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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.

The Sun cubE onE (SEE) is a 12U CubeSat mission proposed for a phase A/B study to the Italian Space Agency that will investigate Gamma and X-ray fluxes and ultraviolet (UV) solar emission to support studies in Sun-Earth interaction and Space Weather from LEO. More in detail, SEE's primary goals are to measure the flares emission from soft-X to Gamma ray energy range and to monitor the solar activity in the Fraunhofer Mg II doublet at 280 nm, taking advantage of a full disk imager payload. The Gamma and X-ray fluxes will be studied with unprecedented temporal resolution and with a multi-wavelength approach thanks to the combined use of silicon photodiode and silicon photomultiplier (SiPM) -based detectors. The flare spectrum will be explored from the keV to the MeV range of energies by the same payload, and with a cadence up to 10 kHz and with single-photon detection capabilities to unveil the sources of the solar flares. The energy range covers the same bands used by GOES satellites, which are the standard bands for flare magnitude definition. At the same time SiPM detectors combined with scintillators allow to cover the non-thermal bremsstrahlung emission in the gamma energy range. Given its UV imaging capabilities, SEE will be a key space asset to support detailed studies on solar activity, especially in relation to ultraviolet radiation which strongly interacts with the upper layers of the Earth's atmosphere, and in relation to space safety, included in the field of human space exploration. The main goal for the UV payload is to study the evolution of the solar UV emission in the Mg II band at two different time scales: yearly variations along the solar cycle and transient variations during flare events., 11 pages, 4 figures

ObjectivesRadiopharmaceuticals, since the discovery of the first medical application of radioactive isotope, have been essential therapeutics for the diagnosis and treatment of numerous diseases. Since the Directive 2001/83/EC entered in force, European regulatory authorities have established a harmonised framework to set quality requirements for the industrial production of radiopharmaceuticals. However, little is known about the harmonisation of extemporaneous preparation of radiopharmaceutical preparations (EPRPs) among European countries. In this context, this study aims to provide an overview of the national regulatory framework on the production of EPRPs of five European countries (i.e. UK, Spain, France, Germany and Italy).MethodsFive different national regulatory frameworks were compared based on the results of a literature search on electronic databases (i.e. PubMed, Google scholar).Key findingsUnlike industrially produced radiopharmaceuticals, the results highlighted that the regulatory framework on EPRPs is still not fully harmonised at the European level and many provisions are regulated by local national laws. Similarities and differences exist among the European countries, both regarding quality standards and educational courses the operators involved in the preparation of EPRPs have to attend.ConclusionsThe regulatory framework on the EPRPs is still not harmonised at the European level affecting the access to therapies of European citizens who are not equally guaranteed when an extemporaneous radiopharmaceutical has to be prepared to meet their needs.

The rising costs of new medicinal products are a challenge to the economic sustainability of national healthcare systems in ensuring patients' access to therapies. European Union (EU) and US legislators have provided regulatory pathways aimed at simplifying Marketing Authorization (MA) applications for new medicinal products in cases when safety and efficacy profiles can be derived from the data of already-marketed products. In this review, we discuss the different regulatory pathways towards the MA of new medicinal products containing old drug substances and intended to improve the therapeutic value of a treatment, to obtain a new therapeutic indication (drug repositioning), or to ensure the same therapeutic value of a reference product at lower costs.

Purpose To analyse the pattern of use and cost of antihypertensive drugs in new users in an Italian population, and explore the patient/treatment factors associated with the risk of therapy discontinuation. Patients and methods In this retrospective study, information was collected from a population-based electronic primary-care database. Persistence with medication use 1 year from therapy initiation was evaluated for each user using the gap method. Each new user was classified according to his/her pattern of use as: "continuer", "discontinuer" "switching" or "add-on". A Cox regression model was used to analyse the factors influencing therapy discontinuation. Primary-care costs comprised specialists' visits, diagnostic procedures and pharmacologic therapies. Results Among 14,999 subjects included in persistence analyses, 55.1% of cases initially started on monotherapy were classified as discontinuers vs 36.5% of cases taking combination therapy (42.3% vs 32.7%, respectively, for free and fixed combinations, P < 0.01). Old age, high cardiovascular risk and being in receipt of fixed-combination therapy were associated with greater persistence. Overall, the primary-care cost/person/year of hypertension management was ~€95.3 (IQR, 144.9). The monotherapy cost was €88 per patient (IQR, 132.9), and that for combination therapy was €151±148.3. The median cost/patient with a fixed combination was lower than that for a free combination (€98.4 (IQR, 155.3) and €154.9 (IQR, 182.6), respectively). Conclusion The initial type of therapy prescribed influences persistence. Prescribing fixed combinations might be a good choice as initial therapy.

The drying of biodegradable polymeric nanoparticles (NP) is mandatory to improve their physical and chemical stability over time. Spray- or freeze-drying can induce irreversible aggregation of NP and, therefore, the use of drying auxiliary agents is required. The ability of four grades of maltodextrins differing in dextrose equivalent (DE) (i.e. DE2, DE6, DE12 and DE38) to protect PLGA NP from stresses was studied. High Mw maltodextrin (DE2) was not functional for obtaining an easily resuspendable dried product, since it needs a prolonged time to fully hydrate. Maltodextrins at intermediate DE showed a poor ability to protect NP from irreversible aggregation probably because too sensitive to environmental variation. DE38, which did not alter ζ-potential of NP, allowed to obtain an easily resuspendable nanosuspension independently of the drying process. The effectiveness of such material was attributed to the easiness of spray-dry a low viscous solution and to the ability of substitute the water molecules’ hydrogen bonds with NP during freeze-drying.

Upper gastrointestinal (GI) symptoms are usual complaints among patients presenting to Italian community pharmacies. However, information on treatment history of those patients is often lacking. This descriptive, cross-sectional study aims at exploring the medication history of individuals with upper GI tract symptoms visiting one of the 20 enrolled community pharmacies, over a period of 7 months, based on the administration of a questionnaire. Of 1,020 interviewees, 62.1% had asked for a medical consultation. The most frequent symptom was epigastric burning (31.8%), followed by acid regurgitation (14.6%) and post-prandial fullness (12.0%). Of the 1,609 therapies, proton pump inhibitors constituted the most represented therapeutic class (35.6%) followed by antacids (17.5%) and alginate-based products (17.2%). In treating symptoms, 38.1% of the patients do not seek medical advice, while 42.0% rely on non-prescription therapies. As findings suggest, support to patients with GI disorders in community pharmacies can be enhanced for a safer self-medication.

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 [TiOThis is a proof-of-concept of the feasibility to print ODF loaded with a thermosensitive drug substance by hot-melt technologies.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,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 (Hot-melt printing can be suitable to prepare palatable ODF loaded with bitter thermosensitive drugs.

Graphical abstract 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.

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.

The paper entitled “Mucoadhesive Budesonide Formulation for the Treatment of Eosinophilic Esophagitis Pharmaceutics 2020, 12, 211” discusses the physicochemical and technological characterization of a formulation to treat eosinophilic esophagitis [...]

Background: Low back pain (LBP) is one of the most frequent diseases for which patients seek advice in a community pharmacy. The study aimed to evaluate the feasibility of the administration by community pharmacists of questionnaires to assess the LBP intensity and disability degree in patients entering community pharmacies and the attitudes they have toward pain management by pharmacological and non-pharmacological strategies. Methods: An explorative, cross-sectional, observational, and quantitative study was performed. Twelve Italian community pharmacists were asked to submit a questionnaire on LBP to patients visiting their pharmacies. The questionnaire included a pain intensity scale, and two validated tools: the Roland and Morris Disability Questionnaire (RMDQ) and the Start Back Screening Tool (SBST) to determine the degree and risk of patient disability, respectively. Results: 872 patients filled out the questionnaires in 6 months. No statistical differences between genders (p &gt, 0.30) were recorded for pain intensity (Female: median score 6, IQR 4&ndash, 7, Male: median scores 5, IQR 4&ndash, p &gt, 0.30) and disability associated with LBP (RMDQ high-disability level: Females, 14.7%, Males, 15.0%, 0.90). Most of the patients (69%) reported a low degree of disability, but the risk of disability was medium and high in 36% and 18% of them, respectively (p &lt, 0.05). About 14% of patients declare to never seek for physician&rsquo, s advice despite their medium-high degree of disability. Conclusion: The study demonstrated the feasibility of validated tools for assessing the degree and risk of disability in LBP patients administrable in community pharmacies. Moreover, the community pharmacy resulted in an important care portal for patients suffering from moderate LBP and for intercepting patients who suffered from severe LBP but had never reported their problem to their physician.

The COVID-19 outbreak is now one of the most critical crises to manage for most of the national healthcare systems in the world. In the absence of authorised pharmacological treatments, many antiretrovirals, including darunavir/cobicistat fixed combination, are used off-label in the hospital wards as life-treating medicines for COVID-19 patients. Unfortunately, for most of them, the drug products available on the market are not designed to be administered by a nasogastric tube to inpatients of intensive care units. Therefore, their manipulation, even if it can strongly affect the product quality, is necessary for the preparation of suspension to meet patients' need. In this situation, it is urgent to provide data and guidance to support hospital pharmacists and clinicians in their activity. The data in this article indicate that darunavir/cobicistat suspensions compounded by pharmacists using as active ingredient a commercially available tablet can be stable at least for one week.

Tattoo prevalence has been increasing in the last 25 years, but specific regulations on tattoo inks are still missing. In the European Union, no supranational regulation is available and only few national provisions cover them. In the United States, tattoo inks are classified as cosmetics but are not approved for injection into the dermis. Health risks for consumers may derive from microbiological contamination and the presence of toxic substances or nanomaterials. However, current regulations and non-binding recommendations, where present, only address the microbiological and chemical risks, completely overlooking nanotoxicity. The aim of this paper is to promote awareness of the risks associated with tattoo inks and the nanomaterials contained therein. In particular, the need for a harmonised regulation or, at least, a set of minimal requirements is highlighted to improve the safety of tattoo inks and market surveillance by regulatory authorities.

The experience gained with biosimilars has made it clear that copies of complex drugs are more challenging to produce and put on the market than generics. In the case of so-called nonbiological complex drugs (NBCDs), the complexity can arise either from a complex active substance or by other factors, such as formulation or route of delivery. Regulatory policies in the USA and the EU for the marketing of NBCD copies are reviewed, using glatiramer acetate copies as a case study. In the USA, they are approved and marketed as generics (although needing additional data), and so they are interchangeable with the originator. In the EU, they are managed with a hybrid application, and their interchangeability and substitution are established by individual member states.

Graphical abstract, 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.

Background and importance Medicine shortages in Italy are an increasing phenomenon with significant impact on clinical activity. Aim and objectives The aim of the study was to analyse the phenomenon, creating monitoring methods that can support the health workers (HW) involved in the problem. Material and methods The hospital pharmacy (HP) developed a survey for HW, aimed at determining which types of drugs are most subject to unavailability, incidence and average duration of the phenomenon, approach used in managing any criticality and the impact on clinical practice. Results A total of 59 HW from 14 different departments were interviewed. The classes of drugs reported most were: antibiotics (38.0%), corticosteroids (10.6%), gastroprotectors (8.8%), antihypertensives (7.1%), benzodiazepines and psychostimulants (5.2%), nutritional agents (4.4%), antihistamines (4.4%), blood products (3.5%), biologicals (2.6%) and others (14.8%). In 88% of the shortages, at least one medicine in the reference period (12 months) was reported, with an average duration of 2–8 weeks. Thirty-four per cent of respondents stated that the shortage of drugs had a negative impact—namely, the effect was perceived as very relevant in 5.9% of reporter cases since HW had to wait for the Italian Medicines Agency Nulla Osta for parallel importation; and relevant in 41.2% of cases, as HW had to wait for the HP to obtain supplies. In the remaining 52.9%, the impact was judged to be minor due to the presence of alternative therapeutic solutions. Specifically, in 11.4% of cases, a generic medicine was prescribed, based on the same active substance (AS) but with a different pharmaceutical form (8.6%) or different dosage (14.3%), and in the remaining 65.7% a medicine contained a different AS. The 17% of HW stated that the deficiency had never been solved, as in the case of oxacillin 1 g vials, ceftazidime 2 g vials, lysine acetylsalicylate 500 mg vials and danazol 200 mg tablets. Conclusion and relevance The data collected confirm that the phenomenon of shortages is growing, highlighting the classes of medicines that are to be monitored to prevent the phenomenon. The tool used may be useful for improvement of the activity and efficiency of HP, with the aim of reducing the negative effects on daily clinical activity through constant comparisons between HW and HP. References and/or acknowledgements No conflict of interest.

Transdermal patches and medicated plasters are designed to sustain efficacious systemic or loco-regional drug concentrations, respectively. In both cases, drug skin permeation is a critical attribute from the early stage of the pharmaceutical development. In 2014, the EMA introduced the "Guideline on the quality of transdermal patches", in which the importance of equivalence of drug fluxes in in vitro skin permeation study was particularly emphasized to generic or abridged applications for the marketing authorization or manage dossier variations during the product cycle life. Moving from experimental data, this work provides information on the set-up of such studies and the statistical evaluation of obtained fluxes. In particular, the impact of the inter-sample variability on the equivalence assessment was deeply investigated by using formulation pairs containing propranolol, diclofenac or nitroglycerine. The main outputs of the work were attributable to the definition of the acceptability interval and number of replicates to be performed. As an example, the equivalence of two propranolol patches (flux variability lower than 25%) can be assessed using six replicas and a confidence limit within the 0.8–1.25 range (α = 0.05; power 90%). In contrast, the equivalence of diclofenac plasters, which exhibit a variability near the 50%, can be demonstrated increasing the number of replicas (i.e., 20 skin samples) for each formulation and widening the acceptance range according to the statistical approach proposed in the work.

The data presented in this article are related to the research article entitled “Design of in vitro skin permeation studies according to the EMA Guideline on quality of transdermal patches” (https://doi.org/10.1016/j.ejps.2018.09.014) (Cilurzo et al., 2018) [1]. In vitro permeation studies are generally carried out by Franz’s diffusion cell method using human epidermis as a membrane (Franz, 1975) [2]. The evaluation of membrane integrity is mandatory to assure the quality of the experiments. However, the methods used for this determination are different and the results are strictly dependent on the operative conditions. The article reports the electrical resistance values of human epidermis samples and in vitro skin permeability data of caffeine and benzoic acid. The data are used to establish a cut-off suitable for checking the skin integrity. This information may be useful to enable critical or extended analyses in order to contribute to the development of a compendial method.

Background The medicines’ shortage has arisen as a global crisis, which jeopardizes the continuity of care and overloads pharmacists and healthcare professionals. Purpose The paper aims 1) to determine the therapeutic classes mostly affected by shortages in pre-COVID scenario and investigate their impact; 2) to collect the perception of physicians and nurses on shortages to assess the effect on clinical practice and to improve interprofessional collaboration. Methods A 16-question survey developed by hospital pharmacists was administered to physicians and nurses at Presidio Ospedaliero Luigi Sacco in Milan (Italy). Discussion A total of 148 medicinal products were reported as unavailable by 58 interviewees. Since in 66% of cases therapeutic alternatives were available, healthcare professionals did not perceive them as so critical since effect on patients can be mitigate by effective interprofessional collaboration. Conclusion Risk assessment and management of shortages should be based on a bottom-up approach that takes in consideration the ward operability and the perception of healthcare professionals.

Topical propranolol has been used in clinics for treating cutaneous infantile haemangiomas, but frequent applications of semi-solid preparations are required to maintain therapeutic drug concentrations in the skin layers over time. This work aims to study the preparation of cutaneous propranolol patches by hot-melt ram extrusion printing, a novel technique suitable for the personalization of the dosage forms. The preparation steps are: i) mixing of a poly-ammonium methacrylate polymer (Eudragit RL) with a suitable amount of plasticizer [acetyl triethyl citrate (ATEC), triacetin or tributyl citrate, TBC] and the drug (propranolol base, or hydrochloride), ii) the melting in the ram extruder, and iii) the printing on the backing layer foil. All formulations released the loaded drug in a reasonable time and exhibited suitable adhesive properties. The determination of permeation profiles of the drug revealed the patch made of Eudragit RL and TBC and containing 1% propranolol hydrochloride as the most promising formulation for ensuring the drug retention on the human epidermis (Qret/J = 1.32) and, therefore, it can be selected when a superficial haemangioma has to be treated. Conversely, the patch made of Eudragit RL and ATEC and 1% propranolol base can be used in the case of deep haemangiomas.

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.

Recently, an increasing number of pharmacists had to supply medicinal products based on Cannabis sativa L. (Cannabaceae), prescribed by physicians to individual patients. Cannabis olive oil preparation is the first choice as a concentrated extract of cannabinoids, even though standardized operative conditions for obtaining it are still not available. In this work, the impact of temperature and extraction time on the concentration of active principles was studied to harmonize the different compounding methods, optimize the extraction process, and reduce the variability among preparations. Moreover, starting from the cannabis inflorescence, the effect of temperature on tetrahydrocannabinolic acid decarboxylation was evaluated. For the analysis, a GC/MS method, as suggested by the Italian Ministry of Health, and a GC/flame ionization detection method were developed, validated, and compared.

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.

A film forming system based on Eudragit ® RL (EuRL) was designed aiming to evidence the relevance of formulative variables on the following critical attributes: film forming rate, outward stickiness, Young modulus ( Y ) and in vitro drug skin permeation. Different solvent mixtures (acetone and isopropanol in the range from 10:90 to 40:60 v/v), polymer concentrations (10–30% w/w), and plasticizer types and concentrations (triacetin or tributyl citrate, up to 50% of EuRL) were evaluated. EuRL dissolved in 80/20 or 70/30 v/v isopropanol/acetone mixtures at the concentration of 20% and plasticized with tributyl citrate (20 or 30% with respect to polymer) gave films with negligible stickiness and Y lower than 3 MPa. This value should assure an intimate and prolonged contact with the skin since it was significantly lower than Y of human stratum corneum (55 MPa). The optimized formulations were able to sustain the skin permeation of ibubrofen, ketoprofen and flurbiprofen and evidenced the importance of each formulative variable. In particular, relatively slow solvent evaporation rate can determine an initial “burst” effect and can influence the drug permeation in the initial hours. Conversely, when the solvent evaporation rate is not discriminant, the thermodynamic activity remains the main parameter driving the skin permeation.

Transdermal administration can solve the biopharmaceutical issues of several drugs, thereby improving patient compliance. Nevertheless, overcoming the skin barrier is not an easy task. In the past years, high expectations for nanotechnologies have been raised. In particular liposomes have been the most investigated carriers because of the composition that resembles that of the extracellular environment of the stratum corneum. This chapter provides a brief description of the skin architecture and the main limits of transdermal drug delivery. Then the use and the potentialities of all classes of lipid vesicles developed as carriers for cutaneous application are discussed. Finally the main clinical outcomes of the studies on these nanocarriers are reviewed focusing on the products that really reached the pharmaceutical market.

Medication adherence is a growing concern for public health and poor adherence to therapy has been associated with poor health outcomes and higher costs for patients. Interventions for improving adherence need to consider the characteristics of the individual therapeutic regimens according to the needs of the patients. In particular, geriatric and paediatric populations as well as dermatological patients have special needs/preferences that should be considered when designing drug products. Patient Centric Drug Product Pharmaceutical Design (PCDPD) offers the opportunity to meet the needs and preferences of patients. Packaging, orodispersible formulations, fixed dose combinations products, multiparticulate formulations, topical formulations and 3D printing are of particular relevance in a PCDPD process. These will be addressed in this review as well as their impact on medication adherence.

The COVID-19 outbreak is now one of the most critical crises to manage for most of the national healthcare systems in the world. The situation has been complicated by the absence of a vaccine and authorised pharmacological treatments, except for remdesivir. In this context, many medicaments, including different Ebola or HIV antivirals, are used off-label in the hospital wards as life-treating medicines for COVID-19 patients. Authorized medicaments manipulation is sometimes necessary because they are not always formulated to be administered to non-cooperative patients or they are in shortage. It is this the case of the fixed combination of lopinavir/ritonavir, which was extensively used in the first phase of the outbreak inducing a shortage of the oral solution available in the EU market as an oral liquid solution and. Unfortunately, the increased worldwide demand and the reduced goods movements are causing the shortage of the liquid solution. This work provides data on size distribution, osmolarity other than drug chemical stability of a lopinavir/ritonavir extemporaneous preparation prepared by using as drug source the solid dosage form (i.e., tablet) available on the market. The reported data indicate that such preparation is suitable to be delivered through a nasogastric tube, and enough stable for two weeks from the preparation at room temperature.

To assure the safety and the efficacy of a medicinal product, quality and batch-to-batch reproducibility need to be guaranteed. In the case of parenteral long-acting products, the European Union (EU) and US Regulatory Authorities provide different indications, from the classification to the in vitro release assays related to such products. Despite their relevance, there are few in vitro experimental set-ups enabling researchers to discriminate among products with different in vivo behaviors. Consequently, most copies are authorized through hybrid instead of generic applications. Here, we review the actual regulatory frameworks to evaluate the in vitro release of drugs from polymer-based long-acting parenterals to highlight the directions followed by the Regulatory Agencies in the USA and EU.

Background Orodispersible films (ODF) have been proposed as a valid alternative to conventional oral dosage forms to personalise the therapies and to improve patient adherence, especially in special populations (e.g., dysphagics, paediatrics, geriatrics). Since manufacturing technologies used by the industries (e.g., the solvent-casting technique) cannot be easily applied in a pharmacy setting, alternative methods have been proposed for compounding. 3D-printing permits the preparation of ODF of different strengths and geometries that fulfil the Ph.Eur. specifications concerning the uniformity of dosage units. Purpose To demonstrate the feasibility of the preparation of ODF by hot-melt ram extrusion 3D printing.1 Material and methods This novel technology consists of three simple operations. First, maltodextrins, drug and other excipients (e.g., colourants, flavours, sweeteners) are mixed in a mortar and wetted with the plasticiser (i.e., glycerine). Then, the mixture is fed into the chamber of the ram-extruder and heated. ODF are individually printed using an 18G needle on the packaging material foil and sealed without further manipulation. The critical formulation attributes and process variables were investigated to define the processability space and their impact on the disintegration time and tensile properties of the ODF. The paracetamol (PAR) was used as a model drug to assess the drug-loading capacity of the ODF and the dissolution profile. Results Preliminary results allowed to the optimization of the process parameters (heating temperature, 85°C; maximum print rate, 50 mm/s; filling angle, 120°) and composition (maltodextrins/glycerine: 80/20 w/w) to obtain homogeneous ODF. The compounded ODF (6 cm2; thickness 150–250 µm) disintegrated in less than 1 min and showed acceptable tensile properties for product handling. Different doses of PAR (12.5, 25, 37.5% w/w) were loaded to such basic composition without altering the ODF performances. The CV% of PAR assay remains lower than 5%. The PAR dissolution profile of printed ODF (t80 Conclusion The overall results suggested that hot-melt ram extrusion 3D printing can be used in a pharmacy setting to prepare well-accepted orodispersible dosage forms and to personalise the drug dose according to the needs of the patient. Reference and/or acknowledgements Musazzi, et al. Int J Pharm 2018;551:52–9. No conflict of interest.

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.

Atrial fibrillation (AF) is the most common heart arrhythmia. It is associated with an increased risk of morbidity and mortality and its prevalence rises with age. The arrhythmia is often asymptomatic, and systematic AF screening could help identify asymptomatic individuals to implement therapeutic and preventive strategies. The main study aims were to test the technical feasibility and citizens’ acceptance of a freely offered service in older people using community pharmacies. During 2 months, a 30-s single-lead electrocardiogram (ECG) with a telemedicine device was used for screening in 20 pharmacies in a mixed rural–urban health district of Northern Italy. A total of 289/335 older adults 70 years old or more agreed to participate in the study. A cardiologist considered 80% of the ECG tracings readable and unknown AF was identified in 1.3%. The screening scheme appears technically feasible and acceptable both to professionals and citizens/participants. Training the pharmacists could ensure broader participation and substantially improve the pharmacies’ overall performance.

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.

Pharmaceutical compounded medicinal preparations are aimed to fulfill the special needs of a subpopulation of patients for whom a medicinal product is not commercially available. Nowadays, this activity remains an important component of pharmacy practice and an integral part of the modern healthcare system. In 2011, the Committee of Ministers of the Council of Europe adopted a resolution to harmonize quality assurance and safety standards for medicinal products prepared in pharmacies for the special needs of patients in European countries. This article discusses the actual rules and technical norms that regulate the compounding activity in Italy in the light of the new European laws.

Full dataset used to evaluate the spray-drying process parameters on the preparation of a micronized powder made of maltodextrin (MDX) is herein reported. The process parameters (namely, feed flow rate (FFR); inlet temperature (Tin); nozzle pressure (PN); noozle diameter (DN) and difference of pressure between cyclone and chamber (ΔP)) were screened through a Central Composite Design (25−1; 2∗5; nC=2) using the following responses: product yield, powder size and size dispersity (span) and the outlet temperature of the exhausted air (Tout). Data indicate that, in the considered range, only the product yield and the powder median diameter were influenced by the process. The product yield progressively increased on increasing inlet temperature and decreasing the amount or the size of droplets to be dried. The powder median diameter was positively influenced only by the nozzle diameter. This data presented in this article completes a wider work related on “Maltodextrins as drying auxiliary agent for the preparation of easily resuspendable nanoparticles” (Magri et al., 2019). Keywords: Spray-drying, Maltodextrins, Process optimization

Chlorhexidine (CLX) is a wide spectrum cationic antimicrobial used for prevention and treatment of infections of buccal and vaginal cavities. To increase the residence time of CLX-based formulations at the application site and consequently reduce the daily dose frequency, new formulations composed of mucoadhesive polymers should be designed. The objective of this work was the development of matrices based on polyanionic polymers, such as sodium alginate, carboxymethylcellulose, xanthan gum and sodium hyaluronate, aimed to prolong the local release of CLX into the buccal or vaginal cavity. Matrices were prepared by freeze-drying and comply with 2 different preparative methods and characterized in terms of resistance to compression, water uptake ability, mucoadhesion, in vitro drug release behavior and antimicrobial activity toward representative pathogens of buccal and vaginal cavities. Results showed that the selection of suitable polymers associated to the adequate preparative method allowed to modulate matrix ability to hydrate, adhere to the mucosa and release the drug as well as to exert antimicrobial activity. In particular, matrix based on sodium hyaluronate was found to be the best performing formulation and could represent a versatile system for local release of CLX with potential application in both buccal and vaginal cavities.

An innovative delivery system for melatonin, based on the incorporation of solid lipid microparticles in orodispersible films (ODFs) made of maltodextrin, was designed and developed. Lipid microparticles at two different melatonin concentrations (10 and 20% w/w) were produced by the spray congealing technology using two different lipid carrier (tristearin and hydrogenated castor oil) and characterized in terms of size, solid state, drug loading and drug release pattern. Tristearin microparticles were discarded due to a polymorphic modification of the carrier. The incorporation of hydrogenated castor oil microparticles in ODFs by using the casting method did not alter significantly the shape and dimension of the microparticles and the mechanical properties (elasticity and strength) of the films, which remained acceptable for manufacturing and handling. The in vitro release studies performed in saliva, gastric and intestinal simulated media on ODFs containing melatonin loaded in hydrogenated castor oil microparticles revealed the possibility to combine with an immediate release of the drug and a sustained release over at least 5 h period. In conclusion, the proposed drug delivery system maintains the advantages of ODFs, i.e. the suitability to be swallowed without water, and permits the tuning of drug release according to the clinical needs by modulating the ratio of free and microencapsulated drug in the ODF.

Complex drugs may be either biological, if the active ingredients are derived from a biological source, or non-biological, if obtained by chemical synthesis. In both cases, their quality depends considerably on the manufacturing process. In the case of Non Biological Complex Drugs (NBCDs), complexity may arise either from the active substance, as in the case of glatiramer acetate, or from other sources, such as the formulation, as in the case of liposomes. In this paper, the case of glatiramer acetate (GA) - a NBCD relevant for clinical and economic reasons - is considered and the differences between US and EU regulatory approaches to GA marketing authorization are highlighted. Indeed, though US and EU regulatory agencies have chosen a generic approach integrated with additional data the implementation is different in the two jurisdictions. In the US, the additional data required are listed in a product specific guideline and copies of Copaxone® have been approved as generics. In the EU, instead regulatory agencies followed a hybrid approach requiring an additional comparative study, and interchangeability policies and substitution schemes have been left to national agencies.