International Journal of Pharmaceutics最新文献

Niclosamide and colistin sulfate exhibit strong in vitro synergistic activity against multidrug-resistant Gram-negative pathogens in cystic fibrosis; however, their co-formulation for inhaled delivery is constrained by differences in physicochemical properties and the high drug loading required for activity. Here, we report a formulation-focused strategy to enable excipient-minimized pulmonary co-delivery of niclosamide with colistin sulfate by engineering microparticles through liquid antisolvent precipitation followed by spray drying. Colistin sulfate was intentionally leveraged as a surface-active crystallization excipient, functioning both as an antimicrobial agent and as an interfacial stabilizer during niclosamide microcrystal formation. By varying the colistin:niclosamide molar ratio, median niclosamide particle size could be tuned from ∼7.7 µm at 1:1 to ∼1.3 µm at 24:1. Colistin adsorption inverted particle surface charge and suppressed time-dependent growth, consistent with interfacial stabilization during crystallization. The COL-NIC 8:1 formulation was downstream-processed via spray drying (geometric median size = 1.46 ± 0.50 μm) and exhibited favorable aerosol performance when delivered using a medium-resistance dry powder inhaler (FPF < 5 µm 75.3 ± 1.0%). Solid-state characterization indicated that niclosamide retained its crystalline structure, with no evidence of strong interaction with colistin. Finally, a preliminary in vivo lung infection model was used to assess the feasibility of pulmonary administration and the antibacterial response of the co-processed formulation relative to a standard-of-care comparator. Together, these results establish a particle-engineering platform for producing high-drug-loading niclosamide-colistin inhalation powders, highlighting how one active ingredient can function as a processing aid for excipient-minimized co-delivery of antibiotic combinations.

The aim of this work was to develop dendrimer-based nanocarriers of Vismodegib (VDG) for the topical treatment of Kaposi's sarcoma (KS). Previous molecular docking studies have shown that VDG is capable of inhibiting cyclooxygenase-2 (COX-2), an enzyme transcriptionally induced by the viral oncoprotein vGPCR and critically involved in the angioproliferative phenotype of KS. In this study, VDG was complexed with generation 4 poly(amidoamine) (PAMAM) dendrimers bearing hydroxyl terminal groups (G4-OH), and surface-functionalized with folic acid (G4-FA). The resulting G4-OH@VDG and G4-FA@VDG complexes significantly enhanced the apparent aqueous solubility of VDG, achieving experimental stoichiometries of approximately 4 and 8 mol of VDG per mole of dendrimer, respectively. G4-OH@VDG displayed a hydrodynamic diameter of 225.1 ± 122.0 nm (PdI = 0.44 ± 0.02), while G4-FA@VDG exhibited a size of 210.5 ± 54.7 nm (PdI = 0.66 ± 0.08). Dendrimer-drug associations were confirmed by FT-IR spectroscopy, and in vitro release studies revealed distinct, pH-dependent release mechanisms. Cytotoxicity was evaluated using ex vivo (red blood cells) and in vitro (HaCaT keratinocytes) models, both relevant to topical KS treatment, and no cytotoxic effects were observed. Skin penetration studies using the Saarbrücken ex vivo model demonstrated that both systems were able to deliver VDG into the skin, with G4-OH@VDG achieving higher drug accumulation, particularly within the stratum corneum. Antitumoral activity was assessed in an in vitro KS model, where cytotoxic effects were observed at 48 h post-incubation. Notably, G4-OH@VDG exhibited the most favorable therapeutic profile, including significant reduction of cell viability and inhibition of cell migration at sublethal concentrations. Overall, these results demonstrate that the combination of drug repurposing and dendrimer-based nanotechnology for topical delivery enhances the therapeutic performance of VDG in in vitro models of Kaposi's sarcoma.

The sublingual route offers an efficient alternative for drug administration, improving patient comfort and drug bioavailability. Films are an interesting pharmaceutical solid dosage form for application to the sublingual mucosa. Nifedipine is an anti-hypertensive drug; however, it presents low oral bioavailability and short half-life, being a candidate for sublingual administration. Thus, films containing nifedipine (GGP-NIFE-HG-F) were developed. The printing inks were prepared with a blend of guar gum (4%) and pullulan (4%) using dimethyl sulfoxide (DMSO) to solubilize nifedipine. The polysaccharide blend exhibited a rheological profile suitable for producing films using the semisolid extrusion (SSE) technique. The films were successfully obtained, with nifedipine content close to theoretical values (95.26 ± 3.55%), and demonstrated the possibility of customizing drug doses. Mechanical evaluation indicated that DMSO improved flexibility, acting as a plasticizer. All films exhibited rapid dispersion (>30 s) and disintegration (>3 min), consistent with their high swelling index (<700%). The hemolysis and HET-CAM assays suggest that films are safe for human use, and texture analysis showed that GGP-NIFE-HG-F has adhesion to sublingual mucosa (919.7 ± 159.3 mN/mm), classified as mucoadhesive. The in vitro release test confirmed that guar gum effectively controlled nifedipine release. Despite this controlled release, the polymeric vehicle did not obstruct/hinder the passage of nifedipine through the sublingual mucosa, indicating that the drug can reach the bloodstream. These findings indicate that films designed for sublingual administration could serve as a promising new method for delivering nifedipine.

Wound healing is a complex process involving various stages such as hemostasis, inflammation, cell proliferation, and tissue remodeling. If a wound fails to heal promptly, it can lead to ulcers, necrosis, and even limb amputation, resulting in significant losses. Over the years, many clinical studies have explored the role of dressings in wound healing. Although numerous dressings have been introduced to the market, traditional ones typically influence only external factors such as temperature, humidity, and pH, often causing issues like excessive moisture or dryness, allergic reactions, secondary injuries, and limited applicability across different wound types. In response, paracrine effect hydrogels, a novel class of biomaterials, have shown great promise in overcoming these limitations. Unlike traditional dressings or simple bioactive delivery systems, paracrine-oriented hydrogels function as microenvironmental regulators that influence intercellular communication, immune responses, and tissue regeneration. These dressings target the internal wound microenvironment, enhancing functions like exudate absorption, anti-inflammatory effects, and antibacterial activity. Although research on paracrine effect-type hydrogels is still developing, they are expected to become a emerging strategy in wound healing. This paper reviews the design principles, classification, mechanisms, and clinical applications of hydrogel dressings that leverage paracrine effects. It also highlights the historical development of hydrogel dressings, recent advancements, and the role of paracrine signaling in tissue repair. Finally, the paper discusses the current challenges and future directions in this field, offering valuable insights for the design of innovative hydrogel-based wound care products.

Gallic acid (GA) offers significant potential for managing atopic dermatitis (AD) owing to its potent antioxidant and anti-inflammatory properties; however, its hydrophilic nature (log P 0.7) severely limits skin permeation and localized bioavailability. To address this, the present study developed and optimized gallic acid-loaded trehalosomes using a D-optimal mixture design and a solvent-free fabrication method to enhance dermal retention and therapeutic outcomes. The optimized formulation (Opt-THL) was selected using a numerical desirability function (D = 0.835) that satisfied predefined constraints. Comprising phospholipid, trehalose, and Pluronic F127, it showed an entrapment efficiency of 72.4 ± 0.76%, particle size of 218.5 ± 0.70 nm, polydispersity index of 0.36 ± 0.001, and zeta potential of -32.2 ± 1.62 mV. It exhibited sustained release over 8 h, with release efficiency (RE%) of 56.81 ± 0.7% and mean dissolution time (MDT) of 1.87 ± 0.09 h. Integration of Opt-THL into a hydroxypropyl methylcellulose (HPMC) hydrogel (Opt-THL-Hgel) facilitated a biphasic release profile, effectively suppressing the initial burst and extending GA release for up to 24 h. Ex-vivo deposition studies revealed a significant 2.8-fold increase in skin retention compared to a conventional GA-hydrogel. In-vivo evaluation in a dinitrochlorobenzene-induced AD mouse model confirmed that Opt-THL-Hgel acts as a potent immuno-redox modulator, significantly reducing SCORAD indices and ear thickness, while restoring cutaneous antioxidant defenses (SOD, GPx, GSH) and downregulating pro-inflammatory cytokines (TNF-α, IL-6) compared with the AD model group (p < 0.05). These findings establish trehalosomes as a superior platform for the localized delivery of GA, offering a clinically relevant strategy for the long-term management of AD.

Levonorgestrel intrauterine systems (LNG-IUSs) are poly(dimethyl siloxane) (PDMS)-based long-acting drug delivery systems. No generic versions of LNG-IUSs are available; this is due, in part, to challenging aspects of developing and testing these products. One issue is the long timescale of real-time in vitro release tests (IVRTs) and the difficulty of developing accelerated IVRTs. This study developed a correlation between accelerated release rates in organic/aqueous release media and the Hansen Solubility Parameters (HSPs) of LNG, PDMS, and the release media. This study had three parts. First, the LNG-IUS Skyla was analyzed by real-time IVRT and various physicochemical characterization techniques. The purpose of this was to characterize Skyla's release mechanism and develop a model system termed Drug Reservoir-Membrane (DR-M). Second, the HSPs of LNG and PDMS were determined by assessing LNG's solubility and PDMS's swelling in 22 different solvents. This allowed comparison of the HSPs of LNG and PDMS with the HSPs of organic/aqueous accelerated-release media. Third, DR-M samples were tested in accelerated IVRTs and the accelerated release rates were correlated to a novel HSP-based quantity termed HSP Area, which is the triangular area in HSP space between LNG, PDMS, and the tested organic/aqueous release medium. This correlation captured accelerated release rates that were up to nine times faster than the real-time release rate. Additionally, this correlation captured release rates in media with different organic solvents (e.g., ethanol and isopropyl alcohol), and in media with different loadings of organic solvent (e.g., 10%, 20% and 30% organic solvent). We posit that the HSP Area correlation captures two mechanistic effects of the organic/aqueous accelerated-release media: first, this correlation accounts for organic solvent sorption into PDMS and increased drug permeation through PDMS; second; this correlation accounts for increased LNG solubility in the release medium and corresponding increased partitioning of LNG from PDMS into the release medium.

Enteric-coated dosage forms often suffer from sluggish post-gastric emptying drug release. This work focuses on developing novel enteric polymers as an approach to overcome this problem. The well-known polymer structures of Eudragit® L 100 and L 100-55 were esterified with the α-hydroxycarboxylic acids l-lactic, d,l-lactic and glycolic acid. A resulting partial positive charge arises within the ester linkage, reducing the pK_a value of the polymer. This translates to more facile deprotonation of the carboxylic acid moieties, which enables more rapid polymer dissolution and consequently faster drug release. The dissolution pH threshold was reduced from pH 5.5 for the established Eudragit® L 100-55 to around 5, while the valuable acid-resistant properties of the polymethacrylates were preserved. Capsules filled with paracetamol were coated with the modified polymers as well as with the commercially available materials Eudragit® L 100 and L 100-55. In 0.01 M hydrochloric acid all coated capsules remained intact without any significant drug release. However, in 15 mM phosphate buffer (pH 6.5) the drug release from the formulations based on the novel polymers was significantly enhanced compared to formulations with Eudragit® L 100 and L 100-55. The increased release rate was connected to the faster dissolution of the modified polymers. This novel series of enteric polymers could help to overcome clinical problems associated with the currently used enteric polymers.

Surface-engineered probiotics represent a promising therapeutic strategy for treating ulcerative colitis (UC). However, their therapeutic efficacy is often compromised by the complex pathological conditions and limited drug integration capacity. To overcome these therapeutic challenges, we developed a single-cell probiotic encapsulation system featuring with a sandwich-structured nanocoating (LGG@PLD-AS/ALG). The inner poly (L-dopa) (PLD) layer not only exhibited potent radical-scavenging capability, but also facilitated the dynamic loading of anti-inflammatory small molecule drugs (5-aminosalicylic acid, 5-ASA). Specifically, pathological reactive oxygen species (ROS) at the UC site triggered the cleavage of covalent bonds, resulting in on-demand 5-ASA release. Meanwhile, the outer alginate layer enabled intestinal-targeted delivery of probiotics and preventing premature 5-ASA leakage by undergoing pH-responsive degradation. In a dextran sulfate sodium (DSS)-induced murine colitis model, LGG@PLD-AS/ALG effectively promoted restoration of the intestinal barrier, rebalanced gut microbiota and alleviated colonic inflammation. This work proposes a novel single-cell probiotic encapsulation system with a sandwich-structured nanocoating, paving a new avenue for UC therapy.

The intricate architecture and physiology of the eye present ocular drug delivery with a significant challenge, resulting in restricted drug absorption and an insufficient therapeutic impact. Conventional delivery systems, however, fail to maintain an effective drug concentration over time, resulting in inadequate patient compliance and suboptimal treatment outcomes. Nanofiber-based ocular inserts have emerged as a viable alternative formulation for prolonged drug release, offering enhanced bioavailability and improved patient compliance. The current article provides a comprehensive analysis of the fabrication techniques for nanofiber-based ocular inserts, with particular emphasis on electrospinning and other innovative technologies. The article discusses the release mechanisms and their applications in various ocular diseases. Applications extend further to the care of ocular infections, glaucoma, retinal disorders, dry eye, and the regeneration of ocular tissue. Critical elements such as biocompatibility, immunological response, sterilization, and long-term stability, together with several evaluation methodologies and in vivo models, are examined. Product and process development considerations, including commercialization potential and scale-up, are discussed with a focus on market trends. Lastly, a regulatory perspective, along with future directions such as gene delivery, smart drug release, and tailored therapy, is discussed, highlighting the transformative potential of nanofiber technology in ophthalmology.