The subcutaneous administration route is widely used to administer different types of drugs given its high bioavailability and rapid onset of action. However, the sensation of pain at the injection site might reduce patient adherence. Apart from a direct effect of the drug itself, several factors can influence the sensation of pain: needle features, injection site, volume injected, injection speed, osmolality, viscosity and pH of formulation, as well as the kind of excipients employed, including buffers and preservatives. Short and thin needles, conveniently lubricated and with sharp tips, are generally used to minimize pain, although the anatomic injection site (abdomen versus thigh) also affects the sensation of pain. Large subcutaneous injection volumes are associated with pain. In this sense, the maximum volume generally accepted is around 1.5 ml, although volumes of up to 3 ml are well tolerated when injected in the abdomen. Injected volumes of up to 0.5–0.8 ml are not expected to increase substantially the pain produced by the needle insertion. Ideally, injectable products should be formulated as isotonic solutions (osmolality of about 300 mOsm/kg) and no more than 600 mOs/kg have to be used in order to prevent pain. A pH close to the physiological one is recommended to minimize pain, irritation, and tissue damage. Buffers are frequently added to parenteral formulations to optimize solubility and stability by adjusting the pH; however, their strength should be kept as low as possible to avoid pain upon injection. The data available recommend the concentration of phosphate buffer be limited to 10 mM and that the concentration of citrate buffer should be lower than 7.3 mM to avoid an increased sensation of pain. In the case of preservatives, which are required in multiple-dose preparations, m-cresol seems to be more painful than benzyl alcohol and phenol. Funding: Sandoz SA.

Introduction: Human immunodeficiency virus (HIV) type‐1 non‐nucleoside and nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of acquired immune deficiency syndrome (AIDS)/HIV infection.Discussion: First‐generation NNRTIs, nevirapine (NVP), delavirdine (DLV) and efavirenz (EFV) are drugs with a low genetic barrier and poor resistance profile, which has led to the development of new generations of NNRTIs. Second‐generation NNRTIs, etravirine (ETR) and rilpivirine (RPV) have been approved by the Food and Drug Administration and European Union, and the next generation of drugs is currently being clinically developed. This review describes recent clinical data, pharmacokinetics, metabolism, pharmacodynamics, safety and tolerability of commercialized NNRTIs, including the effects of sex, race and age differences on pharmacokinetics and safety. Moreover, it summarizes the characteristics of next‐generation NNRTIs: lersivirine, GSK 2248761, RDEA806, BILR 355 BS, calanolide A, MK‐4965, MK‐1439 and MK‐6186.Conclusions: This review presents a wide description of NNRTIs, providing useful information for researchers interested in this field, both in clinical use and in research.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Vancomycin is a glycopeptide antibiotic commonly used to treat resistant gram‐positive infections in neonates. While adult dosing guidelines are generally well established, a lack of consensus for optimal dosing regimens in neonates remains.• The large variance in pharmacokinetic values in premature neonates compared with full‐term infants is a major barrier to the development of optimal dosing regimens. Pharmacokinetic values have been reported for vancomycin in neonates. However, the studies have included small groups with differing, clinical conditions, serum sampling times and pharmacokinetic models. There are many proposed neonatal dosing guidelines for vancomycin, but few, if any, have been prospectively evaluated. In addition, the complexity of the dose and interval selection has led to errors in use. WHAT THIS STUDY ADDS • The purpose of this investigation was to determine population pharmacokinetic parameters of vancomycin in neonatal patients with a wide range of gestational age and birth weight and to study the effect of the co‐administration of amoxicillin‐clavulanic acid and spironolactone on the pharmacokinetics of vancomycin in this cohort of patients. The aim was to find covariates with a relevant influence on the pharmacokinetic parameters of this drug, and to use this information for the design of an initial dosing schedule of vancomycin in neonates. Additionally, the obtained population pharmacokinetic parameters can be used to perform modifications of the initial dosing schedule in neonates with serum concentrations outside of the therapeutic range, by means of a Bayesian approach.AIM: To determine the population pharmacokinetic parameters of vancomycin in neonatal patients with a wide range of gestational age and birth weight, and subsequently to design an initial dosing schedule for vancomycin in neonates.METHODS: Using nonlinear mixed‐effects modelling (NONMEM VI), the pharmacokinetics of vancomycin were investigated in 70 neonates with postmenstrual age and body weight ranging 25.1–48.1 weeks and 0.7–3.7 kg, respectively. A one‐compartment linear disposition model with zero order input and first‐order elimination was used to describe the data. Nine demographic characteristics and 21 co‐administered drugs were evaluated as covariates of clearance (CL) and distribution volume (V_d) of vancomycin.RESULTS: Weight‐normalized clearance of vancomycin was influenced by postmenstrual age (PMA) and co‐administration of amoxicillin‐clavulanic acid. Weight‐normalized volume of distribution was influenced by co‐administration of spironolactone. CL and V_d of the typical individual in this study population (PMA = 34.6 weeks, weight = 1.7 kg) were estimated to be 0.066 l h⁻¹ kg⁻¹ (95% CI 0.059, 0.073 l h⁻¹ kg⁻¹) and 0.572 l kg⁻¹ (95% CI 0.505, 0.639 l kg⁻¹), respectively. This model was used to predict a priori serum vancomycin concentrations in a validation group (n= 41), which were compared with observed concentrations to determine the predictive performance of the model. The 95% confidence interval of mean prediction error included zero for both peak and trough vancomycin concentrations.CONCLUSIONS: Postmenstrual age, co‐administration of amoxicillin‐clavulanic acid and spironolactone have a significant effect on the weight‐normalized CL and V_d. An initial dosage guideline for vancomycin is proposed for preterm and full‐term neonates, whereas the population pharmacokinetic model can be used for dosage individualization of vancomycin.

The aim of this work was to deliver curcumin into the lungs by incorporating it into innovative vesicles obtained using phospholipids and high concentrations of glycerol (50%, v/v), so called glycerosomes, which were then combined with two polymers: sodium hyaluronate and trimethyl chitosan to form polymer-glycerosomes. These systems were prepared without the use of organic solvents or acidic solutions and their physico-chemical properties were fully characterized. Cryogenic transmission electron microscopy and small-angle X-ray scattering showed that both glycerosomes and polymer-glycerosomes were spherical, mainly unilamellar and of nanometric size (65–112 nm). The vesicles were readily nebulized with the largest amount of curcumin being found in the latest stages of the Next Generation Impactor™. In vitro results revealed the high biocompatibility of samples especially those containing the polymers. Curcumin loaded vesicles were also able to protect in vitro A549 cells stressed with hydrogen peroxide, restoring healthy conditions, not only by directly scavenging free radicals but also by indirectly inhibiting the production of cytokine IL6 and IL8. Moreover, in vivo results in rats showed the high capacity of these formulations to favour the curcumin accumulation in the lungs confirming their potential use as a target system for the treatment of pulmonary diseases.

Magnolia spp. extracts are known for their use in traditional Korean, Chinese, and Japanese medicine in the treatment of gastrointestinal disorders, anxiety, and allergies. Among their main components with pharmacological activity, the most relevant are magnolol and honokiol, which also show antitumoral activity. The objectives of this work were to study some physicochemical properties of both substances and their stability under different conditions of temperature, pH, and oxidation. Additionally, liposomes of honokiol (the least stable compound) were formulated and characterized. Both compounds showed pH-dependent solubility, with different solubility–pH profiles. Magnolol showed a lower solubility than honokiol at acidic pH values, but a higher solubility at alkaline pH values. The partition coefficients were similar and relatively high for both compounds (log P_o/w ≈ 4.5), indicating their lipophilic nature. Honokiol was less stable than magnolol, mainly at neutral and basic pH values. To improve the poor stability of honokiol, it was suitably loaded in liposomes. The obtained liposomes were small in size (175 nm), homogeneous (polydispersity index = 0.17), highly negatively charged (−11 mV), and able to incorporate high amounts of honokiol (entrapment efficiency = 93.4%). The encapsulation of honokiol in liposomes increased its stability only at alkaline pH values.

Neem oil, a plant-derived product rich in bioactives, has been incorporated in liposomes and hyalurosomes modified by adding argan oil and so called argan-liposomes and argan-hyalurosomes. Argan oil has also been added to the vesicles because of its regenerative and protective effects on skin. In the light of this, vesicles were specifically tailored to protect the skin from oxidative stress and treat lesions. Argan-liposomes were the smallest vesicles (~113 nm); the addition of sodium hyaluronate led to an increase in vesicle size (~143 nm) but it significantly improved vesicle stability during storage. In vitro studies confirmed the free radical scavenging activity of formulations, irrespective of their composition. Moreover, rheological investigation confirmed the higher viscosity of argan-hyalurosomes, which avoid formulation leakage after application. In vitro studies performed by using the most representative cells of the skin (i.e., keratinocytes and fibroblasts) underlined the ability of vesicles, especially argan-liposomes and argan-hyalurosomes, to counteract oxidative stress induced in these cells by using hydrogen peroxide and to improve the proliferation and migration of cells ensuring the more rapid and even complete closure of the wound (scratch assay).