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The well-being of skin and mucous membranes is fundamental for the homeostasis of the body and thus it is imperative to treat any lesion quickly and correctly. In this view, polyphenols might assist and enhance a successful wound healing process by reducing the inflammatory cascade and the production of free radicals. However, they suffer from disadvantageous physico–chemical properties, leading to restricted clinical use. In this work, a complex mixture of PEGylated lipid, Glyceryl monoester, 18-β-Glycyrrhetinic Acid and Menthol was designed to entrap Resveratrol (RSV) as the active ingredient and further produce lipid nanoparticles (LNPs) by homogenization followed by high-frequency sonication. The nanosystem was properly characterized in terms of particle size (DLS, SEM), zeta potential, drug loading, antioxidant power (DPPH), release behaviour, cytocompatibility, wound healing and antibiofilm properties. The optimized lipid mixture was homogeneous, melted at 57–61 °C and encapsulated amorphous RSV (4.56 ± 0.04% w/w). The RSV-loaded LNPs were almost monodispersed (PDI: 0.267 ± 0.010), with nanometric size (162.86 ± 3.12 nm), scavenger properties and suitable DR% and LE% values (96.82 ± 1.34% and 95.17 ± 0.25%, respectively). The release studies were performed to simulate the wound conditions: 1-octanol to mimic the lipophilic domains of biological tissues (where the First Order kinetic was observed) and citrate buffer pH 5.5 according to the inflammatory wound exudate (where the Korsmeyer–Peppas kinetic was followed). The biological and microbiological evaluations highlighted fibroblast proliferation and migration effects as well as antibiofilm properties at extremely low doses (LNPs: 22 μg/mL, corresponding to RSV 5 µM). Thus, the proposed multicomponent LNPs could represent a valuable RSV delivery platform for wound healing purposes.

Oral squamous cell carcinoma (OSCC) is one of the most prevailing and aggressive head and neck cancers, featuring high morbidity and mortality. The available conventional treatments suffer from several adverse effects and are often inefficient in terms of their survival rates. Thus, seeking novel therapeutic agents and adjuvants is of the utmost importance for modern society. Natural polyphenolic compounds have recently emerged as promising chemopreventive and anticancer agents. Specifically, the natural compound resveratrol (RSV) has recently gained momentum for this purpose. RSV is useful for treating OSCC due to its antiproliferative, antimetastatic, and proapoptotic effects. Additionally, RSV acts against tumor cells while synergically cooperating with chemotherapeutics, overcoming drug resistance phenomena. Despite these wide-spectrum effects, there are few specific investigations regarding RSV’s effects against OSCC animal models that consider different routes and vehicles for the administration of RSV. Interestingly, an injectable RSV-loaded liposome-based formulation was proven to be effective against both in vitro and in vivo OSCC models, demonstrating that the development of RSV-loaded drug delivery systems for systemic and/or loco-regional applications may be the turning point in oral cancer treatment, leading to benefits from both RSV’s properties as well as from targeted delivery. Given these premises, this review offers a comprehensive overview of the in vitro and in vivo effects of RSV and its main derivative, polydatin (PD), against OSCC-related cell lines and animal models, aiming to guide the scientific community in regard to RSV and PD use in the treatment of oral precancerous and cancerous lesions.

The comparison of grapefruit IntegroPectin powders isolated via spray drying and via freeze drying in terms of phenolic content, quantification of the most representative flavonoids (naringin and hesperidin), radical scavenging activity, total protein content and pH of the aqueous solutions provides relevant information. Except for the protein content and the antioxidant power, the two drying methods afford similar pectins. Optimization of the spray drying parameters allowed to maximize the yield of isolated pectin that nearly approached (>95%) the quantitative yield obtained via freeze drying.

As transcorneal drug delivery is still a challenge, the scope of the present study was to prepare useful nanosystems able to enhance transcorneal permeation/penetration of drugs. Moreover, this work aims to evaluate the effectiveness of inulin-based nanosystems in the specific field of ocular drug delivery and the effect of PEG chains to promote mucoadhesion, stability and transcorneal penetration/permeation enhancer effect of self-assembling nanoparticles in vitro (transwell systems and HCE) and ex vivo (Franz cells and bovine cornea). In particular, inulin was chosen as the starting natural polysaccharide polymer to design a novel amphiphilic derivative named INU-EDA-RA-PEG capable of self-assembling to form self-assembling nanoparticles and corticosteroids-loaded self-assembling nanoparticles. As observed, self-assembling nanoparticles show appropriate particle size values, mucoadhesivity and cytocompatibility. Moreover, self-assembling nanoparticles are able to act efficiently as permeation/penetration enhancer. Additionally, the presence of PEG has positive influence. Thus, the developed inulin-based nanosystems represent a promising tool to improve transcorneal delivery of corticosteroids.

In this work a new copolymer of inulin (INU) derivatized with ethylendiamine (EDA) and retinoic acid (RA), named INU-EDA-RA, was synthetized, characterized and employed to produce micelles as carriers for topical administration of corticosteroids for the potential treatment of diseases of posterior eye segment. Spectroscopic analysis confirmed a molar derivatization degree of 11.30 and 4.30% in EDA and RA, respectively. INU-EDA-RA micelles are capable of strong mucoadhesive interactions which result time-independent and stable over time but concentration depending. Moreover micelles are able to encapsulate efficiently from 3 to 13% (w/w) of lipophilic drugs, as dexamethasone, triamcinolone and triamcinolone acetonide. Drug loaded micelles are stable for three months when stored as freeze-dried powders and able to release high amount of drug when compared to drug dissolution profiles from suspensions. Moreover, drug loaded micelles are compatible with different ocular cell lines that are also able to internalize fluorescent micelles. Finally, drug loaded micelles enhance drug fluxes and permeability coefficients across corneal epithelial cells, thus reducing drug loss due to retention inside the cells.

Nowadays the therapeutic strategies to manage Parkinson&rsquo, s Disease are merely symptomatic and consist of administering L-DOPA and/or dopamine receptor agonists. Among these, Ropinirole (ROP) is a widely orally-administered molecule, although it is extensively susceptible to hepatic metabolism. Since literature reports the buccal mucosa as a potentially useful route to ROP administration, the development of novel, effective, and comfortable oromucosal formulations should prove desirable in order to both enhance the therapeutic efficacy of the drug and allow a personalized therapeutic strategy able to meet the patient&rsquo, s needs. The results of the proposed ROP film as a new dosage form show that it is flexible, uniform, and characterized by suitable surface pH, good mucoadhesiveness, low swelling degree, and fast, complete drug release. Moreover, after ex vivo evaluation on a film having an area of 0.282 cm2 and dose of 2.29 mg, the results of drug flux through the buccal mucosa are closely comparable to the amount of ROP that reaches the bloodstream at the steady-state condition after ROP-PR 4 mg oral administration, calculated according to the literature (0.237 mg/cm2&middot, h&minus, 1 vs. 0.243 mg/h, respectively). Moreover, drug flux and ROP dose could be accurately modulated time-by-time depending on the patient&rsquo, s need, by varying the administered disk area. In addition, the proposed ROP film displays no lag time, producing an immediate drug input in the bloodstream, which could result in a prompt therapeutic response. These findings make ROP film a potentially comfortable and patient-friendly formulation, and a promising candidate for further clinical trials.

Despite eye drops generally represent the most convenient, simple and patient-friendly formulations to treat ocular diseases, they suffer from poor retention on the ocular surface and low drug bioavailability leading to the necessity of prolonged and continuous treatment over time. Therefore, ocular insert could represent an innovative way to benefit from ocular topical administration while minimizing all the relevant limitation related to this route of administration. Polymeric non-erodible mucoadhesive ocular inserts should be comfortable and should rapidly adhere on the ocular surface, remain in situ for prolonged period, assure a reproducible and controlled drug release as well as act as transcorneal absorption promoters. In this study, a well-known aliphatic polyester, poly(1,4-butylene succinate) (PBS), was used as starting material to produce hydrophobic microfibrillar scaffolds by means of electrospinning technique. Plasma-assisted chemical surface functionalization of the PBS scaffolds with appropriate biopolymers (inulin, α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide, heparin) was carried out to confer to the final ocular inserts ad hoc properties as wettability, mucoadhesion and cytocompatibility on human corneal epithelial cells, by improving surface hydrophilicity without modifying the bulk properties of the material. The lipophilic drug triamcinolone acetonide was loaded into the obtained ocular insert and release studies were carried out to demonstrate the ability of drug loaded inserts to release the active until 30 days.

In this work, new micellar systems able to cross corneal barrier and to improve the permeation of imatinib free base were prepared and characterized. HA-EDA-C-16, HA-EDA-C-16-PEG, and HA-EDA-C-16-CRN micelles were synthesized starting from hyaluronic acid (HA), ethylenediamine (EDA), hexadecyl chains (C-16), polyethylene glycol (PEG), or L-carnitine (CRN). These nanocarriers showed optimal particle size and mucoadhesive properties. Imatinib-loaded micelles were able to interact with corneal barrier and to promote imatinib transcorneal permeation and penetration. In addition, a study was conducted to understand the in vitro imatinib inhibitory effect on a choroidal neovascularization process. Imatinib released from polymeric micelles was able to inhibit endothelial cell sprouting and to promote cell tube disruption.

The aim of this work was to obtain polymeric micelles able to cross corneal barrier and to improve the permeation of imatinib free base. Micelles were prepared by using hyaluronic acid (HA) derivatives containing ethylenediamine (EDA), chains of hexadecyl (C16), polyethylene glycol (PEG) and/or L-carnitine (CRN). The resulting samples, named as HA-EDA-C16, HA-EDA-C16-PEG and HA-EDA-C16-CRN micelles, were designed to allow a non-invasive way of administration, i.e. topical ocular instillation. These nanocarriers showed an optimal particle size in aqueous media and mucoadhesive properties. Imatinib-loaded micelles were able to interact with corneal barrier and to promote imatinib transcorneal permeation and penetration. An interesting in vitro study was conducted to investigate imatinib inhibitory effect on a choroideal neovascularization process (1). Imatinib was able to inhibit endothelial cell sprouting and to reduce the formation of functional vessels. In addition, imatinib released from polymeric micelles was able to inhibit cell tube formation and to promote cell tube disruption. Obtained results suggested that prepared micelles could represent optimal candidates for off-label use of imatinib in the treatment of retinopathies.

Here, for the first time, branched polyaminoacids bearing α-amino acids as side functions, namely PAA-co-AA and PGA-co-AA, are prepared by heterophase ring opening of polysuccinimide (PSI) with l -arginine or glycine in aqueous environment and at controlled pH. The modulation of the pH of the reaction leads to high-molecular-weight copolymers with tunable functionalization and, as consequence, with tailor-made physicochemical properties. Furthermore, a branched polyaminoacid carrying a preformed bioactive peptide ( l -trileucine) and l -arginine as side pendants, named PATA-co-AA, was synthesized via a similar pathway thus leading to complex biomimetic materials potentially exploitable in several biomedical fields. Acid-base titrations, circular dichroism studies and spectrofluorimetric analysis show that the physicochemical behavior of this class of bioinspired copolymers can be predicted considering the starting features of the selected building blocks, implying that a careful choice of functional amino acids or peptides provides good chance for obtaining macromolecule libraries with selected properties.

Chitosan oligosaccharide (C) was functionalized with L-arginine (A) and short hydrocarbon chains (C-8) to design an amphiphilic copolymer, henceforth CAC(8), leading to microparticles (MPs) consisting of an arginine-decorated hydrophilic shell and inner hydrophobic domains allowing the encapsulation of high amount hydrophobic drugs such as sorafenib tosylate (>10% w/w). L-arginine side chains were selected in order to impart the final MPs enhanced transcorneal penetration properties, thus overcoming the typical biological barriers which hamper the absorption of drugs upon topical ocular administration. The mucoadhesive properties and drug release profile of the CAC(8) MPs (CAC(8)-MPs) were studied, showing that CAC(8)-MPs can strongly interact with mucin, and thus gradually release their payload in situ to potentially improve the bioavailability of the drug after topical administration. In vitro transcorneal studies also showed that CAC(8)-MPs are endowed with effective permeation enhancer ability combined with negligible toxicity. (c) 2019 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.

Nowadays, chemoprevention by administering natural supplements is considered an attractive strategy to reverse, suppress, or prevent the evolution of premalignant oral lesions. In particular, Barbaloin exhibits anti-proliferative, anti-inflammatory, and anti-cancer properties, and it results useful in multi-therapy with classic chemotherapeutics. Therefore, in this work, mucoadhesive buccal films, as locoregional drug delivery system able to provide a targeted and efficient therapeutic delivery of Barbaloin, are proposed. Thus, Aloin extract-loaded Eudragit (R) RL100 or Eudragit (R) RS100-based buccal films were designed in order to obtain an easily self-administrable formulation capable of promoting Barbaloin penetration into buccal mucosa and assuring high patient compliance. Large amounts of extract (44%) were loaded into the polymer matrix and six formulations were prepared varying polymers and plasticizers ratios. For all formulations, physical form (thermogravimetric analysis-differential scanning calorimetry, TGA-DSC), swelling degree, mucoadhesiveness, drug release, and ability to promote drug penetration in mucosa have been investigated. After a sequential selection process, Eudragit RS 100-based film, with low PVP and high plasticizers amounts, emerged as the most promising. It results appropriately flexible, uniform in terms of weight, thickness and drug content, as well as characterized by suitable surface pH, good mucoadhesiveness, and low swelling degree. It displays a Higuchian drug release behavior up to 89% of Barbaloin released, thus demonstrating that diffusion through the matrix is the main release mechanism. Remarkable penetration enhancer properties of film were demonstrated by evidence of Barbaloin accumulation into buccal mucosa up to 10-fold higher than those obtained following administration of Aloin solution.

Context: Chemoprevention of potential malignant disorders or cancerous lesions that affect oral mucosae requires extended duration of treatment. Locoregional delivery of natural products could represent a promising strategy for this purpose. Objective: To investigate the aptitude of aloin to permeate through, or accumulate in, the buccal mucosa and to develop a new prolonged oro-mucosal drug delivery system. Materials and Methods: Permeation/accumulation of aloin from Curacao Aloe (containing 50% barbaloin) was evaluated ex vivo, using porcine buccal mucosa as the most useful model to simulate human epithelium. Oro-mucosal matrix tablets were prepared by dispersing aloin (10% w/w) in Eudragit® RS 100 as, biocompatible, low permeable, pH-independent, and non-swelling polymer. The prepared tablets were evaluated for drug-polymer compatibility, weight variation, drug uniformity content, diameter, thickness, hardness, friability, swelling, mucoadhesive strength, and drug release. Results: Aloin has low tendency to cross buccal mucosa, permeation is marginal, and high drug amounts remain entrapped into the epithelium. Matrix tablets characteristics were in agreement with pharmacopoeial requirements. Drug release showed highly reproducible Higuchian profile. Delivery through matrix tablets promoted drug accumulation in the mucosal tissue. Discussion and conclusion: Following application of matrix tablets on porcine buccal mucosa, the amount of discharged drug recovered in the tissue should be sufficient to produce the desired effects, providing therapeutic drug levels directly at the site of action. Aloin loaded tablets are valid candidates for prevention/treatment of potentially malignant disorders and oral cancer and could potentially lead to clinically relevant drug delivery system as coadjuvant of conventional chemotherapy/radiation therapy.

Background: IntegroPectin is a new family of citrus pectins of broad biological activity obtained via hydrodynamic cavitation of citrus biowaste carried out in water only. These pectins have already been isolated by freeze drying, a time-consuming and expensive procedure difficult to be scaled up. Since recently the spray drying technique has been greatly appreciated for food and pharmaceutical applications, this work proposes a comparison between Grapefruit IntegroPectin powders isolated via spray drying (SD) and via freeze drying (FD). Methods: A mini Spray Dryer B-290 with B-295 inert loop (Büchi) and a FreeZone 2.5 Liter freeze dry system (Labconco) were used. Dried powders comparison was carried out in terms of total phenolic content (Folin-Ciocalteu), amount of the most representative flavonoids (HPLC-DAD analysis), radical scavenging activity (DPPH assay), total protein content (Bradford assay) and pH on the re-dissolved powders. Results and discussion: the optimized SD process led to a very high yield (>95%) referred to the fully quantitative yield of FD process and resulted extremely quick and thus advantageous (30-50 min/100 mL of water extract versus 3 days/30 mL, respectively). The two resulting IntegroPectin powders displayed analogous Naringin and Hesperidin content and similar pH in water solution (≈4-5). The total phenolic content and the antioxidant power of the SD IntegroPectin were slightly higher than those of the FD powder. Instead, in the SD sample the protein content resulted nearly 4 times lower than the FD one, probably due to denaturation which might occur at the relatively high temperature required for the SD process. This could be favourable to achieve long-term protection of the biophenols contained in the powder. Conclusions: considering the broad-spectrum potentiality of these new pectins from citrus waste, the spray drying technique results effective, convenient and easily scalable with less technical effort and costs than the freeze drying process.

Introduction: In an ever-growing perspective of circular economy, the development of conscious, sustainable and environmental-friendly strategies to recycle the waste products is the key point1. The exhausted bentonite, from the grape processing industries, could become a precious matrix to produce new pharmaceutical/cosmetic excipients enriched in functional polyphenols2. Materials & Methods: The exhausted bentonite recovered after the fining process (supplied by Bono&Ditta s.p.a., Campobello di Mazara TP, Italy) was stored at -20°C. Solid-liquid extractions on both freeze-dried and as-collected (wet) bentonite were carried out by using PEG200 or propylene glycol as solvents. The liquid extracts were evaluated in terms of yield, pH, total phenolic (Folin-Ciocalteu) and protein (Bradford) contents, antioxidant power (DPPH) and amount of representative polyphenols (HPLC-DAD). Results: Both solvents extracted significant amounts of polyphenols from the waste bentonite, leading to coloured fluids characterized by acidic pH after water-dilution. Among all, the best extract was obtained from wet bentonite treated with PEG200 as it highlighted the highest phenolic content and consequently the strongest antioxidant activity. Conclusion: The waste bentonite emerged as a valuable source of functional polyphenols, and it could be treated with such solvents currently used in the pharmaceutical/cosmetic field to directly obtain novel enriched raw materials and excipients.

Topically administered ocular Drug Delivery Systems are the most desirable formulations for the treatment of ocular chronic diseases, being the most simple, convenient and patient-friendly ocular route of administration, despite it requires prolonged and continuous treatment over time. At this regard, ocular insert represent an innovative and effective strategy. Ocular inserts are solid/semisolid sterile preparations characterized by dimensions and shape specifically designed for topical ocular administration. They are able to rapidly adhere on the ocular surface and remain in situ for prolonged period while assuring a controlled drug release and potentially increasing drug transcorneal absorption. Based on these assumptions, the aim of this work was to opportunely design and characterize novel useful polymeric inserts based on a 3D scaffold. Poly-butylene succinate (PBS) scaffolds were prepared by electrospinning, functionalized with biopolymers (inulin, poly(hydroxyethyl)aspartamide [PHEA], heparin) by plasma-assisted reaction and loaded with triamcinolone acetonide (TA). The obtained products were evaluated in terms of physico-chemical, technological-applicative and biological properties. Ocular inserts resulted non-bioerodible, with a very low swelling degree and a high drug loading ability, cytocompatible and extremely mucoadhesive. Moreover, inserts are also able to slowly release TA after firmly adhering on the corneal tissue. This translates into a significant increase of transcorneal permeation and penetration (enhancement of both Kp and Ka values up to an order magnitude). In conclusion, inserts can be an effective strategy to increase patient compliance by reducing the frequency of administration and avoiding pulsatile drug entry into the eye.

αs1-Casein is a natural protein which constitutes the most prevalent form of casein in bovine milk. αs1-Casein is amphiphilic, almost unfolded, and consist of two highly hydrophobic zones separated by an hydrophilic region. Previous studies have demonstrated the ability of αs1-Casein to inhibit in vitro the nucleation phase of amyloid β-peptide (Aβ) fibrillogenesis by sequestering Aβ species on its surface. One of the main hallmark for Alzheimer Disease (AD) is the extracellular deposition in brain tissues of proteinaceous plaques, rich of well-ordered Aβ peptide amyloid aggregates. Although such an evidence, oligomeric intermediates in the fibrillogenesis have been discovered to be the most toxic species able to interfere with membranes and disturbing the cell functioning. In this context, a challenging therapeutic approach could target such early toxic oligomeric species. In order to exploit the inhibiting action of αs1-Casein as a possible AD treatment, it is crucial to define a controlled method to efficiently load, protect and deliver the protein to the brain. Liposomes are spherical phospholipids-based vesicles characterized by excellent biocompatibility and biodegradability, low toxicity, ability to incorporate and protect both hydrophilic and hydrophobic drugs as well as to cross the Blood Brain Barrier in order to access the Central Nervous System. Based on all these considerations, novel proteoliposomes composed by phospholipids, cholesterol and αs1-Casein were prepared and characterized. The proteoliposome preparation protocol was optimized in order to obtain the best results. Nanosystems were characterized by different biophysics techniques, such as light scattering, zeta-potential, laurdan fluorescence, chromatography and AFM imaging.