Special Issue: Biopolymers in Drug Delivery and Regenerative Medicine

S

Green Processing of Nanoporous Biodegradable Carriers of Bioactive Agents for Pharmaceutical and Biomedical Applications

Pharmaceutical and biomedical industries demand simple, safe and reproducible processing methods thus urging the development of novel straightforward manufacturing approaches. The product manufacturing by the green processing of admixtures and end-product would avoid long and costly purification (downstream) steps. In this work, the green supercritical fluid technology is used for the processing of nanoporous carriers (aerogels) for bioactive agents [1,2]. Aerogels in the form of one micron-sized particles were processed and loaded with a model bioactive compound (ketoprofen). Results show that the carrier has excellent textural properties (specific surface area of 200 m2/g) and a high loading capacity (7 wt.%) of the bioactive compound in the amorphous form. Release profile tests show the capacity of the carrier to modulate the drug release to the medium (PBS pH 7.4). The resulting material can be incorporated in the formulation of several pharmaceutical and biomedical products

Bioaerogels: Promising Nanostructured Materials in Fluid Management, Healing and Regeneration of Wounds

Wounds affect one’s quality of life and should be managed on a patient-specific approach, based on the particular healing phase and wound condition. During wound healing, exudate is produced as a natural response towards healing. However, excessive production can be detrimental, representing a challenge for wound management. The design and development of new healing devices and therapeutics with improved performance is a constant demand from the healthcare services. Aerogels can combine high porosity and low density with the adequate fluid interaction and drug loading capacity, to establish hemostasis and promote the healing and regeneration of exudative and chronic wounds. Bio-based aerogels, i.e., those produced from natural polymers, are particularly attractive since they encompass their intrinsic chemical properties and the physical features of their nanostructure. In this work, the emerging research on aerogels for wound treatment is reviewed for the first time. The current scenario and the opportunities provided by aerogels in the form of films, membranes and particles are identified to face current unmet demands in fluid managing and wound healing and regenerationThis work was carried out in the frame of COST Action CA18125 “Advanced Engineering and Research of aeroGels for Environment and Life Sciences (AERoGELS)”, funded by the European Commission. This work was supported by National Funds from Fundação para a Ciência e a Tecnologia (FCT), through project UIDB/50016/2020, and by Xunta de Galicia [ED431C 2020/17], MCIUN [RTI2018-094131-A-I00], Agencia Estatal de Investigación [AEI] and FEDER fundsS

Hazelnut (Corylus avellana l.) shells extract: Phenolic composition, antioxidant effect and cytotoxic activity on human cancer cell lines

Hazelnut shells, a by-product of the kernel industry processing, are reported to contain high amount of polyphenols. However, studies on the chemical composition and potential effects on human health are lacking. A methanol hazelnut shells extract was prepared and dried. Our investigation allowed the isolation and characterization of different classes of phenolic compounds, including neolignans, and a diarylheptanoid, which contribute to a high total polyphenol content (193.8 ± 3.6 mg of gallic acid equivalents (GAE)/g of extract). Neolignans, lawsonicin and cedrusin, a cyclic diarylheptanoid, carpinontriol B, and two phenol derivatives, C-veratroylglycol, and β-hydroxypropiovanillone, were the main components of the extract (0.71%-2.93%, w/w). The biological assays suggested that the extract could be useful as a functional ingredient in food technology and pharmaceutical industry showing an in vitro scavenging activity against the radical 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) (EC50 = 31.7 µg/mL with respect to α-tocopherol EC50 = 10.1 µg/mL), and an inhibitory effect on the growth of human cancer cell lines A375, SK-Mel-28 and HeLa (IC50 = 584, 459, and 526 µg/mL, respectively). The expression of cleaved forms of caspase-3 and poly(ADP-ribose) polymerase-1 (PARP-1) suggested that the extract induced apoptosis through caspase-3 activation in both human malignant melanoma (SK-Mel-28) and human cervical cancer (HeLa) cell lines. The cytotoxic activity relies on the presence of the neolignans (balanophonin), and phenol derivatives (gallic acid), showing a pro-apoptotic effect on the tested cell lines, and the neolignan, cedrusin, with a cytotoxic effect on A375 and HeLa cells

Aerodynamic Properties and Drug Solubility of Dry Powders Prepared by Spray Drying: Clarithromycin Versus its Hydrochloride Salt

Aerodynamic Properties and Drug Solubility of Dry Powders Prepared by Spray Drying: Clarithromycin Versus its Hydrochloride Salt. Russo P, Manniello M.D., Simonetti A., Petrone A.M., Porta A., Del Gaudio P., Aquino R.P. Department of Pharmacy (DIFARMA), University of Salerno, Fisciano (SA) – Italy; ([email protected]). Introduction and Objectives. The antibiotic therapy for a direct administration to the lung in cystic fibrosis patients has to provide suitable drug availability, possibly in the lower respiratory tract characterized by the presence of thick secretions. Apart from deposition, systemic or local pharmacological activity of an inhalation product depends on drug dissolution into the biological fluids lining the lung. Therefore, one of the crucial step in the therapeutic management of the respiratory disease is the drug solubilization in this site of action. Clarithromycin (CLA; fig.1) is a broad spectrum and a well know macrolide antibiotic usually prescribed particularly for the treatment of respiratory infections, interestingly showing an additional anti-inflammatory effect (Pukhalsky et al., 2004); CLA is characterized by a very poor water solubility (0.33 mg/L). One of the common strategy, for increasing drug solubility in aqueous medium is represented by the production of dry powders in amorphous form using the spray drying technique (Yonemochi et al., 1999). Moreover, CLA has a dimethylamino group, which can be salified for solubility/dissolution improvement (fig.1). Hence, the aim of the present study was to obtain respirable powders of clarithromycin, while improving drug aqueous solubility. Powders were produced with CLA or CLA hydrochloride and characterized in terms of drug content, aerodynamic properties and drug solubility. Finally, in order to assess the effect of the spray-drying process on the antibiotic activity of the engineered particles, microbiological tests were performed. Materials and Methods. Several batches of micronized particles were prepared by spray drying different feed solutions; critical process parameters were solvent composition (isopropyl alcohol/water ratio), drug concentration and pH of the liquid feeds (table 1). Saturated solubility measurements were carried out keeping an excess amount of CLA raw material (RM), CLA spray-dried suspension and hydrochloride spray-dried in phosphate buffer (0.05 M, pH 6.75) at 37°C for 72h. After filtration, the solubility was measured by HPLC method and expressed in mg/ml. The results were reported as mean of three measurements and standard deviation. Particle size distribution of Raw Material and engineered particles was determined using a light-scattering laser granulometer, while particle morphology was assessed by scanning electron microscopy (SEM). The in vitro deposition of the micronized powders was evaluate by means of a Single-Stage Glass Impinger (SSGI; apparatus A; European Pharmacopoeia 8.0), using a proper device for the aerosolization. The antibacterial assay was carried out in MHB by microdilution method using 96-well microtiter plates. Briefly, 200 µl of 1X107 CFU/ml of P. aeruginosa ATCC 27853 were incubated at 37°C with different concentration of drug (4, 6 and 8 µg/ml). Results and Discussion. Morphology and aerodynamic properties of spray-dried particles were strongly dependent on organic solvent concentration as well as on pH of the liquid feeds processed, both influencing drug solubility. Adding clarithromycin to hydroalcoholic mixtures, alkaline feeds (pH~10.5; #1, #2, tab.1) in form of suspensions were obtained.   The resulting spray-dried powders showed good process yield, but unsatisfactory aerodynamic properties, due to a high particle size (tab. 1) and the presence of residual drug crystals mixed to spherical particles (fig.2; #2). With the aim to obtain clear feeds in form of solutions, we tested clarithromycin in its hydrochloride salt form, obtained lowering pH values of feed solutions (pH 6.5). Micronized salified powders showed higher process yield and very interesting FPF values, thanks to smaller and wrinkled particles (fig.2 #4, #6; tab.1). Moreover, water solubility of spray-dried powders was strongly influenced by clarithromycin form. Powders obtained from alkaline feed suspensions showed lower solubility in a phosphate buffer 0.05 M, pH 6.75 (fig.3, # 1). A substantial increase in drug solubility was obtained, at the same conditions, with powders dried from feed solution containing clarithromycin hydrochloride (fig.3 #9-#5). To verify the ability of the produced formulations to was performed. Three different drug concentrations were tested in a multi-well plate. Clarithromycin raw material (RM, line C, figure 4) and #1 (line D, figure 4) showed a lower activity against P. aeruginosa growth compared to #4, #5, #6, containing the hydrochloride form. This different behavior against P. aeruginosa may be due to the lower CLA solubility; at higher concentration, clarithromycin precipitates in RM and #1 wells, becoming unavailable for antibiotic purpose. Conclusions. Clarithromycin inhalable powders containing the drug in its hydrochloride form showed good aerodynamic properties and higher water solubility. Thanks to a fine-tuning of the process parameters and liquid feed composition, no excipients were necessary to obtain respirable powders. The spray drying process of CLA hydrochloride not only preserved antimicrobial activity, but also, increasing drug solubility, improved drug efficacy against P. aeruginosa. References. Pukhalsky, A. L., Shmarina, G. V., Kapranov, N. I., Kokarovtseva, S. N., Pukhalskaya, D., & Kashirskaja, N. J. (2004). Anti-inflammatory and immunomodulating effects of clarithromycin in patients with cystic fibrosis lung disease. Mediators Inflamm, 13(2), 111-117. doi: 10.1080/09629350410001688495 Yonemochi, E., Kitahara, S., Maeda, S., Yamamura, S., Oguchi, T., & Yamamoto, K. (1999). Physicochemical properties of amorphous clarithromycin obtained by grinding and spray drying. Eur J Pharm Sci, 7(4), 331-338

Nanospray Drying as a Novel Technique for the Manufacturing of Inhalable NSAID Powders

The aim of this research was to evaluate the potential of the nanospray drier as a novel apparatus for the manufacturing of a dry powder for inhalation containing ketoprofen lysinate, a nonsteroidal anti-inflammatory drug able to control the inflammation in cystic fibrosis patients. We produced several ketoprofen lysinate and leucine powder batches by means of nanospray dryer, studying the influence of process parameters on yield, particle properties (size distribution and morphology), and, mainly, aerodynamic properties of powders. Micronized particles were prepared from different hydroalcoholic solutions (alcohol content from 0 to 30% v/v) using ketoprofen in its lysine salt form and leucine as dispersibility enhancer in different ratios (from 5 to 15% w/w) with a total solid concentration ranging from 1 to 7% w/v. Results indicated that the spray head equipped with a 7 µm nozzle produced powders too big to be inhaled. The reduction of nozzle size from 7 to 4 µm led to smaller particles suitable for inhalation but, at the same time, caused a dramatic increase in process time. The selection of process variables, together with the nozzle pretreatment with a surfactant solution, allowed us to obtain a free flowing powder with satisfying aerosol performance, confirming the usefulness of the nanospray drier in the production of powder for inhalation

Beta-Blocker Use in Older Hospitalized Patients Affected by Heart Failure and Chronic Obstructive Pulmonary Disease: An Italian Survey From the REPOSI Register

Beta (β)-blockers (BB) are useful in reducing morbidity and mortality in patients with heart failure (HF) and concomitant chronic obstructive pulmonary disease (COPD). Nevertheless, the use of BBs could induce bronchoconstriction due to β2-blockade. For this reason, both the ESC and GOLD guidelines strongly suggest the use of selective β1-BB in patients with HF and COPD. However, low adherence to guidelines was observed in multiple clinical settings. The aim of the study was to investigate the BBs use in older patients affected by HF and COPD, recorded in the REPOSI register. Of 942 patients affected by HF, 47.1% were treated with BBs. The use of BBs was significantly lower in patients with HF and COPD than in patients affected by HF alone, both at admission and at discharge (admission, 36.9% vs. 51.3%; discharge, 38.0% vs. 51.7%). In addition, no further BB users were found at discharge. The probability to being treated with a BB was significantly lower in patients with HF also affected by COPD (adj. OR, 95% CI: 0.50, 0.37-0.67), while the diagnosis of COPD was not associated with the choice of selective β1-BB (adj. OR, 95% CI: 1.33, 0.76-2.34). Despite clear recommendations by clinical guidelines, a significant underuse of BBs was also observed after hospital discharge. In COPD affected patients, physicians unreasonably reject BBs use, rather than choosing a β1-BB. The expected improvement of the BB prescriptions after hospitalization was not observed. A multidisciplinary approach among hospital physicians, general practitioners, and pharmacologists should be carried out for better drug management and adherence to guideline recommendations

Pain and Frailty in Hospitalized Older Adults

Introduction: Pain and frailty are prevalent conditions in the older population. Many chronic diseases are likely involved in their origin, and both have a negative impact on quality of life. However, few studies have analysed their association. Methods: In light of this knowledge gap, 3577 acutely hospitalized patients 65 years or older enrolled in the REPOSI register, an Italian network of internal medicine and geriatric hospital wards, were assessed to calculate the frailty index (FI). The impact of pain and some of its characteristics on the degree of frailty was evaluated using an ordinal logistic regression model after adjusting for age and gender. Results: The prevalence of pain was 24.7%, and among patients with pain, 42.9% was regarded as chronic pain. Chronic pain was associated with severe frailty (OR = 1.69, 95% CI 1.38–2.07). Somatic pain (OR = 1.59, 95% CI 1.23–2.07) and widespread pain (OR = 1.60, 95% CI 0.93–2.78) were associated with frailty. Osteoarthritis was the most common cause of chronic pain, diagnosed in 157 patients (33.5%). Polymyalgia, rheumatoid arthritis and other musculoskeletal diseases causing chronic pain were associated with a lower degree of frailty than osteoarthritis (OR = 0.49, 95%CI 0.28–0.85). Conclusions: Chronic and somatic pain negatively affect the degree of frailty. The duration and type of pain, as well as the underlying diseases associated with chronic pain, should be evaluated to improve the hospital management of frail older people