RSC Pharmaceutics最新文献

Alzheimer's disease (AD) is a progressive, neurodegenerative condition. There are clear markers for the presence and progression of the disease, including β-amyloid (Aβ) plaques and Tau tangles, with many potential causes debated in the scientific community. Most existing treatments only provide symptomatic solutions. Due to poor aqueous solubility and possibly limited uptake across the blood–brain barrier (BBB), medications targeting the hallmarks of AD are still under study despite enormous efforts. Recently, nanoparticle-based drug delivery systems have demonstrated remarkable promise as precision medicines that may effectively increase bioavailability, permeate the BBB, and improve the targeting ability of a variety of pharmaceuticals. Polymer therapeutics have made tremendous progress in recent years, particularly in cancer treatment. Polymer–drug conjugates (PDCs) typically have a longer half-life, higher stability, and enhanced water solubility. Polymers serve as carriers for the administration of drugs, proteins, targeting moieties, and imaging agents in polymeric and macromolecular prodrugs. Numerous commercially viable PDCs for the treatment of various diseases have already proved their potential. This paper focuses mainly on the rationale for the design, synthesis, and potential use of PDCs as a multi-target treatment for neurodegenerative diseases.

The bitter taste of pharmaceuticals majorly impacts patient adherence. Co-crystallisation has been proposed as a novel way for taste masking using sweetener-based co-formers, while other co-formers also have a positive effect. We hypothesise that the sweetness of the co-formers is not the key factor but rather the molecular aggregation between the drug and co-former in solution, i.e., the stronger the interaction, the better the taste masking effect. Here, we explore the solution aggregation between the bitter-tasting drug nevirapine and five co-formers by ¹H NMR spectroscopy. The co-formers benzoic acid, salicylic acid and maleic acid show strong interaction with nevirapine, while glutaric acid and saccharin have weak and no interaction, respectively. The taste of the resulting co-crystal, as assessed by the electrical taste sensing system e-tongue, reveals that the bitterness of nevirapine has been covered with the co-crystal benzoic acid, maleic acid and glutaric acid but not saccharin or salicylic acid. From the taste results we deduct that both solution aggregation and the taste of the pure co-former play an important role in taste masking. It is likely that a large variety of co-formers can be used to cover bitter drugs and we show that the investigation of molecular aggregation in solution can help screen the co-formers before any in vitro or in vivo taste test.

Asiaticoside (AC) is a naturally occurring phytoconstituent that aids in wound healing by stimulating collagen biosynthesis. However, the physical properties of AC, such as its high molecular weight (959.12 g mol⁻¹), poor water solubility, and low permeability, restrict its therapeutic benefits. Additionally, the management of inflammation and angiogenesis in wound healing using AC-loaded wound dressings can be challenging in terms of its delivery across the skin layers. These challenges can be rectified by utilizing nanotechnology. The concept of nanotechnology is widely utilized in dermatology to boost the therapeutic efficacy of the entrapped drug. The AC-loaded nano-carriers deliver the drug at their target site in order to increase their efficacy, stability, and safety. These carriers efficiently distribute the loaded drug to the different skin layers. The current review focuses on the limitations associated with the topical administration of asiaticoside and the many initiatives made so far for effective and safe topical delivery using innovative constituents and techniques, along with other potential benefits of AC in wound healing, diabetes, inflammation, and depression.

3-(Aryl)-6-piperazin-1,2,4-triazolo[3,4-a]phthalazines have shown great potential as leishmanicidal agents. Herein, we prepared a series of PLGA-, PLA- and PCL-based-microparticles/nanoparticles of different particle sizes and loaded them with active 3-(aryl)-6-piperazin-1,2,4-triazolo[3,4-a]phthalazines TF1 and TF2. The synthesized microparticles/nanoparticles seek to improve the leishmanicidal activity of 3-(aryl)-6-piperazin-1,2,4-triazolo[3,4-a]phthalazines and extend its effect to the T. cruzi parasite. The encapsulates were prepared using a microemulsification method, achieving an encapsulation percentage between 89% and 99% for PLGA-, PLA- and PCL-microparticles/nanoparticles. The encapsulation of triazolo-phthalazines was confirmed through UV-Vis or EDX analyses. From SEM analysis, two nanoparticle or microparticle/nanoparticle system-loaded TF1 or TF2 with mean sizes of 250, 400, 600–900 or 900–2000 nm were obtained for each of PLGA, PLA and PCL polymeric matrices. TEM analysis revealed that all the prepared microparticles/nanoparticles consisted of particles and not spheres. The microencapsulates/nanoencapsulates showed an acceptable drug release under physiological conditions, achieving a continuous release for up to 96 hours for most of the studied cases. From biological evaluation, encapsulation with PLGA and PLA showed a positive effect against the in vitro model of both parasites showing a decrease in their EC₅₀ values compared with free compounds. Conversely, no improvement in trypanosomaticidal activity was found with PCL encapsulation. Importantly, it was found that that either the small particle size of the capsulate system or facile drug release favored anti-trypanosomatid activity. The three polymeric matrices showed a discrete but slight increase in toxicity toward J774.1 macrophages compared to free compounds. This may be associated with the facile penetration of the polymeric matrix across the macrophage membrane, favoring against intracellular forms of parasites. This study shows that either the particle size or the type of polymer represent key issues for improving the trypanosomaticidal activity of polymeric nanoformulations.

A common challenge in infection control is uncontrolled and unpredictable rapid release of antimicrobials – with ramifications on antimicrobial resistance (AMR) development and pollution – that makes it difficult to determine appropriate dosage levels and treatment times. An important class of antimicrobials is surface-active cationic substances, whose charge can be exploited for manipulating both their encapsulation and controlled release. As a proof of concept, the cationic antimicrobial octenidine dihydrochloride (OCT) was encapsulated in a microcapsule matrix of poly(D,L-lactide-co-glycolide) (PLGA) bearing anionic carboxylate end groups. The strong PLGA–OCT interaction was verified by infrared spectroscopy and by comparing the release of OCT to its uptake into empty microcapsules. By expanding a Fickian diffusion model, the binding event was estimated to result in a 10-fold reduction in effective diffusivity resulting in a sustained release maintained for several months. Using this model, the impacts of temperature and release medium solubilizers were globally examined to improve predictability. By exceeding the glass transition temperature of hydrated PLGA, the diffusional release was significantly faster at 37 °C with a diffusivity 200 times that at room temperature. The addition of solubilizers increased the OCT partitioning towards the aqueous phase without affecting its diffusivity.

Bacterial resistance to antibiotics has emerged as a major health issue. Developing new antibacterial systems is crucial. We propose to exploit cerium oxide particles which present interesting physicochemical and biological properties. We demonstrated by zeta potential measurement that according to the pH, cerium oxide particles present either negatively or positively charged surfaces (isoelectric point determined around 8). We then take advantage of this property for modifying the particle surfaces with charged polysaccharides (dextran derivative to limit aggregation in aqueous media). The surface modification of particles has been examined by FT-IR, DRX and TGA measurements. The physicochemical properties of the resulting dispersion have been investigated as the size, dispersity and potential zeta value in physiological media. A fluorescent probe (Nile red) has then been loaded as a model of hydrophobic cargo, and then a hydrophobic antibiotic has been loaded (e.g. ciprofloxacin). Finally, the inhibitory effect on bacterial growth of the resulting antibiotic-loaded particles has been evaluated against antibiotic-resistant bacteria, namely spectinomycin-resistant Escherichia coli. These findings demonstrated the potential of the particles to be employed as an antimicrobial material, more specifically those resistant to antibiotic therapy.

Active pharmaceutical ingredient (API) complexes with cyclodextrins (CDs) and their derivatives are widely formulated. Previously, we reported on the supersaturation effect and its benefits for CD inclusion complexes without polymers. The degree of amorphization and percentage of remaining crystals were determined using X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) techniques. However, these properties clash with the stoichiometry of the solution according to the phase solubility diagram. In this study, the complexation contents of the prepared mixtures of indomethacin, piroxicam, diclofenac, and loxoprofen sodium with the 2-hydroxypropylated derivative of CD (HP-β-CD) were comparatively analyzed using dissolution curves. XRPD and DSC measurements indicated that equimolar mixtures were favorable for the interaction between these APIs and HP-β-CD. Enhancing the API solubility of HP-β-CD can be achieved through dissolution experiments. Mixtures of indomethacin with HP-β-CD consisted of an equimolar complex and corresponding remains. If the remaining component was HP-β-CD, then a gradual release of the equimolar complex was induced, and the release of diclofenac indicated similar dissolution behaviors. In contrast, the mixtures of indomethacin and diclofenac at molar ratios of 2 : 1 and 1 : 1 showed immediate supersaturation and a gradual decrease in the equilibrium concentration. These results indicate that the unbound HP-β-CD in the mixture acts as a matrix for controlled release.

Indocyanine green (ICG) is an FDA-approved near-infrared (NIR) dye used as a contrast agent for medical diagnosis in such techniques as image-guided surgery (IGS) and IGS-supported mapping for sentinel lymph node biopsy (SNLB). However, there are numerous disadvantages to its use in clinical applications: (i) self-aggregation in solution, (ii) poor targeting and (iii) short half-life in vivo, due to the rapid uptake by the liver. Herein, to overcome these obstacles, we utilized polymeric micelles (PMs) based on the amphiphilic linear and branched block poly(ethylene oxide)–poly(propylene oxide) (PEO–PPO) copolymers (Pluronic® and Tetronic®) for ICG stabilization, vehicleization and to directionally target breast cancer tissues. Because of their singular properties, PMs offer several advantages such as the ability to modify their surfaces with a variety of receptor-targeting ligands and their nano-scale size, which is suitable for taking advantage of the enhanced permeability and retention (EPR) effect for cancer diagnosis. In this work, we prepared ICG within pristine F127 and T1307 and their glucosylated derivatives (F127-Glu and T1307-Glu, respectively). These systems have a sub-30 nm-nanosized hydrodynamic diameter (19–27 nm), moderate negative Z-potentials (until −10 mV), and satisfactory stability in water even after lyophilisation and reconstitution, at 25 and 37 °C, respectively. Particularly, ICG within T1307-Glu PMs displayed maximum solubility and excellent encapsulation efficiency (100%), with a potentially large in vivo uptake according to high specificity and efficacious capture in lymph nodes (LNs) and tumors. All the results presented in this work, indicate that ICG-loaded PMs can potentially be used as image probe agents for IGS, SLNB and breast cancer imaging.

The acute kidney injury (AKI) and dose-limiting nephrotoxicity, which occurs in 20–60% of patients following systemic administration of colistin, represents a challenge in the effective treatment of multi-drug resistant Gram-negative infections. To reduce clinical toxicity of colistin and improve targeting to infected/inflamed tissues, we previously developed dextrin–colistin conjugates, whereby colistin is designed to be released by amylase-triggered degradation of dextrin in infected and inflamed tissues, after passive targeting by the enhanced permeability and retention effect. Whilst it was evident in vitro that polymer conjugation can reduce toxicity and prolong plasma half-life, without significant reduction in antimicrobial activity of colistin, it was unclear how dextrin conjugation would alter cellular uptake and localisation of colistin in renal tubular cells in vivo. We discovered that dextrin conjugation effectively reduced colistin's toxicity towards human kidney proximal tubular epithelial cells (HK-2) in vitro, which was mirrored by significantly less cellular uptake of Oregon Green (OG)-labelled dextrin–colistin conjugate, when compared to colistin. Using live-cell confocal imaging, we revealed localisation of both, free and dextrin-bound colistin in endolysosome compartments of HK-2 and NRK-52E cells. Using a murine AKI model, we demonstrated dextrin–colistin conjugation dramatically diminishes both proximal tubular injury and renal accumulation of colistin. These findings reveal new insight into the mechanism by which dextrin conjugation can overcome colistin's renal toxicity and show the potential of polymer conjugation to improve the side effect profile of nephrotoxic drugs.

Neuroactive steroids are a promising class of substances with many potential therapeutic applications, but their preclinical evaluation is challenging due to very low aqueous solubility. A common practice is to “solubilise” such drugs using water-miscible solvents, but this approach has drawbacks: the drug can precipitate uncontrollably after injection, the solvent can artificially increase membrane permeability, and such formulations are not directly transferrable to humans. It would be beneficial to use the same physical form of the drug during preclinical and clinical studies. This work reports an approach based on an aqueous suspension of phospholipid-coated nanocrystals of zuranolone, chosen as a representative of poorly soluble neuroactive steroid drugs. The wet stirred media milling method was used for creating a nanosuspension with a mean particle size of d_1,0 = 114 ± 39 nm, colloidally stable in PBS over 24 months at a concentration up to 100 mg mL⁻¹. The applicability of the nanosuspension was demonstrated in a study of pentylenetetrazol-induced seizures in developing rats as a model of human generalized tonic–clonic seizures. The incidence and severity of seizures were assessed for the zuranolone nanosuspension and compared to an established dosage as a cyclodextrin complex. The incidence of generalized seizures with or without the tonic phase was found to be lower in P12 rats receiving zuranolone in doses of 0.5 and 1 mg kg⁻¹ in the nanocrystal formulation than in those receiving the cyclodextrin solution. In contrast, both formulations significantly decreased seizure severity in P25 rats at a dose of 1 mg kg⁻¹. Crucially, the nanocrystal formulation enabled the creation of a concentration series independent of the thermodynamic solubility of the drug. A constant volume appropriate to the body size of the young rats could therefore be injected during the in vivo study.