Drug Delivery and Translational Research最新文献

Buspirone hydrochloride (BSP) is an anxiolytic agent approved for the management of anxiety disorders. The current US-FDA approved medications of BSP are administered via the oral route, which is linked to several disadvantages such as low oral bioavailability and low half-life necessitating multiple daily doses. For chronic diseases such as anxiety disorders, where long-term or lifelong management is often required, these factors impact patient compliance and treatment adherence. The present study offers an alternative treatment approach by investigating the feasibility of sustained transdermal delivery of BSP via long-acting microneedles (MNs). Needle-tip-loaded MNs were fabricated via micro-molding technique using various grades of poly-vinyl alcohol (PVA) namely 4-88, 8-88, 18-88, and 26-88. These MNs were compared using characterization techniques such as Parafilm^® insertion testing, scanning electron microscopy (SEM), confocal microscopy, Fourier transform infrared spectroscopy (FTIR), and histological evaluation of MNs-treated human skin. The effect of different grades of PVA on the structural and mechanical properties of the fabricated MNs was evaluated. Further, in vitro release and permeation tests were conducted to assess the drug release patterns and transdermal delivery across dermatomed human skin over 7-day study periods. The highest release (5507.37 ± 456.88 µg/cm²) and delivery (4705.42 ± 634.57 µg/cm²) were observed from PVA 4-88, with significant differences among the PVA grades based on their properties. Notably, all four types of the fabricated PVA MNs crossed the daily and weekly therapeutic targets for the systemic delivery of BSP. Overall, this study established the feasibility of sustained delivery of BSP across the skin using PVA MNs for the management of anxiety disorders.

Procto-colectomy with an ileal pouch anal anastomosis is performed in Ulcerative Colitis patients as a potential curative surgical option. However, in many patients a non-specific inflammation of the ileal reservoir can occur, named pouchitis. Some patients further develop a chronic antibiotic-resistant disease. Rifaximin, an oral, broad-spectrum antibiotic has been shown to have efficacy for some patients. In the present study CB0125, a novel Rifamycin SV in situ gelling formulation, was developed as a potential pouchitis therapy. This mixture undergoes sol to gel transition under physiological pH and temperature upon administration to the target organ by enema. The in vivo efficacy of the in situ gel was performed using dextran sodium sulphate-induced colitis model in C57/Bl6 mice. The clinical parameters such as body weight changes, rectal bleeding and stool consistency were compared to mesalamine (positive control). In addition, a histopathological investigation was conducted to assess severity of mucosal damage and inflammation infiltrate. CB0125 was well tolerated and there was a significant reduction in disease activity, improved colon weight to length ratio, and improved histology score for the CB-01-25 in situ gel group compared to placebo gel. In addition, CB0125 was superior to mesalamine and to rifamycin SV dissolved in water. We propose that the rifamycin SV in situ gel may provide a longer duration of exposure of this dual acting antibiotic / anti-inflammatory drug at the site of the damaged intestinal mucosa resulting in a superior combined effect, relative to rifamycin SV dissolved in water, for the treatment of pouchitis.

Allergic conjunctivitis (AC) is the most common inflammatory disease affecting the eye's ocular surface, lid, conjunctiva, and cornea. However, effective ocular drug delivery remains challenging due to physiological barriers such as the corneal barrier. Ketotifen (KF), a widely used antihistamine and mast cell stabilizer, for treating AC and atopic asthma but belongs to the Biopharmaceutical Classification System (BCS II) have poor solubility. This study developed a multiple strategies approach for the first time, utilizing the spanlastics nano-vesicular carriers' system (SP) containing KF using an ethanol injection method. The optimized KF-SP exhibited the smallest particle size, largest zeta-potential and entrapment efficiency ∼232.5 ± 1.9 nm, -28 ± 0.51 and 73 ± 0.02%, respectively were further incorporated into PVA/PVP polymeric dissolving microneedles (MNs) by using a micromolding technique. Scanning electron microscopy (SEM) analysis confirmed well-defined tips and morphology, and in vitro studies showed a controlled 93% cumulative release over 72 h, with a zero-order kinetic release profile, providing stable therapeutic levels. Pharmacodynamic evaluation using the Ovalbumin/Aluminium hydroxide-induced AC model demonstrated significant reductions in IgE, TNF-α, and IL-6 levels by 68.7%, 71.3%, and 67.6%, respectively, while TGF-β and IL-10 levels increased by 70.1% and 62.7% using ELISA (Enzyme-Linked Immunosorbent Assay). Gene expression analysis (IGF-1, Annexin A1, and Bcl2) further supported the therapeutic potential of this system. In this study, we proved the topical application of the multiple strategies approach KF-SP loaded PVA/PVP MNs patch offers a targeted, sustained release treatment for AC, with promising implications for prolonged ocular therapy.

Hollow microneedles represent a promising approach for overcoming the protective barrier of the stratum corneum, facilitating direct drug infusion into viable skin tissue and thereby enhancing the efficacy of transdermal delivery. However, delivery outcomes across different skin layers and into the systemic circulation can vary substantially due to the diverse properties of drug delivery systems, clinical settings, and environmental factors. The optimal strategies for enhancing the efficiency of hollow microneedle-mediated transdermal drug delivery remain to be elucidated. This study employs mathematical modelling and a reconstructed skin model with realistic anatomical structures to investigate drug transport and accumulation across different skin layers and into the bloodstream under different delivery conditions. The modelling results reveal the crucial role of interstitial fluid flow in determining drug transport in this transdermal delivery. Delivery outcomes of each skin layer and blood exhibit distinct responses to changes in delivery conditions. Specifically, increasing the vascular permeability or nanocarrier diffusivity raises drug concentration in the blood or reticular dermis, respectively, while leading to reductions in other skin layers. The use of microneedles with narrower infusion channels can only enhance drug availability in the viable epidermis. Optimisation requires a tailored approach to several parameters depending on the target skin layer, including drug release rate, infusion rate, infusion duration, and microneedle length. Environmental factors that promote trans-epidermal water loss can increase drug concentration in the viable epidermis but have a limited impact on deeper skin tissues. The findings support the selection or customisation of hollow microneedles and nanocarriers to address specific therapeutic needs, such as targeting specific skin layers or systemic circulation, while minimising the risk of side effects from high drug concentrations in normal tissues. This study provides guidance for optimising transdermal drug delivery systems.

Psoriasis is a chronic inflammatory skin disease that, like other immune-mediated conditions, may benefit from small interfering RNA (siRNA)-based therapies, which are emerging as a promising alternative by addressing several limitations of current treatments. In this study, topical formulations of chitosan-based vectors were developed to deliver siRNA targeting tumor necrosis factor alpha (TNFα) to inflamed skin. Grafting diisopropylethylamine (DIPEA) and polyethylene glycol (PEG) onto the chitosan backbone enhanced siRNA delivery efficiency under physiological conditions, forming robust polymeric vectors with high structural and colloidal stability. These vectors provided siRNA protection against RNAse degradation and oxidative damage. Additionally, the chitosan derivatives displayed lysozyme-mediated biodegradability comparable to native chitosan, while PEG was released in response to reductive environments, supporting controlled vector disassembly. The PEGylated DIPEA-chitosan/siRNA polyplexes demonstrated positive zeta potentials (up to + 11 mV), particle sizes of 100-200 nm, and very low cytotoxicity in keratinocyte and fibroblast cell lines. In vitro, the polyplexes achieved TNFα knockdown levels (65%) in RAW macrophages, comparable to those obtained with Lipofectamine™. Topical formulations showed enhanced interaction of vectors with skin models (Strat-M^® and porcine ear skin) compared to naked siRNA. Furthermore, in vivo studies indicated that hair follicles were a key route for polyplexes to penetrate deeper skin layers. A rodent model of psoriasis induced by imiquimod was treated topically with these vectors, resulting in approximately a 50% reduction in TNFα levels at inflammation sites, decreased immune cell infiltration, and preservation of epidermal structure. These findings collectively underscore the potential of DIPEA-chitosan-based vectors for topical siRNA-based therapies.

Due to the unique physiological barriers within the lungs, there are considerable challenges in developing drug delivery systems enabling prolonged drug exposure to respiratory epithelial cells. Here, we report a PulmoSphere-based dry powder technology that incorporates a drug-phospholipid complex to promote intracellular retention of dehydroandrographolide succinate (DAS) in respiratory epithelial cells following pulmonary delivery. The DAS-phospholipid complex has the ability to self-assemble into nanoparticles. After spray-drying to produce PulmoSphere microparticles loaded with the drug-phospholipid complex, the rehydrated microparticles discharge the phospholipid complex without altering its physicochemical properties. The microparticles containing the DAS-phospholipid complex exhibit remarkable aerodynamic properties with a fine particle fraction of ∼ 60% and a mass median aerodynamic diameter of ∼ 2.3 μm. These properties facilitate deposition in the alveolar region. In vitro cell culture and lung tissue explants experiments reveal that the drug-phospholipid complex prolongs intracellular residence time and lung tissue retention due to the slow intracellular disassociation of drug from the complex. Once deposited in the lungs, the DAS-phospholipid complex loaded microparticles increase and extend drug exposure to the lung tissues and the immune cells compared to the free DAS counterpart. The improved drug exposure to airway epithelial cells, but not immune cells, is related to a prolonged duration of pulmonary anti-inflammation at decreased doses in a mouse model of acute lung injury induced by lipopolysaccharide. Overall, the phospholipid complex loaded microparticles present a promising approach for improved treatment of respiratory diseases, e.g. pneumonia and acute respiratory distress syndrome.

Nanogel (NG) drug delivery systems have emerged as promising tools for targeted and controlled drug release, revolutionizing treatment approaches across various diseases. Their unique physicochemical properties, such as nano size, high surface area, biocompatibility, stability, and tunable drug release, make them ideal carriers for a wide range of therapeutic agents. Nanogels (NGs), characterized by their 3D network of crosslinked polymers, offer unique edges like high drug loading capacity, controlled release, and targeted delivery. Additionally, the diverse applications of NGs in medical therapeutics highlight their versatility and potential impact on improving patient outcomes. Their application spans cancer treatment, infectious diseases, and chronic conditions, allowing for precise drug delivery to specific tissues or cells, minimizing side effects, and enhancing therapeutic efficacy. Despite their potential, challenges such as scalability, manufacturing reproducibility, and regulatory hurdles must be addressed. Achieving clinical translation requires overcoming these obstacles to ensure therapeutic payloads' safe and efficient delivery. Strategies such as surface modification and incorporating stimuli-responsive elements enhanced NG performance and addressed specific therapeutic challenges. Advances in nanotechnology, biomaterials, and targeted drug design offer opportunities to improve the performance of NGs and address current limitations. Tailoring NGs for exploring combination therapies and integrating diagnostics for real-time monitoring represent promising avenues for future research. In conclusion, NG drug delivery systems have demonstrated tremendous potential in diverse disease applications. Overcoming challenges and leveraging emerging technologies will pave the way for their widespread clinical implementation, ushering in a new era of precision medicine and improved patient care.

Photodynamic Therapy (PDT) is a promising paradigm for treating cancer, especially superficial cancers, including skin and oral cancers. However, the effectiveness of PDT is hindered by the hydrophobicity of photosensitizers. Here, chlorin e6 (Ce6), a hydrophobic photosensitizer, was loaded into pluronic F127 micelles to enhance solubility and improve tumor-specific targeting efficiency. The resulting Ce6@F127 Ms demonstrated a significant increase in solubility and singlet oxygen generation (SOG) efficiency in aqueous media compared to free Ce6. The confocal imaging and fluorescence-activated cell sorting (FACS) analysis confirmed the enhanced internalization rate of Ce6@F127 Ms in murine melanoma cell lines (B16F10) and human oral carcinoma cell lines (FaDu). Upon laser irradiation (666 nm), the cellular phototoxicity of Ce6@F127 Ms against B16F10 and FaDu was approximately three times higher than the free Ce6 treatment. The in vivo therapeutic investigations conducted on a murine model of skin cancer demonstrated the ability of Ce6@F127 Ms, when combined with laser treatment, to penetrate solid tumors effectively, which resulted in a significant reduction in tumor volume compared to free Ce6. Further, the Ce6@F127 Ms demonstrated upregulation of TUNEL-positive cells, downregulation of proliferation markers in tumor tissues, and prevention of lung metastasis with insignificant levels of proliferating cells and collagenase, as validated through immunohistochemistry. Subsequent analysis of serum and blood components affirmed the safety and efficacy of Ce6@F127 Ms in mice. Consequently, the developed Ce6@F127 Ms exhibits significant potential for concurrently treating solid tumors and preventing metastasis. The photodynamic formulation holds great clinical translation potential for treating superficial tumors.

Lewisite, a chemical warfare agent, causes skin blisters, erythema, edema, and inflammation, requiring mitigation strategies in case of accidental or deliberate exposure. 4-phenyl butyric acid (4-PBA), a chemical chaperone, reduces endoplasmic reticulum stress and skin inflammation. The study aimed to encapsulate 4-PBA in microsponges for effective, sustained delivery against lewisite injury. Porous microsponges in a topical gel would potentially sustain delivery and improve residence time on the skin. Microsponges were developed using the quasi-emulsion solvent diffusion method with Eudragit RS100. Optimized formulation showed 10.58%w/w drug loading was incorporated in a carboxymethylcellulose (CMC) and Carbopol gel for in vitro release and permeation testing using dermatomed human skin. A sustained release was obtained from all vehicles in the release study, and IVPT results showed that compared to the control (41.52 ± 2.54 µg/sq.cm), a sustained permeation profile with a reduced delivery was observed for microsponges in PBS (14.16 ± 1.23 µg/sq.cm) along with Carbopol 980 gel (12.55 ± 1.41 µg/sq.cm), and CMC gel (10.09 ± 1.23 µg/sq.cm) at 24 h. Optimized formulation showed significant protection against lewisite surrogate phenyl arsine oxide (PAO) challenged skin injury in Ptch1^+/-/SKH-1 hairless mice at gross and molecular levels. A reduction in Draize score by 29%, a reduction in skin bifold thickness by 8%, a significant reduction in levels of IL-1β, IL6, and GM-CSF by 54%, 30%, and 55%, respectively, and a reduction in apoptosis by 31% was observed. Thus, the translational feasibility of 4-PBA microsponges for effective, sustained delivery against lewisite skin injury is demonstrated.

Apocynin (APO) is a plant derived antioxidant exerting specific NADPH oxidase inhibitory action substantiating its neuroprotective effects in various CNS disorders, including epilepsy. Due to rapid elimination and poor bioavailability, treatment with APO is challenging. Correspondingly, novel APO-loaded lipid nanocapsules (APO-LNC) were formulated and coated with lactoferrin (LF-APO-LNC) to improve br ain targetability and prolong residence time. Lavender oil (LAV) was incorporated into LNC as a bioactive ingredient to act synergistically with APO in alleviating pentylenetetrazol (PTZ)-induced seizures. The optimized LF-APO-LAV/LNC showed a particle size 59.7 ± 4.5 nm with narrow distribution and 6.07 ± 1.6mV zeta potential) with high entrapment efficiency 92 ± 2.4% and sustained release (35% in 72 h). Following subcutaneous administration, LF-APO-LAV/LNC brought about ⁓twofold increase in plasma AUC and MRT compared to APO. A Log BB value of 0.2 ± 0.14 at 90 min reflects increased brain accumulation. In a PTZ-induced seizures rat model, LF-APO-LAV/LNC showed a Modified Racine score of 0.67 ± 0.47 with a significant increase in seizures latency and decrease in duration. Moreover, oxidant/antioxidant capacity and inflammatory markers levels in brain tissue were significantly improved. Histopathological and immunohistochemical assessment of brain tissue sections further supported these findings. The results suggest APO/LAV combination in LF-coated LNC as a promising approach to counteract seizures.