Equivalence assessment of creams with quali-quantitative differences in light of the EMA and FDA regulatory framework.

EMA and FDA are upgrading guidelines on assessing the quality and the equivalence of topically applied drug products for developing copies of originator products and supporting post-marketing variations. For topical products having remarkably similar composition, both EMA and FDA accept the equivalence on the bases of the comparison of rheological properties and in vitro drug release constant (k) and skin permeation flux (J) values, instead of clinical studies. This work aims to evaluate the feasibility to expand this approach to variations of the composition of complex semi-solid preparations. Ibuprofen (IB) creams at two different strengths (i.e., 1 % and 10 %) were used as a model formulation. Two formulative changes were performed: (a) the addition of the humectant to simulate a minor post-marketing variation; (b) the substitution of the emulsifying system to simulate a major one. These variations impacted only in 1 % IB formulations where both the equivalences of rheological data and J-values failed. At the highest concentration, the presence of IB crystals broke down the differences in rheological patterns and lead the IB thermodynamic activity at the maximum figuring out an overlapping of the J-values. Such data suggest the combination of these studies, which are thought mainly for the development of copies, could be also applied to the management of post-marketing variations that involve product composition.

Design of New Polyacrylate Microcapsules to Modify the Water-Soluble Active Substances Release.

Despite the poor photochemical stability of capsules walls, polyacrylate is one of the most successful polymers for microencapsulation. To improve polyacrylate performance, the combined use of different acrylate-based polymers could be exploited. Herein butyl methacrylate (BUMA)-based lattices were obtained via free radical polymerization in water by adding (i) methacrylic acid (MA)/methyl methacrylate (MMA) and (ii) methacrylamide (MAC) respectively, as an aqueous phase in Pickering emulsions, thanks to both the excellent polymer shells' stability and the high encapsulation efficiency. A series of BUMA_MA_MMA terpolymers with complex macromolecular structures and BUMA_MAC linear copolymers were synthesized and used as dispersing media of an active material. Rate and yield of encapsulation, active substance adsorption onto the polymer wall, capsule morphology, shelf-life and controlled release were investigated. The effectiveness of the prepared BUMA-based microcapsules was demonstrated: BUMA-based terpolymers together with the modified ones (BUMA_MAC) led to slow (within ca. 60 h) and fast (in around 10 h) releasing microcapsules, respectively.

Design of pressure-sensitive adhesive suitable for the preparation of transdermal patches by hot-melt printing.

This work aimed to design low-melting pressure sensitive adhesives and to demonstrate the feasibility of the preparation of (trans)dermal patches by hot-melt ram extrusion printing. This approach allows defining both the geometry of (trans)dermal patch and the drug strength easily according to patient needs. The preparation steps are the mixing of a poly-ammonium methacrylate polymer (i.e. Eudragit RL and RS) with a suitable amount of plasticizer (triacetin or tributyl citrate) and drug (ketoprofen or nicotine), the melting in the ram extruder, and the printing on the backing layer foil. The formulations were characterized in terms of rheological and adhesive properties, in vitro drug release and skin permeation profiles. The (trans)dermal patches made of Eudragit RL or Eudragit RS plasticized with the 40% triacetin could be printed at 90 °C giving formulations with suitable adhesive properties and without cold flow after 1 month of storage at 40 °C. Furthermore, the overall results showed that the performances of printed (trans)dermal patches overlapped those made by solvent casting, suggesting that the proposed solvent-free technology can be useful to treat cutaneous pathologies when the availability of (trans)dermal patches with size and shape that perfectly fit with the skin area affected by the disease improves the safety of the pharmacological treatment.

Personalized orodispersible films by hot melt ram extrusion 3D printing.

This work demonstrates the feasibility of the extemporaneous preparation of maltodextrins orodispersible films (ODF) by hot-melt ram-extrusion 3D printing. This method consists of three simple technological operations which can be also implemented in a pharmacy setting. First, maltodextrins, drug, and other excipients are mixed in a mortar and wetted with the plasticizer (i.e. glycerine). Then, the mixture is fed in the chamber of the ram-extruder and heated. ODF are individually printed on the packaging material foil and sealed without further manipulations. The critical formulation attributes and process variables were investigated to define the processability space. In particular, the optimal conditions to print a mixture of maltodextrins/glycerine in a 80/20 w/w ratio resulted: heating temperature: 85 °C; needle gauge: 18 G; needle-packaging material foil distance: 0.6 mm; maximum print rate: 50 mm/s; filling angle: 120°. The maximum drug loading was about 40%, when paracetamol was used as model drug. The compounded ODF complied with USP and Ph. Eur. specifications for disintegration time (<1 min). The dissolution pattern of paracetamol overlapped with that obtained from ODF with a similar composition prepared by the consolidated solvent casting technique, demonstrating the suitability of the proposed technology.

Comparison of Branched and Linear Perfluoropolyether Chains Functionalization on Hydrophobic, Morphological and Conductive Properties of Multi-Walled Carbon Nanotubes.

The functionalization of multi-walled carbon nanotubes (MW-CNTs) was obtained by generating reactive perfluoropolyether (PFPE) radicals that can covalently bond to MW-CNTs' surface. Branched and linear PFPE peroxides with equivalent molecular weights of 1275 and 1200 amu, respectively, have been thermally decomposed for the production of PFPE radicals. The functionalization with PFPE chains has changed the wettability of MW-CNTs, which switched their behavior from hydrophilic to super-hydrophobic. The low surface energy properties of PFPEs have been transferred to MW-CNTs surface and branched units with trifluoromethyl groups, CF3, have conferred higher hydrophobicity than linear units. Porosimetry discriminated the effects of PFPE functionalization on meso-porosity and macro-porosity. It has been observed that reactive sites located in MW-CNTs mesopores have been intensively functionalized by branched PFPE peroxide due to its low average molecular weight. Conductivity measurements at different applied pressures have showed that the covalent linkage of PFPE chains, branched as well as linear, weakly modified the electrical conductivity of MW-CNTs. The decomposed portions of PFPE residues, the PFPE chains bonded on carbon nanotubes, and the PFPE fluids obtained by homo-coupling side-reactions were evaluated by mass balances. PFPE-modified MW-CNTs have been characterized by X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), static contact angle (SCA), surface area, and porosity measurements.

In situ film forming fibroin gel intended for cutaneous administration.

The possible use of regenerated silk fibroin gels as in situ film forming formulations for cutaneous administration of drugs was studied. Ethanol was selected as volatile and skin tolerant solvent to favor the sol-gel transition of silk fibroin solutions. Glycerin was chosen to ameliorate the gel texture profile. Eighteen placebo formulations were prepared to individuate the optimal component ratios as a function of the texture analysis, spreadability and drying time. The in vitro biopharmaceutical performance was investigated by in vitro permeation test through human epidermis on formulations loading caffeine as a model drug. The data evidenced that the optimal technological performances were achieved using gels containing 70% ethanol and silk fibroin/glycerin ratio from 0.18 to 0.36. The caffeine flux (J) through the skin was significantly improved due to an increase of the drug thermodynamic activity (hydro-alcoholic solution: J∼0.8µg/cm(2)/h; in situ formed film: J∼1.4-1.7µg/cm(2)/h). In conclusion, silk fibroin can be advantageously proposed as a novel film forming material to develop dosage forms to be topically applied.