Blind Spots in Development of Nanomedicines.

The field of nanomedicine demonstrates immense advantages and noteworthy expansion compared to conventional drug delivery systems like tablet, capsules, etc. Despite the innumerable advantages, it holds certain shortcomings in the form of blind spots that need to be assessed before the successful clinical translation. This perspective highlights the foremost blind spots in nanomedicine and emphasizes the challenges faced before the entry into the market, including the need for provision of safety and efficacy data by the regulatory agencies like FDA. The significant revolution of nanomedicine in the human life, particularly in patient well-being, necessitates to identify the blind spots and overcome them for effective management and treatment of ailments.

Unveiling the synergy: a combined experimental and theoretical study of ß-cyclodextrin with melatonin.

Melatonin (MT) is a vital hormone controlling biorhythms, and optimizing its release in the human body is crucial. To address MT's unfavorable pharmacokinetics, we explored the inclusion complexes of MT with ß-cyclodextrin (ß-CD). Nano spray drying was applied to efficiently synthesize these complexes in three molar ratios (MT : ß-CD = 1 : 1, 2 : 1, and 1 : 2), reducing reagent use and expediting inclusion. The complex powders were characterized through thermal analyses (TGA and DSC), Fourier transform infrared spectroscopy (FTIR), and in vitro MT release measurements via high-performance liquid chromatography (HPLC). In parallel, computational studies were conducted, examining the stability of MT : ß-CD complexes by means of unbiased semi-empirical conformational searches refined by DFT, which produced a distribution of MT : ß-CD binding enthalpies. Computational findings highlighted that these complexes are stabilized by specific hydrogen bonds and non-specific dispersive forces, with stronger binding in the 1 : 1 complex, which was corroborated by in vitro release data. Furthermore, the alignment between simulated and experimental FTIR spectra demonstrated the quality of both the structural model and computational methodology, which was crucial to enhance our comprehension of optimizing MT's release for therapeutic applications.

Enhancing Vitamin D3 Efficacy: Insights from Complexation with Cyclodextrin Nanosponges and Its Impact on Gut-Brain Axes in Physiology and IBS Syndrome.

Vitamin D3 (VitD3) plays a crucial role in various cellular functions through its receptor interaction. The biological activity of Vitamin D3 can vary based on its solubility and stability. Thus, the challenge lies in maximizing its biological effects through its complexation within cyclodextrin (ßNS-CDI 1:4) nanosponges (NS) (defined as VitD3NS). Therefore, its activity has been evaluated on two different gut-brain axes (healthy gut/degenerative brain and inflammatory bowel syndrome gut/degenerative brain axis). At the gut level, VitD3-NS mitigated liposaccharide-induced damage (100 ng/mL; for 48 h), restoring viability, integrity, and activity of tight junctions and reducing ROS production, lipid peroxidation, and cytokines levels. Following intestinal transit, VitD3-NS improved the neurodegenerative condition in the healthy axis and the IBS model, suggesting the ability of VitD3-NS to preserve efficacy and beneficial effects even in IBS conditions. In conclusion, this study demonstrates the ability of this novel form of VitD3, named VitD3-NS, to act on the gut-brain axis in healthy and damaged conditions, emphasizing enhanced biological activity through VitD3 complexation, as such complexation increases the beneficial effect of vitamin D3 in both the gut and brain by about 50%.

Preliminary assessment of environmental safety (ecosafety) of dextrin-based nanosponges for environmental applications.

The ability to employ waste products, such as vegetable scraps, as raw materials for the synthesis of new promising adsorbing materials is at the base of the circular economy and end of waste concepts. Dextrin-based nanosponges (D_NS), both cyclodextrin (CD) and maltodextrin (MD), have shown remarkable adsorption abilities in the removal of toxic compounds from water and wastewater, thus representing a bio-based low-cost solution which is establishing itself in the market. Nevertheless, their environmental safety for either aquatic or terrestrial organisms has been overlooked, raising concern in terms of potential hazards to natural ecosystems. Here, the environmental safety (ecosafety) of six newly synthesized batches of D_NS was determined along with their full characterization by means of dynamic light scattering (DLS), thermogravimetric analysis (TGA), Fourier transformed infrared spectroscopy with attenuated total reflection (FTIR-ATR) and transmission electron microscopy (SEM). Ecotoxicity evaluation was performed using a battery of model organisms and ecotoxicity assays, such as the microalgae growth inhibition test using the freshwater Raphidocelis subcapitata and the marine diatom Dunaliella tertiolecta, regeneration assay using the freshwater cnidarian Hydra vulgaris and immobilization assay with the marine brine shrimp Artemia franciscana. Impact on seedling germination of a terrestrial plant of commercial interest, Cucurbita pepo was also investigated. Ecotoxicity data showed mild to low toxicity of the six batches, up to 1 mg/mL, in the following order: R. subcapitata > H. vulgaris > D. tertiolecta > A. franciscana > C. pepo. The only exception was represented by one batch (NS-Q+_BDE_(GLU2) which resulted highly toxic for both freshwater species, R. subcapitata and H. vulgaris. Those criticalities were solved with the synthesis of a fresh new batch and were hence attributed to the single synthesis and not to the specific D_NS formulation. No effect on germination of pumpkin but rather more a stimulative effect was observed. To our knowledge this is the first evaluation of the environmental safety of D_ NS. As such we emphasize that current formulations and exposure levels in the range of mg/mL do not harm aquatic and terrestrial species thus representing an ecosafe solution also for environmental applications.

Antidiabetic Therapy during Pregnancy: The Prescription Pattern in Italy.

Pregestational and gestational diabetes mellitus are relevant complications of pregnancy, and antidiabetic drugs are prescribed to obtain glycemic control and improve perinatal outcomes. The objective of this study was to describe the prescription pattern of antidiabetics before, during and after pregnancy in Italy and to evaluate its concordance with the Italian guideline on treatment of diabetes mellitus. A multi-database cross-sectional population study using a Common Data Model was performed. In a cohort of about 450,000 women, the prescribing profile of antidiabetics seemed to be in line with the Italian guideline, which currently does not recommend the use of oral antidiabetics and non-insulin injection, even if practice is still heterogeneous (up to 3.8% in the third trimester used oral antidiabetics). A substantial variability in the prescription pattern was observed among the Italian regions considered: the highest increase was registered in Tuscany (4.2%) while the lowest was in Lombardy (1.5%). Women with multiple births had a higher proportion of antidiabetic prescriptions than women with singleton births both in the preconception period and during pregnancy (1.3% vs. 0.7%; 3.4% vs. 2.6%) and used metformin more frequently. The consumption of antidiabetics in foreign women was higher than Italians (second trimester: 1.8% vs. 0.9%, third trimester: 3.6% vs. 1.8%).

Effectiveness of different local actions to control vitamin D prescription in Italy.

INTRODUCTION: In the last decade, the significant expenditure and consumption increase of vitamin D in Italy led some regions to adopt strategies to improve prescribing appropriateness and contain expenditure. MATERIALS AND METHODS: Using the statistical analysis method of interrupted time series for consumption and expenditure of cholecalciferol, different types of interventions adopted in four Italian regions and their efficacy were evaluated. RESULTS: Molise achieved the best results by adopting a health professionals' education program in addition to a prescriber-sanction system. Emilia-Romagna also opted for a medical education strategy, but the results were less relevant due to the lack of penalties. Lazio obtained a slowdown in consumption growth by targeting on the utilization of lower-cost per defined daily dose (DDD) packs and adopting a therapeutic plan. Sardinia showed a decrease in expenditure by adopting a target threshold of lower-cost formulation. CONCLUSION: The reimbursement of the lowest-cost packs within the National Health Service (NHS) undoubtedly influences spending trend, but it does not solve prescriptive inappropriateness.

Financial Outcomes of Managed Entry Agreements for Pharmaceuticals in Italy.

Importance: Most countries in the Organisation for Economic Co-operation and Development apply managed entry agreements (MEAs), reimbursement arrangements between manufacturers and payers, to pharmaceuticals. Few data exist regarding their ability to lower expenditures. Objective: To analyze the financial outcomes of MEAs for pharmaceuticals from 2019 to 2021 in Italy. Design, Setting, and Participants: In this observational study of MEAs and pharmaceutical spending in Italy, medications that were monitored through individually collected data and generated paybacks from manufacturers during the 2019 to 2021 study period were included in the analysis. Payback data were collected through pharmaceutical spending monitoring activities conducted by the Agenzia Italiana del Farmaco (Italian Medicines Agency). Expenditure data were collected through the Italian Drug Traceability System. Products were categorized by type of MEA: financial-based, outcome-based, or mixed. Main Outcomes and Measures: The main outcome was median payback as a proportion of expenditure by category of MEA. Results were also provided by subtype: cost sharing or capping models for financial-based MEAs and risk-sharing or payment-by-result models for outcome-based MEAs. Mixed MEAs were considered when medications had multiple indications with different MEA types. Results: A total of 73 medications with MEAs generated a payback by manufacturers during the study period. Six were either not reimbursable or delivered within the Italian National Health Service, and 5 had incomplete data. Of the 62 medications analyzed, 24 (38.7%) had financial-based MEAs, 30 (48.4%) had outcome-based MEAs, and 8 (12.9%) had mixed MEAs. A total payback amount of €327.5 million was calculated during the 3 years, corresponding to 0.9% of the €41.1 billion of total expenditures for medications purchased by public health facilities in Italy. Financial-based MEAs returned the highest payback revenues, €158.1 million; the outcome-based MEAs and mixed MEAs generated smaller paybacks of €74.5 million and €94.9 million, respectively. Overall, the median proportion of payback to expenditure on the medications analyzed was 3.8%. For mixed MEAs, the payback-to-expenditure proportion was 6.7%; for outcome-based MEAs, 3.3%; and for financial-based MEAs, 3.7%. Conclusions and Relevance: This observational study found limited evidence that MEAs lower pharmaceutical expenditures. Determining criteria for prioritizing MEA use, identifying potential design changes, and improving implementation may be needed in the future.

Preparation and evaluation of ßcyclodextrin-based nanosponges loaded with Budesonide for pulmonary delivery.

Budesonide (BUD) is a glucocorticosteroid used to treat chronic obstructive pulmonary disease. Despite this, it is a hydrophobic compound with low bioavailability. To address these hurdles, non-toxic and biocompatible ßcyclodextrin-based nanosponges (ßCD-NS) were attempted. BUD was loaded on five different ßCD-NS at four different ratios. NS with 1,1'-carbonyldiimidazole (CDI) as a crosslinking agent, presented a higher encapsulation efficiency ( Ì´ 80%) of BUD at 1:3 BUD: ßCD-NS ratio (BUD-ßCD-NS). The optimized formulations were characterized by Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), water absorption capacity (WAC), scanning electron microscopy (SEM), X-ray powder diffraction studies (XRD), particle size, zeta potential, encapsulation efficiency, in vitro and in vivo release studies, acute toxicity study, solid-state characterization, and aerosol performance. In vitro-in vivo correlation and cytotoxicity of the formulations on alveolar cells in vitro were further determined. In vitro and in vivo studies showed almost complete drug release and drug absorption from the lungs in the initial 2 h for pure BUD, which were sustained up to 12 h from BUD loaded into nanosponges (BUD-ßCD-NS). Acute toxicity studies and in vitro cytotoxicity studies on alveolar cells proved the safety of BUD-ßCD-NS. Several parameters, including particle size, median mass aerodynamic diameter, % fine particle fraction, and % emitted dose, were evaluated for aerosol performance, suggesting the capability of BUD-ßCD-NS to formulate as a dry powder inhaler (DPI) with a suitable diluent. To sum up, this research will offer new insights into the future advancement of ßCD-NS as drug delivery systems for providing controlled release of therapeutic agents against pulmonary disease.

Dextrin-Based Adsorbents Synthesized via a Sustainable Approach for the Removal of Salicylic Acid from Water.

Pharmaceuticals such as salicylic acid are commonly detected in wastewater and surface waters, increasing concern for possible harmful effects on humans and the environment. Their difficult removal via conventional treatments raised the need for improved strategies, among which the development of bioderived adsorbents gained interest because of their sustainability and circularity. In this work, biobased cross-linked adsorbents, synthesized via a sustainable approach from starch derivatives, namely beta-cyclodextrins and maltodextrins, were at first characterized via FTIR-ATR, TGA, SEM, and elemental analysis, showing hydrophilic granular morphologies endowed with specific interaction sites and thermal stabilities higher than 300 °C. Subsequently, adsorption tests were carried out, aiming to assess the capabilities of such polymers on the removal of salicylic acid, as a case study, from water. Batch tests showed rapid kinetics of adsorption with a removal of salicylic acid higher than 90% and a maximum adsorption capacity of 17 mg/g. Accordingly, continuous fixed bed adsorption tests confirmed the good interaction between the polymers and salicylic acid, while the recycling of the adsorbents was successfully performed up to four cycles of use.

Access and use of WHO essential medicines in Italy.

Background: Many countries use the WHO Essential Medicines List (EML) as a guide for health policy choices to promote the efficient use of healthcare resources or adopt the concept of essential medicines (EMs) to develop their own national list of essential medicines. The aim of this study is to analyse the availability and use of medicines included in the 22nd WHO EML in Italy. Methods: Using the ATC code (5th level), a comparison was made between the medicines included in the WHO EML and those retrieved from the Italian Medicines Agency (AIFA) database. The availability (regulatory and reimbursement status) of EMs, as well as the market share in expenditure (million euros) and consumption [measured in WHO-defined daily doses (DDDs)], compared to all reimbursed medicines in 2021, were analysed. Results: In 2021, approximately 85.2% (n = 414) of medicines included in the WHO EML were commonly marketed in Italy. Of these, 396 EMs were fully reimbursed by the Italian National Healthcare Service (INHS), corresponding to 81.5% (396/486) of the WHO EML, while the remaining 18.5% (90/486) were neither authorised (n = 72) nor reimbursed (n = 18). The study found a low coverage for anti-parasitic, insecticides, and repellent products (ATC P) in addition to medicines for the genitourinary system and sex hormones (ATC G). Even though medicines on the WHO EML, including therapeutic alternatives, accounted for ~48.5% of the expenditure for medicines reimbursed by INHS, the list covered 74% of all national drug consumed. Novel high-cost therapies indicated in high-prevalence diseases and rare conditions, mostly antineoplastic and immune-modulating agents (ATC L) not included in the WHO EML, were also guaranteed. Conclusions: In Italy, high coverage of EMs was found. It was largely reimbursed by the INHS, even when compared to other European countries. Essential medicines represented a high percentage of the overall expenditure and consumption in Italy. The WHO EML could be an important tool to guide the health policy choices of high-income countries, although a more frequent update and easier access to information on rejected medicines are needed.

[The organization of pharmaceutical care in the territory has no effect on patient compliance: the case of direct or account distribution of antidiabetics]. / L'organizzazione dell'assistenza farmaceutica sul territorio non ha effetto sulla compliance del paziente: il caso della distribuzione diretta o per conto degli antidiabetici.

OBJECTIVES: the objective of the study is to assess the effect of the delivery channel on adherence, persistence and potential wastage of new antidiabetic drugs. DESIGN: longitudinal descriptive observational study. New users were defined as subjects who received a first prescription of drugs belonging to the antidiabetic category in the period between 01.01.2021 and 31.03.2021 (index date) and who did not receive prescriptions for drugs belonging to the same category in the previous 6 months, as of 01.07.2020. Each subject was followed for a follow-up period of 9 months. SETTING AND PARTICIPANTS: the study examined adherence and persistence to treatment with antidiabetic drugs in Italy for patients aged>=45 years (information flow of pharmaceutical services performed in direct distribution and on behalf established by Ministerial Decree Health 31 July, 2007). MAIN OUTCOME MEASURES: adherence to treatment measured by the Medication Possession Rate (MPR) indicator, defined as the ratio of the number of days of therapy dispensed (calculated from DDDs) to the number of days covered by drug therapy; persistence to treatment defined as "time elapsed between the initiation and discontinuation of a prescribed drug therapy" estimated by as "time elapsed between the initiation and discontinuation of a drug therapy" estimated by Cox semi-parametric model; difference in terms of waste understood as the number of packs not fully used by non-persistent subjects. RESULTS: the analysis showed that there were no significant differences between the dispensing channels in adherence, persistence, and medication wastage (defined as the distribution of packages to non-persistent patients). Specifically, it turns out that the percentage of highly adherent subjects at 9 months is 62.2 for those on treatment in the direct distribution channel and 64.6 for those on treatment with account distribution; with regard to persistence at 9 months, however, a difference of less than one percentage point was observed between the two channels. Although this study focused on a specific therapeutic class, the results can be generalised to other high-prevalence chronic diseases. However, some limitations of the study were pointed out, such as the difficulty of replicating the results due to the variability of data depending on the drug category and the time period considered. CONCLUSIONS: the choice of distribution channel for antidiabetic drugs should not be based on adherence or persistence to treatment, but on other determinants such as cost of service and logistical complications.

Cyclodextrins for Lithium Batteries Applications.

Due to their high energy and power density, lithium-ion batteries (LIBs) have gained popularity in response to the demand for effective energy storage solutions. The importance of the electrode architecture in determining battery performance highlights the demand for optimization. By developing useful organic polymers, cyclodextrin architectures have been investigated to improve the performance of Li-based batteries. The macrocyclic oligosaccharides known as cyclodextrins (CDs) have relatively hydrophobic cavities that can enclose other molecules. There are many industries where this "host-guest" relationship has been found useful. The hydrogen bonding and suitable inner cavity diameter of CD have led to its selection as a lithium-ion diffusion channel. CDs have also been used as solid electrolytes for solid-state batteries and as separators and binders to ensure adhesion between electrode components. This review gives a general overview of CD-based materials and how they are used in battery components, highlighting their advantages.

Intratumoural Delivery of mRNA Loaded on a Cationic Hyper-Branched Cyclodextrin-Based Polymer Induced an Anti-Tumour Immunological Response in Melanoma.

mRNA technology has demonstrated potential for use as an effective cancer immunotherapy. However, inefficient in vivo mRNA delivery and the requirements for immune co-stimulation present major hurdles to achieving anti-tumour therapeutic efficacy. Therefore, we used a cationic hyper-branched cyclodextrin-based polymer to increase mRNA delivery in both in vitro and in vivo melanoma cancer. We found that the transfection efficacy of the mRNA-EGFP-loaded Ppoly system was significantly higher than that of lipofectamine and free mRNA in both 2D and 3D melanoma cancer cells; also, this delivery system did not show cytotoxicity. In addition, the biodistribution results revealed time-dependent and significantly higher mEGFP expression in complexes with Ppoly compared to free mRNA. We then checked the anti-tumour effect of intratumourally injected free mRNA-OVA, a foreign antigen, and loaded Ppoly; the results showed a considerable decrease in both tumour size and weight in the group treated with OVA-mRNA in loaded Ppoly compared to other formulations with an efficient adaptive immune response by dramatically increasing most leukocyte subtypes and OVA-specific CD8+ T cells in both the spleen and tumour tissues. Collectively, our findings suggest that the local delivery of cationic cyclodextrin-based polymer complexes containing foreign mRNA antigens might be a good and reliable concept for cancer immunotherapy.

Monitoring medicine prescriptions before, during and after pregnancy in Italy.

BACKGROUND: The use of medications during pregnancy is a common event worldwide. Monitoring medicine prescriptions in clinical practice is a necessary step in assessing the impact of therapeutic choices in pregnant women as well as the adherence to clinical guidelines. The aim of this study was to provide prevalence data on medication use before, during and after pregnancy in the Italian population. METHODS: A retrospective prevalence study using administrative healthcare databases was conducted. A cohort of 449,012 pregnant women (15-49 years) residing in eight Italian regions (59% of national population), who delivered in 2016-2018, were enrolled. The prevalence of medication use was estimated as the proportion (%) of pregnant women with any prescription. RESULTS: About 73.1% of enrolled women received at least one drug prescription during pregnancy, 57.1% in pre-pregnancy and 59.3% in postpartum period. The prevalence of drug prescriptions increased with maternal age, especially during the 1st trimester of pregnancy. The most prescribed medicine was folic acid (34.6%), followed by progesterone (19%), both concentrated in 1st trimester of pregnancy (29.2% and 14.8%, respectively). Eight of the top 30 most prescribed medications were antibiotics, whose prevalence was higher during 2nd trimester of pregnancy in women ≥ 40 years (21.6%). An increase in prescriptions of anti-hypertensives, antidiabetics, thyroid hormone and heparin preparations was observed during pregnancy; on the contrary, a decrease was found for chronic therapies, such as anti-epileptics or lipid-modifying agents. CONCLUSIONS: This study represents the largest and most representative population-based study illustrating the medication prescription patterns before, during and after pregnancy in Italy. The observed prescriptive trends were comparable to those reported in other European countries. Given the limited information on medication use in Italian pregnant women, the performed analyses provide an updated overview of drug prescribing in this population, which can help to identify critical aspects in clinical practice and to improve the medical care of pregnant and childbearing women in Italy.

Oxygen Nanocarriers for Improving Cardioplegic Solution Performance: Physico-Chemical Characterization.

Nanocarriers for oxygen delivery have been the focus of extensive research to ameliorate the therapeutic effects of current anti-cancer treatments and in the organ transplant field. In the latter application, the use of oxygenated cardioplegic solution (CS) during cardiac arrest is certainly beneficial, and fully oxygenated crystalloid solutions may be excellent means of myocardial protection, albeit for a limited time. Therefore, to overcome this drawback, oxygenated nanosponges (NSs) that can store and slowly release oxygen over a controlled period have been chosen as nanocarriers to enhance the functionality of cardioplegic solutions. Different components can be used to prepare nanocarrier formulations for saturated oxygen delivery, and these include native α-cyclodextrin (αCD), αcyclodextrin-based nanosponges (αCD-NSs), native cyclic nigerosyl-nigerose (CNN), and cyclic nigerosyl-nigerose-based nanosponges (CNN-NSs). Oxygen release kinetics varied depending on the nanocarrier used, demonstrating higher oxygen release after 24 h for NSs than the native αCD and CNN. CNN-NSs presented the highest oxygen concentration (8.57 mg/L) in the National Institutes of Health (NIH) CS recorded at 37 °C for 12 h. The NSs retained more oxygen at 1.30 g/L than 0.13 g/L. These nanocarriers have considerable versatility and the ability to store oxygen and prolong the amount of time that the heart remains in hypothermic CS. The physicochemical characterization presents a promising oxygen-carrier formulation that can prolong the release of oxygen at low temperatures. This can make the nanocarriers suitable for the storage of hearts during the explant and transport procedure.

[Parole chiave. Appropriatezza prescrittiva, consumi farmaceutici, emofilia, fattori della coagulazione, malattia di von Willebrand, malattie emorragiche congenite.] / Strategie terapeutiche per il trattamento delle malattie emorragiche congenite.

Therapeutic strategies for the treatment of congenital bleeding disorders. Congenital hemorrhagic diseases (CHDs) are a group of rare disorders caused by quantitative or qualitative deficiency of one or more coagulation factors. Haemophilia A, Haemophilia B, and von Willebrand disease are the most common congenital bleeding disorders. Over the past decades, the evolution of CHDs treatments has resulted in an increase in the average life expectancy of patients and in an improvement in their quality of life; it has also enabled the prevention of bleeding complications much more effectively than in the past. This has been possible, especially for haemophilia, mainly because of earlier diagnosis, introduction of recombinant factors, especially long-acting factors, and availability of new non-substitutive therapies. In 2021, there was an increase in the overall expenditure and consumption of coagulation factors in Italy; the increase concerned especially the long-acting recombinant factors used in the treatment of Haemophilia A and B and the monoclonal antibody emicizumab. Waiting for innovative therapies that can enable individually tailored therapies, special attention must be paid to prescriptive appropriateness and to identify the best diagnostic and therapeutic care pathways for patients.

[Pharmacotherapy of Hemophilia A: expenditure and consumption for the year 2022 and future expenditure scenarios.] / Terapia dell'emofilia A: spesa e consumo per l'anno 2022 e scenari di spesa futura.

In 2021, the national expenditure for blood coagulation factors was 541.4 million, growing steadily over the past decade. Hemophilia A is the congenital hemorrhagic disease with the highest drug consumption and expenditure. It has also the highest annual increase. Data from the OsMed report showed an increased use of long-acting recombinant factors and a concomitant reduction in consumption of short-acting ones and also an increasing trend of emicizumab. Based on these findings, two possible expenditure scenarios were described: 1) assuming a 25% of reduction in consumption of short-acting recombinant factors with proportional redistribution to the consumption observed in 2022 for long-acting recombinant factors; 2) assuming that all new patients with a moderate and severe form of the disease will start prophylaxis with emicizumab and also calculating different switch percentages (20%, 30%, 50% or 70%). The first hypothesis showed a potential increase in expenditure of 3.3% (approximately 10 million euros) switching from short- to long-acting factors. In the second one, based on estimated number of patients with Hemophilia A on treatment, a total expenditure of about 457.6 million euros was estimated. Based on these findings, different expenditure outlooks were hypothesized and that there should be a switch from the recombinant factors to emicizumab. Specifically, an expenditure increase of 8% in the case of 20% switch and 28.1% in the case of 70% switch were estimated.

A Comparison between the Molecularly Imprinted and Non-Molecularly Imprinted Cyclodextrin-Based Nanosponges for the Transdermal Delivery of Melatonin.

Melatonin is a neurohormone that ameliorates many health conditions when it is administered as a drug, but its drawbacks are its oral and intravenous fast release. To overcome the limitations associated with melatonin release, cyclodextrin-based nanosponges (CD-based NSs) can be used. Under their attractive properties, CD-based NSs are well-known to provide the sustained release of the drug. Green cyclodextrin (CD)-based molecularly imprinted nanosponges (MIP-NSs) are successfully synthesized by reacting ß-Cyclodextrin (ß-CD) or Methyl-ß Cyclodextrin (M-ßCD) with citric acid as a cross-linking agent at a 1:8 molar ratio, and melatonin is introduced as a template molecule. In addition, CD-based non-molecularly imprinted nanosponges (NIP-NSs) are synthesized following the same procedure as MIP-NSs without the presence of melatonin. The resulting polymers are characterized by CHNS-O Elemental, Fourier Transform Infrared Spectroscopy (FTIR), Thermogravimetric (TGA), Differential Scanning Calorimetry (DSC), Zeta Potential, and High-Performance Liquid Chromatography (HPLC-UV) analyses, etc. The encapsulation efficiencies are 60-90% for MIP-NSs and 20-40% for NIP-NSs, whereas melatonin loading capacities are 1-1.5% for MIP-NSs and 4-7% for NIP-NSs. A better-controlled drug release performance (pH = 7.4) for 24 h is displayed by the in vitro release study of MIP-NSs (30-50% released melatonin) than NIP-NSs (50-70% released melatonin) due to the different associations within the polymeric structure. Furthermore, a computational study, through the static simulations in the gas phase at a Geometry Frequency Non-covalent interactions (GFN2 level), is performed to support the inclusion complex between ßCD and melatonin with the automatic energy exploration performed by Conformer-Rotamer Ensemble Sampling Tool (CREST). A total of 58% of the CD/melatonin interactions are dominated by weak forces. CD-based MIP-NSs and CD-based NIP-NSs are mixed with cream formulations for enhancing and sustaining the melatonin delivery into the skin. The efficiency of cream formulations is determined by stability, spreadability, viscosity, and pH. This development of a new skin formulation, based on an imprinting approach, will be of the utmost importance in future research at improving skin permeation through transdermal delivery, associated with narrow therapeutic windows or low bioavailability of drugs with various health benefits.

Developing New Cyclodextrin-Based Nanosponges Complexes to Improve Vitamin D Absorption in an In Vitro Study.

Vitamin D plays an important role in numerous cellular functions due to the ability to bind the Vitamin D receptor (VDR), which is present in different tissues. Several human diseases depend on low vitamin D3 (human isoform) serum level, and supplementation is necessary. However, vitamin D3 has poor bioavailability, and several strategies are tested to increase its absorption. In this work, the complexation of vitamin D3 in Cyclodextrin-based nanosponge (CD-NS, in particular, ßNS-CDI 1:4) was carried out to study the possible enhancement of bioactivity. The ßNS-CDI 1:4 was synthesized by mechanochemistry, and the complex was confirmed using FTIR-ATR and TGA. TGA demonstrated higher thermostability of the complexed form. Subsequently, in vitro experiments were performed to evaluate the biological activity of Vitamin D3 complexed in the nanosponges on intestinal cells and assess its bioavailability without cytotoxic effect. The Vitamin D3 complexes enhance cellular activity at the intestinal level and improve its bioavailability. In conclusion, this study demonstrates for the first time the ability of CD-NS complexes to improve the chemical and biological function of Vitamin D3.