Extemporaneous printing of diclofenac orodispersible films for pediatrics.

OBJECTIVE: The possible application of a hot-melt ram extrusion printing to the preparation of diclofenac orodispersible films (ODF) made of maltodextrin was studied focusing the attention on the effects of taste-masking agents (i.e. namely mint, licorice-mint, and sucralose) and an opacifier (titanium dioxide [TiO2]). SIGNIFICANCE: This is a proof-of-concept of the feasibility to print ODF loaded with a thermosensitive drug substance by hot-melt technologies. METHODS: Diclofenac sodium (DNa) ODF made of maltodextrin (dextrose equivalent (DE) = 6 ) plasticized with glycerol were prepared by hot-melt extrusion printing. ODF were characterized for disintegration time, drug content, and solid state, in vitro dissolution in deionized water and simulated salivary fluid at pH 5.7, tensile, and adhesive properties. Moreover, the stability of ODF was assessed in accelerated conditions over six months. RESULTS: After the preparation, no variation in drug solid state was evident and the formation of impurity A of DNa was detected, even if it remained below the Pharmacopoeia (Ph. Eur.) limits (< 0.2%). Only the addition of DNa significantly improved the ODF tensile properties: the tensile strength increased from 0.17 ± 0.03 MPa (placebo ODF) to 2.21 ± 0.54 MPa (p ≤ 0.03). All ODF disintegrated in about 1 min, and the t80% was lower than 3 min. TiO2 reduced the static and dynamic peel forces (p ≤ 0.006) favoring the ODF detachment from the primary packaging material. During the accelerated stability study, ODF were easy to handle without fracture; the drug content, impurity A, and dissolution profiles remained superimposable. CONCLUSION: Hot-melt printing can be suitable to prepare palatable ODF loaded with bitter thermosensitive drugs.

Gellan Nanohydrogels: Novel Nanodelivery Systems for Cutaneous Administration of Piroxicam.

The feasibility to use gellan nanohydrogels (Ge-NHs) as delivery system for the cutaneous administration of piroxicam (PRX) was investigated using gellan conjugated with cholesterol or riboflavin. The in vitro skin penetration studies through human epidermis were performed using a saturated aqueous drug solution, a 50% w/v Transcutol aqueous solution, and a commercially available PRX plaster as controls. Confocal microscopy, ATR-FTIR spectroscopy, circular dichroism, and a dynamometer assisted extrusion assay were performed to clarify the permeation mechanism of Ge-NHs. The skin permeation studies evidenced that Ge-NHs enhance the PRX retention in the epidermis and, at the same time, slow down the permeation process with respect to the controls. NHs can penetrate the stratum corneum, and then gradually disassemble thus diffusing in the viable epidermis reaching the spinosum layer. In conclusion, NHs represent a novel strategy to target poorly permeable compounds in the epidermis, thus improving the management of cutaneous pathologies.

Impact of semi-solid formulations on skin penetration of iron oxide nanoparticles.

BACKGROUND: This work aimed to provide useful information on the incidence of the choice of formulation in semi-solid preparations of iron-oxide nanoparticles (IONs). The appropriate analytical methods to assess the IONs physical stability and the effect of the semi-solid preparations on IONs human skin penetration were discussed. The physical stability of IONs (Dh = 31 ± 4 nm; ζ = -65 ± 5 mV) loaded in five semi-solid preparations (0.3% w/v), namely Carbopol gel (CP), hydroxyethyl cellulose gel (HEC), carboxymethylcellulose gel (CMC), cetomacrogol cream (Cet) and cold cream was assessed by combining DLS and low-field pulsed NMR data. The in vitro penetration of IONs was studied using human epidermis or isolated stratum corneum (SC). RESULTS: Reversible and irreversible IONs aggregates were evidenced only in HEC and CMC, respectively. IONs diffused massively through SC preferentially by an intercellular pathway, as assessed by transmission electron microscopy. The semi-solid preparations differently influenced the IONs penetration as compared to the aqueous suspension. Cet cream allowed the highest permeation and the lowest retained amount, while cold cream and CP favored the accumulation into the skin membrane. CONCLUSION: Basic cutaneous semi-solid preparations could be used to administer IONs without affecting their permeation profile if they maintained their physical stability over time. This property is better discriminated by low-field pulsed NMR measurements than the commonly used DLS measurements.

In vitro method to evaluate the barrier properties of medical devices for cutaneous use.

Barrier creams (BC) are marketed as cosmetic products or locally-applied medical devices to protect skin against damages induced by chemical agents or physical insults. However, the determination of the BC effectiveness is still a matter of discussion at both the clinical and the regulatory level. In this context, this work aimed at the development of a reliable, reproducible and easy-to-perform experimental protocol for the evaluation of BC performances. Preliminarily, an in vivo method based on the measurement of trans-epidermal water loss had been matter of investigation and was discarded: it required too much time and was not robust and sensitive enough. In vitro, reduction of the permeation of caffeine (used as a model of irritant), through an epidermal membrane mounted on a Franz cell or through a reconstructed 3D human epidermis model, was evaluated. Six BC among oil in water (O/W) or water in oil (W/O) creams were investigated with respect to the petrolatum, which is an efficient impermeable barrier against hydrophilic molecules. Despite minor differences, both methods could rate the effectiveness of the tested products in preventing caffeine exposure. Both methods enable to evaluate and quantify the BC effectiveness in a simple and fast manner. Their application may help regulatory agencies to prevent the marketing of ineffective products for the benefit of consumers.

Topical Treatment of Infantile Haemangiomas: A Comparative Study on the Selection of a Semi-Solid Vehicle.

BACKGROUND/AIM: Topical ß-blockers have recently been proposed as a valid alternative to oral drugs for treating cutaneous infantile haemangiomas, but clinical results in the literature are inconsistent due to the empirical choice of topical preparations. The current investigation aimed to rationalize the selection of a semi-solid vehicle for a locally applied drug product containing 1% w/w propranolol hydrochloride (PR-Cl). METHODS: A hydrophobic ointment of PR-Cl, two lipophilic creams, and a hydrophilic cream were prepared. In vitro release and skin permeation studies through human epidermis and full-thickness skin were performed by Franz diffusion cells. RESULTS: The overall results highlighted that PR-Cl was able to permeate the human epidermis, and its penetration pattern was strongly influenced by the composition of the semi-solid vehicle. PR-Cl release and permeation from lipophilic vehicles were extremely limited and influenced by their composition. Best results were obtained by using the hydrophilic cream. Furthermore, the retention study evidenced that epidermis acted as a reservoir, releasing the PR-Cl accumulated after preparation removal. CONCLUSION: The 1% w/w PR-Cl cream resulted the most suitable formulation for improving drug permeation through the human epidermis. On the contrary, the negligible permeation profile through full-thickness skin pointed out that PR-Cl cannot diffuse significantly to reach the deeper layers of human skin.

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.

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 NMP's amido group and the drug's 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.

Updating 'Data on the determination of human epidermis integrity in skin permeation experiments by electrical resistance' with Data on pig ear skin.

The data presented in this article are an update of the dataset provided by Musazzi et al. [1] and are related to the research article entitled "Equivalence assessment of creams with quali-quantitative differences in light of the EMA and FDA regulatory framework" [2]. In vitro permeation study (IVPT) is typically conducted using the method of Franz's diffusion cell for assessing the biopharmaceutical performance of topically applied products. While the human epidermis is considered the benchmark, various animal models (for instance, pig ear) have been accepted as a permeation membrane. Nonetheless, it is crucial to evaluate the integrity of the membrane to ensure the quality of the experiments. The methods employed for this assessment vary, and the outcomes are heavily reliant on the operational conditions, and the model membrane. The article contributes to the existing dataset by providing data on the electrical resistance values of pig ear skin samples and their correlation with the in vitro permeability fluxes of caffeine and benzoic acid. This data is utilized to determine a suitable cut-off for verifying the skin integrity of such an animal model. This information could be beneficial for facilitating critical or comprehensive analyses, contributing to the creation of a standard method.

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.

Marketing authorisations for unmet medical needs: A critical appraisal of regulatory pathways in the European Union.

For unmet medical needs, the European Union has established fast-track regulatory pathways for ensuring patients' access to essential treatments. It is the case of the Conditional Marketing Authorisation (CMA) and the Authorisation under "Exceptional Circumstances" (EXC), which can be granted even if the clinical part of a medicinal product's dossier is not yet complete. The article aims to discuss the peculiarity of such regulatory pathways and assess the impact of their application on products' market access and penetration. A review of the regulatory history of medicines authorised with EXC or CMA has been performed on European Institutional databases (e.g., EMA portal, Union Register). Excluding vaccines, 71 CMAs and 51 EXCs were granted in the EU from 2002 and 2006, respectively, to 2022. Most CMAs have been released for the treatment of different types of tumours, while most of EXCs for alimentary tract and metabolism diseases, especially in the paediatric population, addressing unmet medical needs. Therefore, both regulatory pathways are effective for placing on the market essential medicines, preserving the initial positive benefit-risk balance. However, on average, CMAs are converted into "normal" authorisations only after a time which is significantly longer than the provided one-year renewal period, suggesting that such a regulatory pathway is still far from optimized.

Feeding Next-Generation Nanomedicines to Europe: Regulatory and Quality Challenges.

New and innovative nanomedicines have been developed and marketed over the past half-century, revolutionizing the prognosis of many human diseases. Although a univocal regulatory definition is not yet available worldwide, the term "nanomedicines" generally identifies medicinal products that use nanotechnology in their design or production. Due to the intrinsic high structural complexity of these products, the scientific and regulatory communities are reflecting on how to revise the regulatory framework to provide a more appropriate benefit/risk balance to authorize them on the market, considering the impact of their peculiar physicochemical features in the evaluation of efficacy and safety patterns. Herein, a critical perspective is provided on the current open issues regarding regulatory qualification and physicochemical characterization of nanosystems considering the current European regulatory framework on nanomedicine products. Practicable paths for improving their quality assurance and predicting their fate in vivo are also argued. Strengthening the multilevel alliance among academic institutions, industrial stakeholders, and regulatory authorities seems strategic to support innovation by standard approaches (e.g., qualification, characterization, risk assessment), and to expand current knowledge, also benefiting from the new opportunities offered by artificial intelligence and digitization in predictive modelling of the impact of nanomedicine characteristics on their fate in vivo.

3D printed mucoadhesive orodispersible films manufactured by direct powder extrusion for personalized clobetasol propionate based paediatric therapies.

The aim of this work is the development and production by Direct Powder Extrusion (DPE) 3D printing technique of novel oral mucoadhesive films delivering Clobetasol propionate (CBS), useful in paediatric treatment of Oral Lichen Planus (OLP), a rare chronic disease. The DPE 3D printing of these dosage forms can allow the reduction of frequency regimen, the therapy personalization, and reduction of oral cavity administration discomfort. To obtain suitable mucoadhesive films, different polymeric materials, namely hydroxypropylmethylcellulose or polyethylene oxide blended with chitosan (CS), were tested and hydroxypropyl-ß-cyclodextrin was added to increase the CBS solubility. The formulations were tested in terms of mechanical, physico-chemical, and in vitro biopharmaceutical properties. The film showed a tenacious structure, with drug chemical-physical characteristics enhancement due to its partial amorphization during the printing stage and owing to cyclodextrins multicomponent complex formation. The presence of CS enhanced the mucoadhesive properties leading to a significant increase of drug exposure time on the mucosa. Finally, the printed films permeation and retention studies through porcine mucosae showed a marked retention of the drug inside the epithelium, avoiding drug systemic absorption. Therefore, DPE-printed films could represent a suitable technique for the preparation of mucoadhesive film potentially usable for paediatric therapy including OLP.

Liver injury and dietary supplements: Does hydroxycitric acid trigger hepatotoxicity?

Rising rates of obesity has increased the global use of herbal supplements intended to control weight. However, taking these preparations without appropriate medical supervision could increase the risk of manifestation of side effects, especially at the hepatic level. In literature, different cases of acute liver injury consequent to the use of food supplements containing Garcinia cambogia and hydroxycitric acid are reported. This letter aims to review the most recent literature that analysed the herb-induced liver disease due to the use of hydroxycitric acid, from the first alert coming from the European Food and Drug Administration in 2009, to the last recent European food alerts from 2020 to 2021. It is noteworthy that in some cases it demonstrated the relationship between hydroxycitric acid and hepatotoxicity. Therefore, there is a need to draw more attention to the relationship between a safe use and a more awareness in the intake of these supplements, to preserve the safety of the consumers who increasingly purchase food supplements, products that have only nutritive properties and are never curative.

Design and development of topical liposomal formulations in a regulatory perspective.

The skin is the absorption site for drug substances intended to treat loco-regional diseases, although its barrier properties limit the permeation of drug molecules. The growing knowledge of the skin structure and its physiology have supported the design of innovative nanosystems (e.g. liposomal systems) to improve the absorption of poorly skin-permeable drugs. However, despite the dozens of clinical trials started, few topically applied liposomal systems have been authorized both in the EU and the USA. Indeed, the intrinsic complexity of the topically applied liposomal systems, the higher production costs, the lack of standardized methods and the more stringent guidelines for assessing their benefit/risk balance can be seen as causes of such inefficient translation. The present work aimed to provide an overview of the physicochemical and biopharmaceutical characterization methods that can be applied to topical liposomal systems intended to be marketed as medicinal products, and the current regulatory provisions. The discussion highlights how such methodologies can be relevant for defining the critical quality attributes of the final product, and they can be usefully applied based on the phase of the life cycle of a liposomal product: to guide the formulation studies in the early stages of development, to rationally design preclinical and clinical trials, to support the pharmaceutical quality control system and to sustain post-marketing variations. The provided information can help define harmonized quality standards able to overcome the case-by-case approach currently applied by regulatory agencies in assessing the benefit/risk of the topically applied liposomal systems.

Considerations on D-mannose Mechanism of Action and Consequent Classification of Marketed Healthcare Products.

Urinary tract infections (UTIs) are very common disorders that affect adult women. Indeed, 50% of all women suffer from UTIs at least one time in their lifetime; 20-40% of them experience recurrent episodes. The majority of UTIs seems to be due to uropathogenic Escherichia coli that invades urothelial cells and forms quiescent bacterial reservoirs. Recurrences of UTIs are often treated with non-prescribed antibiotics by the patients, with increased issues connected to antibiotics resistance. D-mannose, a monosaccharide that is absorbed but not metabolized by the human body, has been proposed as an alternative approach for managing UTIs since it can inhibit the bacterial adhesion to the urothelium. This manuscript discusses the mechanisms through which D-mannose acts to highlight the regulatory aspects relevant for determining the administrative category of healthcare products placed on the market. The existing literature permits to conclude that the anti-adhesive effect of D-mannose cannot be considered as a pharmacological effect and, therefore, D-mannose-based products should be classified as medical devices composed of substances.

Pre-Drawn Syringes of Comirnaty for an Efficient COVID-19 Mass Vaccination: Demonstration of Stability.

Moving towards a real mass vaccination in the context of COVID-19, healthcare professionals are required to face some criticisms due to limited data on the stability of a mRNA-based vaccine (Pfizer-BioNTech COVID-19 Vaccine in the US or Comirnaty in EU) as a dose in a 1 mL-syringe. The stability of the lipid nanoparticles and the encapsulated mRNA was evaluated in a "real-life" scenario. Specifically, we investigated the effects of different storing materials (e.g., syringes vs. glass vials), as well as of temperature and mechanical stress on nucleic acid integrity, number, and particle size distribution of lipid nanoparticles. After 5 h in the syringe, lipid nanoparticles maintained the regular round shape, and the hydrodynamic diameter ranged between 80 and 100 nm with a relatively narrow polydispersity (<0.2). Samples were stable independently of syringe materials and storage conditions. Only strong mechanical stress (e.g., shaking) caused massive aggregation of lipid nanoparticles and mRNA degradation. These proof-of-concept experiments support the hypothesis that vaccine doses can be safely prepared in a dedicated area using an aseptic technique and transferred without affecting their stability.

Relevance of production method on the physical stability and in vitro biopharmaceutical performances of olanzapine orodispersible film.

This study assessed the relevance of the preparation process, namely solvent casting and hot-melt ram printing, on the biopharmaceutical performances of olanzapine orodispersible films (ODF) made of maltodextrins. Beside the clinical rationale, olanzapine was selected since it is subjected to polymorphism which impacts on its bioavailability. All ODF disintegrated in less than 3 min and showed content uniformity within the acceptable values. Dissolution testing in 3 mL of artificial saliva at pH = 6.8 evidenced that cast and printed ODF released after 5 min about 2% and 100%, respectively; at higher volume, a yellow precipitate was formed after disintegration of the cast ODF. At pH = 1.2, the t85% for cast ODF was reached after about 20 min and only the 90% olanzapine was dissolved increasing the pH to 6.8. These differences were explained by DSC, TGA and X-ray diffraction data which demonstrated that the casting method, which included the preparation of an aqueous slurry, favours the conversion from Form I to a hydrated one. Since extruded ODF resulted physically stable after 30 months, this suggests the potentiality of this technique to load in ODF drugs undergoing solid-state modification after exposure to aqueous media.

Trends in the Characterization Methods of Orodispersible Films.

The recent increased interest in orodispersible films (ODF) stems from their ideal potential to circumvent several pharmacotherapy-related problems, such as improved medication compliance and adherence, especially in children, elderly and uncooperative patients. Their administration is well accepted by the majority of patients because ODF dissolve upon contact with the saliva in the oral cavity without the need for water intake. ODF application in personalized pharmacotherapy is currently being exploited. Moreover, innovative preparation methods and characterization technologies have been evolving in recent years, highlighting a promising future both from the technological and clinical standpoints. However, the key obstacles to the attainment of full potential of ODF in the pharmaceutical field is the lack of harmonized and well-defined quality characterization procedures, standard evaluation parameters, guidance on appropriate final product properties and specifications. This review provides an appraisal on the ODF characterization methods from slurries to the finished medicinal products with a specific focus on the technologies suitable for identification, quantification, and quality evaluation of extemporaneously prepared ODF on small batches in individualized pharmacotherapy. Generally, there is a paradigm shift from the use of the conventional quality evaluation tools and/or protocols for oral solid dosage forms to characterize ODF to more specific equipment and procedures that suit the peculiarities of the ODF.

How Do Hospital Pharmacists Approach Substitution of Nanomedicines? Insights from a Qualitative Pilot Study and a Quantitative Market Research Analysis in Five European Countries.

We conducted research to assess hospital pharmacists' familiarity with/interpretation of data requirements for the different regulatory approval frameworks and the impact of this on their approach to substitution in the formulary. The online questionnaire included a small molecule (acetylsalicylic acid-follow-ons approved via the generic pathway), two biologic drugs (insulin glargine and etanercept-follow-ons approved via the biosimilar pathway), a non-biologic complex drug (NBCD; glatiramer acetate-follow-ons approved via the hybrid pathway) and a nanomedicine, ferric carboxymaltose (no follow-ons approved as yet). The study was conducted in two phases: an initial qualitative pilot study with 30 participants, followed by a quantitative stage involving 201 pharmacists from five European countries. Most expected negligible safety/efficacy differences between reference and follow-on products. Head-to-head clinical data showing therapeutic equivalence as a prerequisite for reference product/follow-on substitution was perceived to be needed most for biologics (47%), followed by NBCDs (44%)/nanomedicines (39%) and small molecules (23%). Overall, 28% did not know the data requirements for follow-on approval via the hybrid pathway; 16% were familiar with this pathway, compared with 50% and 55% for the generic and biosimilar pathways, respectively. Overall, 19% of respondents thought the European Medicines Agency (EMA) was responsible for defining the substitutability of follow-ons. Education is required to increase hospital pharmacist's knowledge of regulatory approval frameworks and their relevance to substitution practices.

Medical Device Development for Children and Young People-Reviewing the Challenges and Opportunities.

Development of specific medical devices (MDs) is required to meet the healthcare needs of children and young people (CYP). In this context, MD development should address changes in growth and psychosocial maturation, physiology, and pathophysiology, and avoid inappropriate repurposing of adult technologies. Underpinning the development of MD for CYP is the need to ensure MD safety and effectiveness through pediatric MD-specific regulations. Contrary to current perceptions of limited market potential, the global pediatric healthcare market is expected to generate around USD 15,984 million by 2025. There are 1.8 billion young people in the world today; 40% of the global population is under 24, creating significant future healthcare market opportunities. This review highlights a number of technology areas that have led to successful pediatric MD, including 3D printing, advanced materials, drug delivery, and diagnostic imaging. To ensure the targeted development of MD for CYP, collaboration across multiple professional disciplines is required, facilitated by a platform to foster collaboration and drive innovation. The European Pediatric Translational Research Infrastructure (EPTRI) will be established as the European platform to support collaboration, including the life sciences industrial sector, to identify unmet needs in child health and support the development, adoption, and commercialization of pediatric MDs.