast and efficient absorption and represents a viable alternative when the oral administration is problematic. The critical structural features in view of optimal encapsulation and transmucosal delivery were assessed by characterizing the NEs with complementary scattering techniques, i.e. dynamic light scattering (DLS), small angle X-ray (SAXS) and neutron scattering (SANS). Combined results allowed for selecting the formulations with the best suited structural properties and in addition establishing their propensity to enter the mucus barrier. To this scope, mucin was used as a model system and the effect of adding chitosan to the NEs, as adjuvant, was investigated. Remarkably, the presence of chitosan had a positive impact on the diffusion of the NE particles through the mucin matrix. We can infer that chitosan-mucin interaction induces density inhomogeneity and an increase in the pore size within the gel matrix that enhances the PEGylated NEs mobility. The coupling of mucoadhesive and mucopenetrating agents is shown to be a promising strategy for innovative transmucosal delivery systems.
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http://dx.doi.org/10.1016/j.colsurfb.2019.110439DOI Listing
November 2019

Dry powder inhaler of colistimethate sodium for lung infections in cystic fibrosis: optimization of powder construction.

Drug Dev Ind Pharm 2019 Oct 30;45(10):1664-1673. Epub 2019 Aug 30.

Department of Life Sciences and Biotechnology , Ferrara , Italy.

Colistimethate sodium (CMS) for treatment of lung infections in cystic fibrosis patient was transformed into a dry powder for inhalation by spray drying. Design of Experiment was applied for understanding the role of the spray-drying process parameters on the critical quality attributes of the CMS spray-dried (SD) powders and agglomerates thereof. Eleven experimental SD microparticle powders were constructed under different process conditions according to a central composite design. The SD microparticles were then agglomerated in soft pellets. Eleven physico-chemical characteristics of SD CMS microparticle powders or agglomerates thereof were selected as critical quality attributes. The yield of SD process was higher than 75%. The emitted fraction of agglomerates from RS01 inhaler was 75-84%, and the fine particle fraction (particles <5 µm) was between 58% and 62%. The quality attributes of CMS SD powders and respective agglomerates that were significantly influenced by spray-drying process parameters were residual solvent and drug content of the SD microparticles as well as bulk density and respirable dose of the agglomerates. These attributes were also affected by the combination of the process variables. The air aspiration rate was found as the most positively influential on drug and solvent content and respirable dose. The residual solvent content significantly influenced the powder bulk properties and aerodynamic behavior of the agglomerates, i.e. quality attributes that govern drug metering in the device and the particles lungs deposition. Agglomerates of CMS SD microparticles, in combination with RS01 DPI, showed satisfactory results in terms of dose emitted and fine particle fraction.
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http://dx.doi.org/10.1080/03639045.2019.1652636DOI Listing
October 2019

Ucuùba () Fat-Based Nanostructured Lipid Carriers for Nail Drug Delivery of Ketoconazole: Development and Optimization Using Box-Behnken Design.

Pharmaceutics 2019 Jun 17;11(6). Epub 2019 Jun 17.

Food and Drug Department, University of Parma, 43124 Parma, Italy.

Ucuùba fat is fat obtained from a plant found in South America, mainly in Amazonian Brazil. Due to its biocompatibility and bioactivity, Ucuùba fat was used for the production of ketoconazole-loaded nanostructured lipid carriers (NLC) in view of an application for the treatment of onychomycosis and other persistent fungal infections. The development and optimization of Ucuùba fat-based NLC were performed using a Box-Behnken design of experiments. The independent variables were surfactant concentration (% /), liquid lipids concentration (% /), solid lipids concentration (% /), while the outputs of interest were particle size, polydispersity index (PDI) and drug encapsulation efficiency (EE). Ucuùba fat-based NLC were produced and the process was optimized by the development of a predictive mathematical model. Applying the model, two formulations with pre-determined particle size, i.e., 30 and 85 nm, were produced for further evaluation. The optimized formulations were characterized and showed particle size in agreement to the predicted value, i.e., 33.6 nm and 74.6 nm, respectively. The optimized formulations were also characterized using multiple techniques in order to investigate the solid state of drug and excipients (DSC and XRD), particle morphology (TEM), drug release and interactions between the formulation components (FTIR). Furthermore, particle size, surface charge and drug loading efficiency of the formulations were studied during a one-month stability study and did not show evidence of significant modification.
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http://dx.doi.org/10.3390/pharmaceutics11060284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630981PMC
June 2019

Lipid-core nanocapsules are an alternative to the pulmonary delivery and to increase the stability of statins.

J Microencapsul 2019 Jun 19;36(4):317-326. Epub 2019 Jun 19.

a Nanoscience Post-Graduation Program , Franciscan University , Santa Maria , Rio Grande do Sul , Brazil.

Lipid-core nanocapsules (LNCs) loaded with simvastatin (SV, SV-LNC) or lovastatin (LV, LV-LNC) were formulated for pulmonary administration. The LNC suspensions were characterized physicochemically, their stability was evaluated, and drug delivery by the pulmonary route was tested . The loaded LNCs had a particle size close to 200 nm, a low polydispersity index, and a zeta potential around -20 mV. The encapsulation efficiency was high for SV (99.21 ± 0.7%) but low for LV (20.34 ± 1.2%). SV release from nanocapsules was slower than it was from SV in solution, with a monoexponential release profile, and the drug emitted and aerosol output rate was higher for SV-LNCs (1.58 µg/s) than for SV in suspension (0.54 µg/s). SV-LNCs had a median aerodynamic diameter of 3.51 µm and a highly respirable fraction (61.9%), indicating that nanoparticles are a suitable system for efficient delivery of simvastatin to the lung.
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http://dx.doi.org/10.1080/02652048.2019.1624849DOI Listing
June 2019

Sodium Hyaluronate Nanocomposite Respirable Microparticles to Tackle Antibiotic Resistance with Potential Application in Treatment of Mycobacterial Pulmonary Infections.

Pharmaceutics 2019 May 1;11(5). Epub 2019 May 1.

Food and Drug Department, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.

Tuberculosis resistant cases have been estimated to grow every year. Besides , other mycobacterial species are responsible for an increasing number of difficult-to-treat infections. To increase efficacy of pulmonary treatment of mycobacterial infections an inhalable antibiotic powder targeting infected alveolar macrophages (AMs) and including an efflux pump inhibitor was developed. Low molecular weight sodium hyaluronate sub-micron particles were efficiently loaded with rifampicin, isoniazid and verapamil, and transformed in highly respirable microparticles (mean volume diameter: 1 μm) by spray drying. These particles were able to regenerate their original size upon contact with aqueous environment with mechanical stirring or sonication. The in vitro drugs release profile from the powder was characterized by a slow release rate, favorable to maintain a high drug level inside AMs. In vitro antimicrobial activity and ex vivo macrophage infection assays employing susceptible and drug resistant strains were carried out. No significant differences were observed when the powder, which did not compromise the AMs viability after a five-day exposure, was compared to the same formulation without verapamil. However, both preparations achieved more than 80% reduction in bacterial viability irrespective of the drug resistance profile. This approach can be considered appropriate to treat mycobacterial respiratory infections, regardless the level of drug resistance.
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http://dx.doi.org/10.3390/pharmaceutics11050203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571635PMC
May 2019

Chitosan-Coated Nanoparticles: Effect of Chitosan Molecular Weight on Nasal Transmucosal Delivery.

Pharmaceutics 2019 02 18;11(2). Epub 2019 Feb 18.

Food and Drug Department, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.

Drug delivery to the brain represents a challenge, especially in the therapy of central nervous system malignancies. Simvastatin (SVT), as with other statins, has shown potential anticancer properties that are difficult to exploit in the central nervous system (CNS). In the present work the physico⁻chemical, mucoadhesive, and permeability-enhancing properties of simvastatin-loaded poly-ε-caprolactone nanocapsules coated with chitosan for nose-to-brain administration were investigated. Lipid-core nanocapsules coated with chitosan (LNC) of different molecular weight (MW) were prepared by a novel one-pot technique, and characterized for particle size, surface charge, particle number density, morphology, drug encapsulation efficiency, interaction between surface nanocapsules with mucin, drug release, and permeability across two nasal mucosa models. Results show that all formulations presented adequate particle sizes (below 220 nm), positive surface charge, narrow droplet size distribution (PDI < 0.2), and high encapsulation efficiency. Nanocapsules presented controlled drug release and mucoadhesive properties that are dependent on the MW of the coating chitosan. The results of permeation across the RPMI 2650 human nasal cell line evidenced that LNC increased the permeation of SVT. In particular, the amount of SVT that permeated after 4 hr for nanocapsules coated with low-MW chitosan, high-MW chitosan, and control SVT was 13.9 ± 0.8 μg, 9.2 ± 1.2 µg, and 1.4 ± 0.2 µg, respectively. These results were confirmed by SVT ex vivo permeation across rabbit nasal mucosa. This study highlighted the suitability of LNC as a promising strategy for the administration of simvastatin for a nose-to-brain approach for the therapy of brain tumors.
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http://dx.doi.org/10.3390/pharmaceutics11020086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409859PMC
February 2019

Anti-inflammatory flurbiprofen nasal powders for nose-to-brain delivery in Alzheimer's disease.

J Drug Target 2019 11 11;27(9):984-994. Epub 2019 Feb 11.

c Department of Pharmacy, University of Salerno , Fisciano (SA) , Italy.

Neuroinflammation occurs in the early stages of Alzheimer's disease (AD). Thus, anti-inflammatory drugs in this asymptomatic initial phase could slow down AD progression, provided they enter the brain. Direct nose-to-brain drug transport occurs along olfactory or trigeminal nerves, bypassing the blood-brain barrier. Nasal administration may enable the drug to access the brain. Here, flurbiprofen powders for nose-to-brain drug transport in early AD-related neuroinflammation were studied. Their target product profile contemplates drug powder deposition in the nasal cavity, prompt dissolution in the mucosal fluid and attainment of saturation concentration to maximise diffusion in the tissue. Aiming to increase drug disposition into brain, poorly soluble flurbiprofen requires the construction of nasal powder microparticles actively deposited in nose for prompt drug release. Two groups of powders were formulated, composed of flurbiprofen acid or flurbiprofen sodium salt. Two spray dryer apparatuses, differing for spray and drying mechanisms, and particle collection, were applied to impact on the characteristics of the microparticulate powders. Flurbiprofen sodium nasal powders disclosed prompt dissolution and fast transport across rabbit nasal mucosa, superior to the acid form, in particular when the powder was prepared using the Nano B-90 spray dryer at the lowest drying air temperature.
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http://dx.doi.org/10.1080/1061186X.2019.1574300DOI Listing
November 2019

Nanoemulsion-Enabled Oral Delivery of Novel Anticancer ω-3 Fatty Acid Derivatives.

Nanomaterials (Basel) 2018 Oct 13;8(10). Epub 2018 Oct 13.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia.

Lipid-based drugs are emerging as an interesting class of novel anticancer drugs with the potential to target specific cancer cell metabolic pathways linked to their proliferation and invasiveness. In particular, ω-3 polyunsaturated fatty acids (PUFA) derivatives such as epoxides and their bioisosteres have demonstrated the potential to suppress growth and promote apoptosis in triple-negative human breast cancer cells MDA-MB-231. In this study, 16-(4'-chloro-3'-trifluorophenyl)carbamoylamino]hexadecanoic acid (ClFPh-CHA), an anticancer lipid derived from ω-3,17,18-epoxyeicosanoic acid, was formulated as a stable nanoemulsion with size around 150 nm and narrow droplet size distribution (PDI < 0.200) through phase-inversion emulsification process followed by high pressure homogenization in view of an oral administration. The ClFPh-CHA-loaded nanoemulsions were able to significantly decrease the relative tumor volume in mice bearing an intramammary tumor xenograft at all doses tested (2.5, 10 and 40 mg/kg) after 32 days of daily oral administration. Furthermore, absolute tumor weight was decreased to 50% of untreated control at 10 and 40 mg/kg, while intraperitoneal administration could achieve a significant reduction only at the highest dose of 40 mg/kg. Results suggest that oral administration of ClFPh-CHA formulated as a nanoemulsion has a sufficient bioavailability to provide an anticancer effect in mice and that the activity is at least equal if not superior to that obtained by a conventional parenteral administration of equivalent doses of the same drug.
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http://dx.doi.org/10.3390/nano8100825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215190PMC
October 2018

Combined hyaluronate-based films loaded with pemetrexed and cisplatin for the treatment of malignant pleural mesothelioma: Preliminary evaluation in an orthotopic tumor recurrence model.

Eur J Pharm Sci 2018 Oct 17;123:89-97. Epub 2018 Jul 17.

Thoracic Surgery, Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy.

Malignant pleural mesothelioma (MPM) is a rare malignancy characterized by a long latency period of 20-50 years after exposure to the main aetiology agent that is asbestos. MPM treatments include surgery, chemotherapy, and radiation therapy, with the combination pemetrexed and cisplatin being the standard chemotherapy approach. Despite this multimodality therapy one of the major issues after surgery is the high rate of local recurrence of the tumor. One possible approach would be the intrapleural application of implants loaded with anticancer drug to be applied during surgery to prevent local tumor recurrence. The implant proposed in the present work is a polymeric film of hyaluronic acid loaded with pemetrexed. The film developed is a hydrophilic, thin and flexible film sufficiently resistant to be applied intrapleurally adhering to the mesothelial surface. The release of pemetrexed from the film was found to be complete within2 h in phosphate buffered saline. In an orthotopic model of mesothelioma recurrence in rats, pemetrexed loaded films showed the same antitumor efficacy of pemetrexed disodium solutions administered intravenously or intrapleurally, while when administered in combination with cisplatin-loaded hyaluronate film, the implants almost completely prevented tumor recurrence. The local administration of drug-loaded polymer implants appears an ideal chemotherapy strategy especially for patients in which surgery is already selected as a viable therapeutic option.
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http://dx.doi.org/10.1016/j.ejps.2018.07.035DOI Listing
October 2018

Dose administration maneuvers and patient care in tobramycin dry powder inhalation therapy.

Int J Pharm 2018 Sep 5;548(1):182-191. Epub 2018 Jun 5.

Food and Drug Department, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.

The purpose of this work was to study a new dry powder inhaler (DPI) of tobramycin capable to simplify the dose administration maneuvers to maximize the cystic fibrosis (CF) patient care in antibiotic inhalation therapy. For the purpose, tobramycin/sodium stearate powder (TobraPS) having a high drug content, was produced by spray drying, characterized and the aerodynamic behavior was investigated in vitro using different RS01 DPI inhalers. The aerosols produced with 28, 56 or 112 mg of tobramycin in TobraPS powder using capsules size #3, #2 or #0 showed that there was quasi linear relationship between the amount loaded in the device and the FPD. An in vivo study in healthy human volunteers showed that 3-6 inhalation acts were requested by the volunteers to inhale 120 mg of TobraPS powder loaded in a size #0 capsule aerosolized with a prototype RS01 device, according to their capability to inhale. The amount of powder emitted at 4 kPa pressure drop at constant air flow well correlated with the in vivo emission at dynamic flow, when the same volume of air passed through the device. The novel approach for the administration of 112 mg of tobramycin in one capsule could improve the convenience and adherence of the CF patient to the antibiotic therapy.
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http://dx.doi.org/10.1016/j.ijpharm.2018.06.006DOI Listing
September 2018

Development and validation of a RP-HPLC method for the simultaneous detection and quantification of simvastatin's isoforms and coenzyme Q10 in lecithin/chitosan nanoparticles.

J Pharm Biomed Anal 2018 Jun 23;155:33-41. Epub 2018 Mar 23.

Food and Drug Department, University of Parma, Parma, PR, Italy. Electronic address:

Hybrid nanocapsules constituted of phospholipids and polysaccharides have been proposed as colloidal systems for the delivery of drugs via non-parenteral administration routes, due their capacity of high drug loading, controlled drug release and targeted delivery to the specific organ. Moreover, nanoparticles systems offer the possibility of co-encapsulation of drugs in the same drug delivery system and, consequently, the simultaneous administration of compounds. Characterization of nanoparticles properties, specifically involves quantification of the active pharmaceutical ingredients and is pivotal in the development of innovative nanomedicines. Therefore, this study has proposed and validated a new RP-HPLC-UV method for the simultaneous determination of simvastatin and coenzyme Q10 in hybrid nanoparticles systems. A reversed phase (RP) C8 column and a gradient elution of water: methanol at flow rate of 1.5 ml/min was used. Simvastatin (SVT), simvastatin hydroxyacid isoform (SVA) and coenzyme Q10 were identified by dual wavelength-UV detection at 238 nm (statins) and 275 nm, respectively. The proposed method was selective and linear in the range of 0.5-25 μg/ml (r > 0.999), precise, with values of relative standard deviation (RSD) lower than 2%, robust and accurate (recovery values of 100 ± 5%), satisfying FDA guidelines. Furthermore, low detection (LOD <0.2 μg/ml) and quantification limits (LOQ <0.4 μg/ml) were suitable for the application of the method for the in vitro study of release kinetics of simvastatin and coenzyme Q10 co-encapsulated in lecithin/chitosan nanoparticles. The proposed method represents, to our knowledge, the only method for the simultaneous quantification of simvastatin, coenzyme Q10 and of the hydrolysed hydroxyacid isoform of the statin in nanoparticles.
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http://dx.doi.org/10.1016/j.jpba.2018.03.046DOI Listing
June 2018

Surface-Modified Nanocarriers for Nose-to-Brain Delivery: From Bioadhesion to Targeting.

Pharmaceutics 2018 Mar 15;10(1). Epub 2018 Mar 15.

Interdipartmental Center for Innovation in Health Products, BIOPHARMANET TEC, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.

In the field of nasal drug delivery, nose-to-brain delivery is among the most fascinating applications, directly targeting the central nervous system, bypassing the blood brain barrier. Its benefits include dose lowering and direct brain distribution of potent drugs, ultimately reducing systemic side effects. Recently, nasal administration of insulin showed promising results in clinical trials for the treatment of Alzheimer's disease. Nanomedicines could further contribute to making nose-to-brain delivery a reality. While not disregarding the need for devices enabling a formulation deposition in the nose's upper part, surface modification of nanomedicines appears the key strategy to optimize drug delivery from the nasal cavity to the brain. In this review, nanomedicine delivery based on particle engineering exploiting surface electrostatic charges, mucoadhesive polymers, or chemical moieties targeting the nasal epithelium will be discussed and critically evaluated in relation to nose-to-brain delivery.
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http://dx.doi.org/10.3390/pharmaceutics10010034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874847PMC
March 2018

Polymeric films loaded with cisplatin for malignant pleural mesothelioma: a pharmacokinetic study in an ovine model.

J Thorac Dis 2018 Jan;10(Suppl 2):S207-S220

Biopharmanet-TEC, University of Parma, Parma, Italy.

Background: Malignant pleural mesothelioma (MPM) continues to be a distressing tumor due to its aggressive biologic behavior and scanty prognosis. Several therapeutic approaches have been tested both in clinical and preclinical settings, being intrapleural chemotherapy one of the most promising. Some years ago, our interest focused on polymeric films loaded with cisplatin for the adjuvant intrapleural treatment of surgical patients. After and studies in a rat recurrence model of MPM, the aim of this study was to evaluate the pharmacokinetics of the polymeric films in a sheep model in view of further studies in a clinical setting.

Methods: An ovine model was used. Animals were divided into four groups according to pharmacologic treatment: control group (three animals undergoing left pneumonectomy and saline-NaCl solution); intrapleural hyaluronate cisplatin films (HYALCIS) group (six animals undergoing left pneumonectomy and intrapleural application of polymeric films loaded with cisplatin); intrapleural cisplatin solution (six animals undergoing left pneumonectomy and intrapleural application of cisplatin solution); intravenous cisplatin (five animals undergoing left pneumonectomy and intravenous administration of cisplatin solution). The primary objective was the plasmatic and pleural concentration of cisplatin in the treatment groups. The secondary objective was the treatment-related toxicity evaluated by plasmatic analysis performed at prearranged time intervals and histological examinations of tissue samples collected during animal autopsy. Analysis of variance (ANOVA) was used for statistical analysis. Bonferroni correction was applied for comparison between all groups.

Results: Twenty female Sardinian sheep with a mean weight of 45.1 kg were studied. All animals survived the surgical procedures. The whole surgical procedure had a mean duration of 113 minutes. Cisplatin blood levels obtained from polymeric films application were low during the first 24 hours after the application; then, the cisplatin blood level increased gradually and progressively until it reached significantly higher plasmatic concentrations after 120 hours compared to intrapleural cisplatin solution (P=0.004) and intravenous administration (P=0.001), respectively. Considering cisplatin concentration at 168 hours after the application, animals treated with polymeric films had higher plasmatic values than animals treated with intrapleural cisplatin solution and intravenous cisplatin (P=0.001). Despite the high cisplatin plasmatic concentrations, treatment related-toxicity towards kidneys and liver was comparatively lower compared to the intravenous and intrapleural cisplatin administration and closer to the control levels.

Conclusions: Polymeric films loaded with cisplatin allowed to reach significantly higher intrapleural and plasmatic cisplatin concentrations compared to intrapleural and intravenous cisplatin solution, providing at the same time, a significant reduction of treatment related toxicity.
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http://dx.doi.org/10.21037/jtd.2017.10.74DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830553PMC
January 2018

Physicochemical and pharmacokinetic properties of polymeric films loaded with cisplatin for the treatment of malignant pleural mesothelioma.

J Thorac Dis 2018 Jan;10(Suppl 2):S194-S206

Thoracic Surgery, Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy.

Background: Malignant mesothelioma is an invasive neoplasm arising from mesothelial surfaces of the pleural and peritoneal cavities. Mesothelioma treatment is unsatisfactory and recurrence is common. Here an innovative locoregional treatment for malignant pleural mesothelioma is presented.

Methods: Chitosan- and hyaluronate-based films were loaded with 0.5% and 4% w/w cisplatin and were studied for their physicochemical, mechanical and drug release characteristics. The performance of the drug delivery systems was assessed on A549 cells and on an orthotopic model of MPM recurrence in rats.

Results: Polysaccharide films produced were thin, flexible and resistant. Cisplatin was completely released from hyaluronic acid films within 96 hours, while drug release was found to be much more prolonged with chitosan films. The drug released from hyaluronate films was effective against A549 cell line, while for chitosan films the release was too slow to produce cytotoxicity. Similarly, cisplatin-loaded chitosan films released minimal quantities of cisplatin and induced inflammation and foreign body reaction. Cisplatin-loaded hyaluronate acid films on the contrary were able to prevent tumor recurrence. The cisplatin-loaded hyaluronate films provided higher C and AUC compared to a solution of cisplatin administered intrapleurally, but did not show any sign of treatment related toxicity.

Conclusions: Hyaluronate-based films appear as an optimal platform for the development of drug delivery systems suitable for the loco-regional post-surgical treatment of lung malignancies.
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http://dx.doi.org/10.21037/jtd.2017.10.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830560PMC
January 2018

In vivo nose-to-brain delivery of the hydrophilic antiviral ribavirin by microparticle agglomerates.

Drug Deliv 2018 Nov;25(1):376-387

b Department of Food and Drug , University of Parma , Parma , Italy.

Nasal administration has been proposed as a potential approach for the delivery of drugs to the central nervous system. Ribavirin (RBV), an antiviral drug potentially useful to treat viral infections both in humans and animals, has been previously demonstrated to attain several brain compartments after nasal administration. Here, a powder formulation in the form of agglomerates comprising micronized RBV and spray-dried microparticles containing excipients with potential absorption enhancing properties, i.e. mannitol, chitosan, and α-cyclodextrin, was developed for nasal insufflation. The agglomerates were characterized for particle size, agglomeration yield, and ex vivo RBV permeation across rabbit nasal mucosa as well as delivery from an animal dry powder insufflator device. Interestingly, permeation enhancers such as chitosan and mannitol showed a lower amount of RBV permeating across the excised nasal tissue, whereas α-cyclodextrin proved to outperform the other formulations and to match the highly soluble micronized RBV powder taken as a reference. In vivo nasal administration to rats of the agglomerates containing α-cyclodextrin showed an overall higher accumulation of RBV in all the brain compartments analyzed as compared with the micronized RBV administered as such without excipient microparticles. Hence, powder agglomerates are a valuable approach to obtain a nasal formulation potentially attaining nose-to-brain delivery of drugs with minimal processing of the APIs and improvement of the technological and biopharmaceutical properties of micronized API and excipients, as they combine optimal flow properties for handling and dosing, suitable particle size for nasal deposition, high surface area for drug dissolution, and penetration enhancing properties from excipients such as cyclodextrins.
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http://dx.doi.org/10.1080/10717544.2018.1428242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058489PMC
November 2018

Nebulized coenzyme Q nanosuspensions: A versatile approach for pulmonary antioxidant therapy.

Eur J Pharm Sci 2018 Feb 21;113:159-170. Epub 2017 Oct 21.

Food and Drug Department, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy; Research Center Pharmaceutical Engineering GmbH, Graz, Austria. Electronic address:

Coenzyme Q (CoQ) is an antioxidant substance indicated as a dietary supplement which has been proposed as adjuvant in the treatment of cardiovascular disorders and cancer for its protective and immunostimulating activities. The aim of this work was the production by high-pressure homogenization, characterization and stability investigation of three different CoQ nanosuspensions designed to be administered to the lungs by nebulization. Three surfactants, i.e. lecithin, PEG32 stearate and vitamin-E TPGS, were selected to stabilize CoQ formulations. Preparations were identified as nanosuspensions (particle size in the range 35-60nm): the smallest particles were obtained with vitamin-E TPGS and denoted a core-shell structure. The CoQ delivered from a commercial air-jet nebulizer was in all the cases around 30% of the loaded dose. The nanosuspension containing PEG32 stearate presented the highest respirable fraction (70.6%) and smallest MMAD (3.02μm). Stability tests showed that the most stable formulation, after 90days, was the one containing vitamin-E TPGS, followed by the CoQ-lecithin formulation. Interestingly, those formulations were demonstrated to be suitable also for nebulizers using other mechanisms of aerosol production such as ultrasound and vibrating mesh nebulizers. Studies focused on in vitro cellular toxicity of the formulations and their single components using A549 human lung cells showed no obvious cytotoxicity for the formulations containing lecithin and PEG 32 stearate. Vitamin-E TPGS alone was shown to be able to damage the plasma membrane, nevertheless, cell damage was decreased when vitamin-E TPGS was present in the formulation with CoQ.
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http://dx.doi.org/10.1016/j.ejps.2017.10.024DOI Listing
February 2018

Opportunity and challenges of nasal powders: Drug formulation and delivery.

Eur J Pharm Sci 2018 Feb 20;113:2-17. Epub 2017 Sep 20.

Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy. Electronic address:

In the field of nasal drug delivery, among the preparations defined by the European Pharmacopoeia, nasal powders facilitate the formulation of poorly water-soluble active compounds. They often display a simple composition in excipients (if any), allow for the administration of larger drug doses and enhance drug diffusion and absorption across the mucosa, improving bioavailability compared to nasal liquids. Despite the positive features, however, nasal products in this form still struggle to enter the market: the few available on the market are Onzetra Xsail® (sumatriptan) for migraine relief and, for the treatment of rhinitis, Rhinocort® Turbuhaler® (budesonide), Teijin Rhinocort® (beclomethasone dipropionate) and Erizas® (dexamethasone cipecilate). Hence, this review tries to understand why nasal powder formulations are still less common than liquid ones by analyzing whether this depends on the lack of (i) real evidence of superior therapeutic benefit of powders, (ii) therapeutic and/or commercial interest, (iii) efficient manufacturing methods or (iv) availability of suitable and affordable delivery devices. To this purpose, the reader's attention will be guided through nasal powder formulation strategies and manufacturing techniques, eventually giving up-to-date evidences of therapeutic efficacy in vivo. Advancements in the technology of insufflation devices will also be provided as nasal drug products are typical drug-device combinations.
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http://dx.doi.org/10.1016/j.ejps.2017.09.027DOI Listing
February 2018

Gel-like TPGS-Based Microemulsions for Imiquimod Dermal Delivery: Role of Mesostructure on the Uptake and Distribution into the Skin.

Mol Pharm 2017 10 1;14(10):3281-3289. Epub 2017 Sep 1.

Food and Drug Department, University of Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.

The aim of this work was to develop an innovative microemulsion with gel-like properties for the cutaneous delivery of imiquimod, an immunostimulant drug employed for the treatment of cutaneous infections and neoplastic conditions. A pseudoternary phase diagram was built using a 1/1 TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate)/Transcutol mixture as surfactant system, and oleic acid as oil phase. Eight microemulsions-selected from the 1.25/8.75 oil/surfactants ratio, along the water dilution line (from 20 to 56% w/w)-were characterized in terms of rheological behavior, optical properties via polarized microscopy, and supramolecular structure using X-ray scattering. Then, these formulations were loaded with imiquimod and the uptake and distribution into the skin was evaluated on full-thickness porcine skin. X-ray scattering experiments revealed the presence of disconnected drops in the case of microemulsion with 20% water content. Diluting the system up to 48% water content, the structure turned into an interconnected lamellar microemulsion, reaching a proper disconnected lamellar structure for the highest water percentages (52-56%). Upon water addition, also the rheological properties changed from nearly Newtonian fluids to gel-like structures, displaying the maximum of viscosity for the 48% water content. Skin uptake experiments demonstrated that formulation viscosity, drug loading, and surfactant concentration did not play an important role on imiquimod uptake into the skin, while the skin penetration was related instead to the microemulsion mesostructure. In fact, drug uptake became enhanced by locally lamellar interconnected structures, while it was reduced in the presence of disconnected structures, either drops or proper lamellae. Finally, the data demonstrated that mesostructure also affects the drug distribution between the epidermis and dermis. In particular, a significantly higher dermal accumulation was found when disconnected lamellar structures are present, suggesting the possibility of tuning both drug delivery and localization into the skin by modifying microemulsions composition.
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http://dx.doi.org/10.1021/acs.molpharmaceut.7b00348DOI Listing
October 2017