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Interest in orodispersible films (ODF) is growing day-by-day, since this dosage form overcomes some therapeutic obstacles, such as impaired swallowing, and offers several benefits, ...such as the possibility to adapt the dosing requirements for a subset of patients. As a consequence, technologies to produce ODF have risen attention for possible applications in the development of patient-centric formulations. This review critically discusses current trends in the technology platforms proposed to manufacture ODF, including the innovation and opportunities to produce very small batches in a pharmacy setting. Although the main Pharmacopoeias recommend testing customized dosage forms for quality assurance, pharmaceutical assays are a matter of debate due to the complexity and high cost of conventional methods. Alternatively, non-disruptive online analytic methods can be proposed to assay ODF properties, above all to assure the uniformity of drug content.
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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.
•Orodisperisible dosage forms improve the patient’s compliance and/or adherence.•Bioavailability must take in consideration the possible pre-gastric absorption.•The EU and USA definitions and ...requirements should be harmonized.•The in vitro disintegration appears one of the most critical quality attributes.
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.
The technological and biopharmaceutical improvements of orodispersible dosage forms are reviewed in the light of regulatory requirements.
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Medicine shortages have been spreading in European countries. In many cases, the unavailability of medicinal products has a substantial impact on the capability of National Healthcare ...Systems in ensuring the continuity of care. Shortages originate from multifactorial causes. In particular, they can be due to supply-related factors (e.g., manufacturing issues, regulatory issues, logistics, distribution) and demand-related ones (e.g., fluctuating drug demand, parallel market, tendering, price and reimbursement policies). However, some extraordinary geopolitical events (e.g., Brexit) may also affect medicines’ availability. The capability of European Regulatory Authorities and other stakeholders, which are involved in the pharmaceutical distribution chain and the healthcare assistance services, to define suitable problem-solving strategies has been limited for years by the fragmentation of the European regulatory framework, starting from the lack of a univocal definition of a medicine shortage. Only in 2019, the EMA and HMA joint task force released the first harmonized “shortage” definition in the European Economic Area (EEA) and guidance on public communication. This manuscript aims to review the current European regulatory framework on medicine shortages. To support the activities of regulators, manufacturers and other healthcare professionals, an algorithm was also proposed to be used as a harmonized procedure to determine the shortage/unavailability impact on public health and to rationalize the problem-solving strategies adopted in all different settings.
Cannabidiol (CBD) is a non-psychoactive cannabinoid isolated from Cannabis sativa which, given its claimed beneficial properties and therapeutic potential, has lately aroused considerable attention ...from the scientific community. Starting from the little literature evidence, the main purpose of this study was to investigate the topical administration of CBD, with particular focus on the influence of vehicle-related aspects on the skin permeation process. This could provide useful information for the design of suitable drug delivery systems which could be used in developing topical medicines and cosmetics. In vitro human skin permeation studies were conducted using modified Franz diffusion cells to compare the performance of four solutions and two semisolid formulations. The Hildebrand solubility parameter was used to better understand the thermodynamic aspects implied in the partitioning process of the cannabinoid compound into the skin. It was interestingly found that a hydrophilic gel, mostly consisting of propylene glycol (79%,
/
), can be an optimal choice for the topical administration of CBD. Moreover, the feasibility of the preparation of CBD-loaded (trans)dermal patches, made with new printing technology, was also demonstrated.
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
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.
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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.
•European regulatory framework is very stratified and far to be consolidated.•EC definition of nanomaterials is not applicable to all healthcare products.•Nanomaterial characterization is limited by ...lack of validated analytical methods.•Safety assessment in cosmetics should exclude any internal exposure to nanomaterials.•Benefit/risk assessment of a medical device or nanomedicine is defined case-by-case.
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.
The review examines the stratified regulatory framework concerning the use of nanomaterials in healthcare products intended to be marketed in the European Economic Area, and highlights the current criticisms associated with the framework.
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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-β-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.
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•Water can induce polymorphic transition of olanzapine during the preparation of ODF.•Aqueous solubility of olanzapine hydrate is ten times lower than form I.•Hot-melting techniques ...assures olanzapine physical stability in ODF up to 30 months.
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.
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