Umberto M. Musazzi

An insight into the skin penetration enhancement mechanism of N-methylpyrrolidone.

This work aims to elucidate the mechanism by which N-methylpyrrolidone (NMP) enhances the skin permeation of a compound by combining experimental data with molecular dynamic (MD) simulations. The addition of 10% NMP significantly increased the propranolol (PR) permeation through the human epidermis (∼ 15 μg/cm(2) vs ∼ 30 μg/cm(2)) while resulting inefficacious on hydrocortisone (HC) diffusion. No significant alterations in the stratum corneum structure were found after the in vitro treatment of human epidermis with NMP dispersed in mineral oil or water by attenuated total reflectance Fourier transform infrared (ATR-FTIR) analyses. MD simulations revealed the formation of a complex by H-bonds and the π-π stacking interactions between the NMPs amido group and the drugs aromatic systems. The size of the depicted NMP/PR clusters was in line with the hydrodynamic radius derived by dynamic light scattering analyses (∼ 2.00 nm). Conversely, no interaction, and consequently cluster formation, between NMP and HC occurred. These results suggest that NMP is effective in enhancing the drug permeation through human epidermis by a cotransport mechanism when NMP/drug interaction occurs.

Resveratrol-loaded nanocarriers: Formulation, optimization, characterization and in vitro toxicity on cochlear cells

The present work aimed to investigate the suitability of polymeric nanoparticles (NPs) loaded with resveratrol (RES) for drug delivery to cochlear cells. RES-loaded NPs were prepared by a solvent-diffusion method without surfactant. The Box-Behnken design was used to study the effect of the formulation variables on the particle mean diameter (PMD), polydispersity index (PDI), zeta-potential (ζ), percent drug encapsulation efficiency (EE%), and ratio between NP size before and after freeze-drying (Sf/Si). The physicochemical stability of the RES-loaded NPs during freeze-drying was investigated using four well-known cryoprotectants (i.e., lactose, mannitol, sucrose, and trehalose) at different concentrations. The RES-loaded NPs were also characterized by powder X-ray diffraction (PXRD) and in vitro drug release studies. Finally, the in vitro toxicity of the synthesized NPs was evaluated on two cochlear cell lines: HEI-OC1 and SVK-1 cells. The optimal formulation (desirability: 0.86) had 135.5±37.3nm as PMD, 0.126±0.080 as PDI, -26.84±3.31mV as ζ, 99.83±17.59% as EE%, and 3.30±0.92 as Sf/Si ratio. The PMD and PDI of the RES-loaded NPs were maintained within the model space only when trehalose was used at concentrations higher than 15% (w/v). Results from the in vitro cytotoxicity studies showed that blank NPs did not alter the viability of both cells lines, except for concentrations higher than 600μg/mL. However, the cell viability was significantly decreased at high concentrations of native RES (>50μM, p<0.05) in both cell lines. Overall, the results suggested that the RES-loaded polymeric NPs could be a suitable template for cochlea antioxidant delivery and otoproctection.

Low molecular weight heparins copies: are they considered to be generics or biosimilars?

The protection rights of low molecular weight heparins (LMWHs) are expired or are expiring, so the extent and nature of the studies required to obtain a market authorization for LMWH copies represents a hot topic. FDA classifies LMWHs as semisynthetic drugs and their copies as generics whereas the EMA views them as biological medicines and consequently their copies as biosimilars. Consequently, FDA requires only in vivo pharmacodynamic studies, while EMA requires also clinical trials. The current work reviews the chemical composition and therapeutic indications of LMWHs available in the EU and USA markets to discuss the two different approaches. Because LMWHs show a high intrinsic variability and a complete characterization is not viable, a conservative approach is desirable.

On the selection of an opioid for local skin analgesia: Structure-skin permeability relationships

Recent studies demonstrated that post-herpetical and inflammatory pain can be locally managed by morphine gels, empirically chosen. Aiming to rationalize the selection of the most suitable opioid for the cutaneous delivery, we studied the in vitro penetration through human epidermis of eight opioids, evidencing the critical modifications of the morphinan core. Log P, log D, solid-state features and solubility were determined. Docking simulations were performed using supramolecular assembly made of ceramide VI. The modifications on position 3 of the morphinan core resulted the most relevant in determining both physicochemical characteristics and diffusion pattern. The 3-methoxy group weakened the cohesiveness of the crystal lattice structure and increased the permeation flux (J). Computational studies emphasized that, while permeation is essentially controlled by molecule apolarity, skin retention depends on a fine balance of polar and apolar molecular features. Moreover, ChemPLP scoring the interactions between the opioids and ceramide, correlated with both the amount retained into the epidermis (Qret) and J. The balance of the skin penetration properties and the affinity potency for μ-receptors evidenced hydromorphone as the most suitable compound for the induction of local analgesia.

Is the European regulatory framework sufficient to assure the safety of citizens using health products containing nanomaterials

The growing application of nanomaterials in healthcare products (i.e., cosmetics, medical devices, and medicinal products) has encouraged the upgrade of the regulatory framework within the European Community to better control their use and manage the risk of negative effects on human health and environment. Unfortunately, despite the efforts of European Authorities, the current legislation is still stratified and several criticisms remain because of the lack of well-established scientific knowledge on nanomaterials. Although the regulatory framework for cosmetic products is almost complete, the efficacy and/or safety assessment of nanomaterials in medicinal products and medical devices is still based on case-by-case evaluation because of the complexity of such systems.

Orodispersible dosage forms: biopharmaceutical improvements and regulatory requirements

Orodispersible dosage forms have a growing presence in the pharmaceutical market because their administration can improve the bioavailability of some drugs and their prescription can ameliorate patient adherence and/or compliance. Here, we review the main features of orodispersible tablets, including oral lyophilisates, and orodispersible films along with their main production technologies. We summarize the bioavailability data and critically discussed their potential to improve patient adherence and/or compliance. We revisit this information in light of both the European Union (EU) and US regulatory frameworks, focusing on the differences in the definitions of such dosage forms and the requirements for marketing authorization.

Caffeic Acid-PLGA Conjugate to Design Protein Drug Delivery Systems Stable to Irradiation

This work reports the feasibility of caffeic acid grafted PLGA (g-CA-PLGA) to design biodegradable sterile microspheres for the delivery of proteins. Ovalbumin (OVA) was selected as model compound because of its sensitiveness of γ-radiation. The adopted grafting procedure allowed us to obtain a material with good free radical scavenging properties, without a significant modification of Mw and Tg of the starting PLGA (Mw PLGA = 26.3 ± 1.3 kDa vs. Mw g-CA-PLGA = 22.8 ± 0.7 kDa; Tg PLGA = 47.7 ± 0.8 °C vs. Tg g-CA-PLGA = 47.4 ± 0.2 °C). By using a W1/O/W2 technique, g-CA-PLGA improved the encapsulation efficiency (EE), suggesting that the presence of caffeic residues improved the compatibility between components (EEPLGA = 35.0% ± 0.7% vs. EEg-CA-PLGA = 95.6% ± 2.7%). Microspheres particle size distribution ranged from 15 to 50 µm. The zeta-potential values of placebo and loaded microspheres were −25 mV and −15 mV, respectively. The irradiation of g-CA-PLGA at the dose of 25 kGy caused a less than 1% variation of Mw and the degradation patterns of the non-irradiated and irradiated microspheres were superimposable. The OVA content in g-CA-PLGA microspheres decreased to a lower extent with respect to PLGA microspheres. These results suggest that g-CA-PLGA is a promising biodegradable material to microencapsulate biological drugs.

On the characterization of medicated plasters containing NSAIDs according to novel indications of USP and EMA: adhesive property and in vitro skin permeation studies

Abstract This work aims to establish if the assays recently introduced by EMA (Guideline on quality of transdermal patches-draft) and USP (Specific tests for transdermal delivery systems) to characterize transdermal patches (TP) are suitable for medicated plasters (MP). Six approved MP differing for type and characteristics of adhesive and backing layer were selected and characterized in terms of adhesive performances by tack, shear adhesion, peel adhesion and release liner removal tests and in vitro skin permeation. As far as the adhesive properties are concerned, the major drawback is related to the measurement of shear adhesion of MP made of an adhesive hydrogel and/or a stretchable backing layer which could be solved by reducing the applied load. Moreover, a concern on the mass balance prescribed by EMA draft for the acceptance of the results of in vitro penetration studies remains. Indeed, the acceptance range is narrow than that reported by Ph. Eur. requirement for uniformity of content. Finally, a novel calculation for evaluating the in vitro efficiency of MP in releasing the loaded drug through the skin was proposed.

A novel oromucosal prolonged release mucoadhesive suspension by one step spray coagulation method.

An oromucosal mucoadhesive suspension (OMS) able to combine the peculiarities of prolonged release mucoadhesive microparticles with those of an immediate release oromucosal solution is described. Microparticles were obtained by ionotropic gelation of alginate blended with another mucoadhesive material in a one step process where the cross-linking bath constituted the suspension vehicle. The effects of formulation and processing conditions on OMS performances were measured in-vitro determining the enhancement of drug penetration in buccal porcine mucosa and inhibition of tooth plaque formation using flurbiprofen and delmopinol as model drugs, respectively. Well-formed and spherical microparticles were obtained combining alginate with carbomer; linear dependence of particle size from the feed composition, viscosity and atomization pressure was found. As demonstrated by using FITC-labelled microparticles, the system remained onto the buccal mucosa at least for a six hour period. As a consequence, 0.1% flurbiprofen OMS guaranteed a concentration of flurbiprofen into buccal porcine mucosa over 6 hours comparable to 0.25% flurbiprofen reference solution, allowing a potential reduction of the 60% administered dose. The use of in-house made artificial mouth revealed that the once-a-day administration of 0.1% delmopinol OMS was as effective in plaque inhibition as the 0.2% delmopinol reference solution product given twice-a-day. These results suggested that the development of bioadhesive oromucosal suspensions, localizing the drug into buccal cavity, can reduce regimen and administrated dose.

Innovative pharmaceutical approaches for the management of inner ear disorders

The sense of hearing is essential for permitting human beings to interact with the environment, and its dysfunctions can strongly impact on the quality of life. In this context, the cochlea plays a fundamental role in the transformation of the airborne sound waves into electrical signals, which can be processed by the brain. However, several diseases and external stimuli (e.g., noise, drugs) can damage the sensorineural structures of cochlea, inducing progressive hearing dysfunctions until deafness. In clinical practice, the current pharmacological approaches to treat cochlear diseases are based on the almost exclusive use of systemic steroids. In the last decades, the efficacy of novel therapeutic molecules has been proven, taking advantage from a better comprehension of the pathological mechanisms underlying many cochlear diseases. In addition, the feasibility of intratympanic administration of drugs also permitted to overcome the pharmacokinetic limitations of the systemic drug administration, opening new frontiers in drug delivery to cochlea. Several innovative drug delivery systems, such as in situ gelling systems or nanocarriers, were designed, and their efficacy has been proven in vitro and in vivo in cochlear models. The current review aims to describe the art of state in the cochlear drug delivery, highlighting lights and shadows and discussing the most critical aspects still pending in the field.