Optimized mucoadhesive niosomal carriers for intranasal delivery of carvedilol: A quality by design approach.

Carvedilol (CV), a ß-blocker essential for treating cardiovascular diseases, faces bioavailability challenges due to poor water solubility and first-pass metabolism. This study developed and optimized chitosan (CS)-coated niosomes loaded with CV (CS/CV-NS) for intranasal (IN) delivery, aiming to enhance systemic bioavailability. Utilizing a Quality-by-Design (QbD) approach, the study investigated the effects of formulation variables, such as surfactant type, surfactant-to-cholesterol (CHOL) ratio, and CS concentration, on CS/CV-NS properties. The focus was to optimize specific characteristics including particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%), and mucin binding efficiency (MBE%). The optimal formulation (Opt CS/CV-NS), achieved with a surfactant: CHOL ratio of 0.918 and a CS concentration of 0.062 g/100 mL, using Span 60 as the surfactant, exhibited a PS of 305 nm, PDI of 0.36, ZP of + 33 mV, EE% of 63 %, and MBE% of 57 %. Opt CS/CV-NS was characterized for its morphological and physicochemical properties, evaluated for stability under different storage conditions, and assessed for in vitro drug release profile. Opt CS/CV-NS demonstrated a 1.7-fold and 4.8-fold increase in in vitro CV release after 24 h, compared to uncoated CV-loaded niosomes (Opt CV-NS) and free CV, respectively. In vivo pharmacokinetic (PK) study, using a rat model, demonstrated that Opt CS/CV-NS achieved faster Tmax and higher Cmax compared to free CV suspension indicating enhanced absorption rate. Additionally, Opt CV-NS showed a 1.68-fold higher bioavailability compared to the control. These results underscore the potential of niosomal formulations in enhancing IN delivery of CV, offering an effective strategy for improving drug bioavailability and therapeutic efficacy.

Topical Administration of Verapamil in Poly(ethylene glycol)-Modified Liposomes for Enhanced Sinonasal Tissue Residence in Chronic Rhinosinusitis: Ex Vivo and In Vivo Evaluations.

Verapamil is a calcium channel blocker that holds promise for the therapy of chronic rhinosinusitis (CRS) with and without nasal polyps. The verapamil-induced side effects limit its tolerated dose via the oral route, underscoring the usefulness of localized intranasal administration. However, the challenge to intranasal administration is mucociliary clearance, which diminishes localized dose availability. To overcome this challenge, verapamil was loaded into a mucoadhesive cationic poly(ethylene glycol)-modified (PEGylated) liposomal carrier. Organotypic nasal explants were exposed to verapamil liposomes under flow conditions to mimic mucociliary clearance. The liposomes resulted in significantly higher tissue residence compared with the free verapamil control. These findings were further confirmed in vivo in C57BL/6 mice following intranasal administration. Liposomes significantly increased the accumulation of verapamil in nasal tissues compared with the control group. The developed tissue-retentive verapamil liposomal formulation is considered a promising intranasal delivery system for CRS therapy.

Cold exposure impairs extracellular vesicle swarm-mediated nasal antiviral immunity.

BACKGROUND: The human upper respiratory tract is the first site of contact for inhaled respiratory viruses and elaborates an array of innate immune responses. Seasonal variation in respiratory viral infections and the importance of ambient temperature in modulating immune responses to infections have been well recognized; however, the underlying biological mechanisms remain understudied. OBJECTIVE: We investigated the role of nasal epithelium-derived extracellular vesicles (EVs) in innate Toll-like receptor 3 (TLR3)-dependent antiviral immunity. METHODS: We evaluated the secretion and composition of nasal epithelial EVs after TLR3 stimulation in human autologous cells and fresh human nasal mucosal surgical specimens. We also explored the antiviral activity and mechanisms of TLR3-stimulated EVs against respiratory viruses as well as the effect of cool ambient temperature on TLR3-dependent antiviral immunity. RESULTS: We found that polyinosinic:polycytidylic acid, aka poly(I:C), exposure induced a swarm-like increase in the secretion of nasal epithelial EVs via the TLR3 signaling. EVs participated in TLR3-dependent antiviral immunity, protecting the host from viral infections through both EV-mediated functional delivery of miR-17 and direct virion neutralization after binding to virus ligands via surface receptors, including LDLR and ICAM-1. These potent antiviral immune defense functions mediated by TLR3-stimulated EVs were impaired by cold exposure via a decrease in total EV secretion as well as diminished microRNA packaging and antiviral binding affinity of individual EV. CONCLUSION: TLR3-dependent nasal epithelial EVs exhibit multiple innate antiviral mechanisms to suppress respiratory viral infections. Furthermore, our study provides a direct quantitative mechanistic explanation for seasonal variation in upper respiratory tract infection prevalence.

Nanocapsules modify membrane interaction of polymyxin B to enable safe systemic therapy of Gram-negative sepsis.

Systemic therapy of Gram-negative sepsis remains challenging. Polymyxin B (PMB) is well suited for sepsis therapy due to the endotoxin affinity and antibacterial activity. However, the dose-limiting toxicity has limited its systemic use in sepsis patients. For safe systemic use of PMB, we have developed a nanoparticulate system, called D-TZP, which selectively reduces the toxicity to mammalian cells but retains the therapeutic activities of PMB. D-TZP consists of an iron-complexed tannic acid nanocapsule containing a vitamin D core, coated with PMB and a chitosan derivative that controls the interaction of PMB with endotoxin, bacteria, and host cells. D-TZP attenuated the membrane toxicity associated with PMB but retained the ability of PMB to inactivate endotoxin and kill Gram-negative bacteria. Upon intravenous injection, D-TZP protected animals from pre-established endotoxemia and polymicrobial sepsis, showing no systemic toxicities inherent to PMB. These results support D-TZP as a safe and effective systemic intervention of sepsis.

Critical quality attributes in the development of therapeutic nanomedicines toward clinical translation.

Nanomedicine is a rapidly emerging field with several breakthroughs in the therapeutic drug delivery application. The unique properties of the nanoscale delivery systems offer huge advantages to their payload such as solubilization, increased bioavailability, and improved pharmacokinetics with an overall goal of enhanced therapeutic index. Nanomedicine has the potential for integrating and enabling new therapeutic modalities. Several nanoparticle-based drug delivery systems have been granted approval for clinical use based on their outstanding clinical outcomes. Nanomedicine faces several challenges that hinder the realization of its full potential. In this review, we discuss the critical formulation- and biological-related quality features that significantly influence the performance of nanoparticulate systems in vivo. We also discuss the quality-by-design approach in the pharmaceutical manufacturing and its implementation in the nanomedicine. A deep understanding of these nanomedicine quality checkpoints and a systematic design that takes them into consideration will hopefully expedite the clinical translation process. Graphical abstract.

Delivery of neurotrophic factors in the treatment of age-related chronic neurodegenerative diseases.

Introduction: Neurodegenerative diseases are those wherein the neurons in the brain or peripheral nervous system lose their function, eventually culminating in neuronal death. Aging acts as the predominant factor here due to the reduced protein turnover rate in aging cells. As neurotrophic factors possess imperative roles in protecting the neurons and restoring their functionality, design of different modalities to deliver them to the brain would significantly enhance the therapeutic benefits.Areas covered: This review covers the various mechanisms of neurodegeneration, its molecular link with aging, different neurotrophic factor classes and their potentials, current treatment strategies, the challenges associated with the delivery of neurotrophic factors, administration routes, design of different delivery vehicle design, alternative modalities of delivery, and the clinical translational challenges of these strategies.Expert opinion: A deeper molecular level understanding about the complexity of neurodegeneration, discovery of potential biomarkers, which helps identifying the right targets, finding the accurate animal model completely recapitulating the human scenario, and a validated design of clinical trials would immensely help in overcoming the present challenges. The substantial developments in the field of gene therapy, usage of small molecules and peptide mimetics, combinatory approaches, etc. definitely give brighter hopes.

Sustained Delivery of Carfilzomib by Tannic Acid-Based Nanocapsules Helps Develop Antitumor Immunity.

A group of chemotherapeutic drugs has gained increasing interest in cancer immunotherapy due to the potential to induce immunogenic cell death (ICD). A critical challenge in using the ICD inducers in cancer immunotherapy is the immunotoxicity accompanying their antiproliferative effects. To alleviate this, a nanocapsule formulation of carfilzomib (CFZ), an ICD-inducing proteasome inhibitor, was developed using interfacial supramolecular assembly of tannic acid (TA) and iron, supplemented with albumin coating. The albumin-coated CFZ nanocapsules (CFZ-pTA-alb) attenuated CFZ release, reducing toxicity to immune cells. Moreover, due to the adhesive nature of the TA assembly, CFZ-pTA-alb served as a reservoir of damage-associated molecular patterns released from dying tumor cells to activate dendritic cells. Upon intratumoral administration, CFZ-pTA-alb prolonged tumor retention of CFZ and showed consistently greater antitumor effects than cyclodextrin-solubilized CFZ (CFZ-CD) in B16F10 and CT26 tumor models. Unlike CFZ-CD, the locally injected CFZ-pTA-alb protected or enhanced CD8+ T cell population in tumors, helped develop splenocytes with tumor-specific interferon-γ response, and delayed tumor development on the contralateral side in immunocompetent mice (but not in athymic nude mice), supporting that CFZ-pTA-alb contributed to activating antitumor immunity. This study demonstrates that sustained delivery of ICD inducers by TA-based nanocapsules is an effective way of translating local ICD induction to systemic antitumor immunity.

Intraperitoneal chemotherapy of ovarian cancer by hydrogel depot of paclitaxel nanocrystals.

Intraperitoneal (IP) chemotherapy is a promising post-surgical therapy of ovarian cancer, but the full potential is yet to be realized. To facilitate IP chemotherapy of ovarian cancer, we developed an in-situ crosslinkable hydrogel depot containing paclitaxel (PTX) nanocrystals (PNC). PNC suppressed SKOV3 cell proliferation more efficiently than microparticulate PTX precipitates (PPT), and the gel containing PNC (PNC-gel) showed a lower maximum tolerated dose than PPT-containing gel (PPT-gel) in mice, indicating greater dissolution and cellular uptake of PNC than PPT. A single IP administration of PNC-gel extended the survival of tumor-bearing mice significantly better than Taxol, but PPT-gel did not. These results support the advantage of PNC over PPT and demonstrate the promise of a gel depot as an IP drug delivery system.

Hot-melts in buccoadhesive patches: an approach for bioavailability enhancement of highly-metabolized drugs with short elimination half-life.

The present study deals with the inclusion or incorporation of hot-melts into buccoadhesive patches. Our aim is to develop a patient-friendly dosage form that is capable of extending release of short elimination half-life drugs so to decrease dosing frequency and to increase the bioavailability of highly-metabolized drugs with the ultimate aim of dose reduction. Tizanidine hydrochloride (TIZ) was used as a model drug.TIZ was incorporated into Compritol-based hot-melts, and then further formulated into buccal patches prepared using HPMC, PVA and Polyox. A Central Composite Face-centered Design was employed to statistically optimize the formulation variables; HPMC solution/PVA solution weight ratio, Compritol/TIZ ratio in the hot-melts and percentage Polyox. The optimized formula suggested by the software was successful in controlling drug release, where 85% of TIZ was released after 4 h and the patch showed acceptable mucoadhesion properties. Pharmacokinetic parameters of TIZ from the optimized formula were compared to those of the immediate release tablet, Sirdalud®, as reference in human volunteers using a randomized crossover design. Significant increase was observed for Cmax, Tmax, AUC(0-12) and AUC(0-1). The increase in relative bioavailability of TIZ from the optimized formula was 2.57 folds.

Chitosan lactate wafer as a platform for the buccal delivery of tizanidine HCl: in vitro and in vivo performance.

Tizanidine HCl is a skeletal muscle relaxant that suffers from extensive hepatic metabolism resulting in 34-40% oral bioavailability. It also suffers from short half-life (2.1-4.2h) that necessitates frequent administration thus reducing patient compliance. In addition, tizanidine HCl is water soluble, so it is a challenging candidate for controlled drug delivery. In our study, tizanidine was encapsulated in chitosan lactate beads cross-linked with sodium tripolyphosphate. The beads were further incorporated into chitosan lactate wafer to be easily applied to buccal mucosa, aiming to bypass the hepatic metabolism. A central composite face-centered design was applied to statistically optimize the formulation variables; tripolyphosphate concentration, chitosan lactate concentration and polymer/drug ratio. The optimized formula suggested by the software composed of; 3.03% tripolyphosphate, 4.92% chitosan lactate and 2.13 polymer/drug ratio. It provided encapsulation efficiency of 56.5% and controlled tizanidine release over 8h. It is also characterized by being mucoadhesive and nonirritant. Pharmacokinetic parameters of tizanidine from the optimized formula were compared to those of the immediate release tablet, Sirdalud(®), as reference in human volunteers using a randomized crossover design. Significant increase was observed for Tmax and AUC(0-∞). The increase in relative bioavailability of TIZ from the optimized formula was 2.27 fold.