Optimized Rivastigmine Nanoparticles Coated with Eudragit for Intranasal Application to Brain Delivery: Evaluation and Nasal Ciliotoxicity Studies

Rivastigmine, a reversible cholinesterase inhibitor, is frequently indicated in the management of demented conditions associated with Alzheimer disease. The major hurdle of delivering this drug through the oral route is its poor bioavailability, which prompted the development of novel delivery approaches for improved efficacy. Due to numerous beneficial properties associated with nanocarriers in the drug delivery system, rivastigmine nanoparticles were fabricated to be administer through the intranasal route. During the development of the nanoparticles, preliminary optimization of processing and formulation parameters was done by the design of an experimental approach. The drug–polymer ratio, stirrer speed, and crosslinking time were fixed as independent variables, to analyze the effect on the entrapment efficiency (% EE) and in vitro drug release of the drug. The formulation (D8) obtained from 23 full factorial designs was further coated using Eudragit EPO to extend the release pattern of the entrapped drug. Furthermore, the 1:1 ratio of core to polymer depicted spherical particle size of ~175 nm, % EE of 64.83%, 97.59% cumulative drug release, and higher flux (40.39 ± 3.52 µg·h/cm2). Finally, the intranasal ciliotoxicity study on sheep nasal mucosa revealed that the exposure of developed nanoparticles was similar to the negative control group, while destruction of normal architecture was noticed in the positive control test group. Overall, from the in vitro results it could be summarized that the optimization of nanoparticles’ formulation of rivastigmine for intranasal application would be retained at the application site for a prolonged duration to release the entrapped drug without producing any local toxicity at the mucosal region.

Intranasal Administration of a Monoclonal Neutralizing Antibody Protects Mice Against SARS-CoV-2 Infection

Despite the recent availability of vaccines against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an urgent need for specific anti-SARS-CoV-2 drugs. Monoclonal neutralizing antibodies are an important drug class in the global fight against the SARS-CoV-2 pandemic due to their ability to convey immediate protection and their potential to be used as both prophylactic and therapeutic drugs. Clinically used neutralizing antibodies against respiratory viruses are currently injected intravenously, which can lead to suboptimal pulmonary bioavailability and thus to a lower effectiveness. Here we describe DZIF-10c, a fully human monoclonal neutralizing antibody that binds the receptor-binding domain of the SARS-CoV-2 spike protein. DZIF-10c displays an exceptionally high neutralizing potency against SARS-CoV-2, retains full activity against the variant of concern (VOC) B.1.1.7 and still neutralizes the VOC B.1.351, although with reduced potency. Importantly, not only systemic but also intranasal application of DZIF-10c abolished the presence of infectious particles in the lungs of SARS-CoV-2 infected mice and mitigated lung pathology when administered prophylactically. Along with a favorable pharmacokinetic profile, these results highlight DZIF-10c as a novel human SARS-CoV-2 neutralizing antibody with high in vitro and in vivo antiviral potency. The successful intranasal application of DZIF-10c paves the way for clinical trials investigating topical delivery of anti-SARS-CoV-2 antibodies.

Intranasal administration of a monoclonal neutralizing antibody protects mice against SARS-CoV-2 infection

Despite recent availability of vaccines against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an urgent need for specific anti-SARS-CoV-2 drugs. Monoclonal neutralizing antibodies are an important drug class in the global fight against the SARS-CoV-2 pandemic due to their ability to convey immediate protection and their potential to be used as both, prophylactic and therapeutic drugs. Clinically used neutralizing antibodies against respiratory viruses are currently injected intravenously, which can lead to suboptimal pulmonary bioavailability and thus to a lower effectiveness. Here we describe DZIF-10c, a fully human monoclonal neutralizing antibody that binds the receptor-binding domain of SARS-CoV-2 spike protein. DZIF-10c displays an exceptionally high neutralizing potency against SARS-CoV-2 and retains activity against the variants of concern B.1.1.7 and B.1.351. Importantly, not only systemic but also intranasal application of DZIF-10c abolished presence of infectious particles in the lungs of SARS-CoV-2 infected mice and mitigated lung pathology. Along with a favorable pharmacokinetic profile, these results highlight DZIF-10c as a novel human SARS-CoV-2 neutralizing antibody with high in vitro and in vivo antiviral potency. The successful intranasal application of DZIF-10c paves the way for clinical trials investigating topical delivery of anti-SARS-CoV-2 antibodies.

Physico-Chemical and In Vitro Characterization of Chitosan-Based Microspheres Intended for Nasal Administration

The absorption of non-steroidal anti-inflammatory drugs (NSAIDs) through the nasal epithelium offers an innovative opportunity in the field of pain therapy. Thanks to the bonding of chitosan to the nasal mucosa and its permeability-enhancing effect, it is an excellent choice to formulate microspheres for the increase of drug bioavailability. The aim of our work includes the preparation of spray-dried cross-linked and non-cross-linked chitosan-based drug delivery systems for intranasal application, the optimization of spray-drying process parameters (inlet air temperature, pump rate), and the composition of samples. Cross-linked products were prepared by using different amounts of sodium tripolyphosphate. On top of these, the micrometric properties, the structural characteristics, the in vitro drug release, and the in vitro permeability of the products were studied. Spray-drying resulted in micronized chitosan particles (2–4 μm) regardless of the process parameters. The meloxicam (MEL)-containing microspheres showed nearly spherical habit, while MEL was present in a molecularly dispersed state. The highest dissolved (>90%) and permeated (~45 µg/cm2) MEL amount was detected from the non-cross-linked sample. Our results indicate that spray-dried MEL-containing chitosan microparticles may be recommended for the development of a novel drug delivery system to decrease acute pain or enhance analgesia by intranasal application.

Comparative pharmacodynamics of intranasal and enteral administration of captopril for uncomplicated hypertensive crises

Uncomplicated hypertensive crises without acute or progressive damage to the target organs pose a potential threat to the patient’s life and require rapid reduction of arterial pressure within hours or days in an outpatient setting. The existing protocol for the treatment of this pathology is not entirely perfect, as it does not offer the primary physician a clear and unambiguous description of the use of effective and complementary drugs. The use in these cases of nasal transport of antihypertensive active pharmaceutical ingredients in appropriate dosage forms makes it possible to ensure their rapid delivery to the bloodstream and perivascular structures of the brain. Based on previous experience, and taking into account biopharmaceutical research on pharmacodynamics and pharmacokinetics of captopril innovative captopril dosage form has been developed and put into practice for trasmucosal administration as 2.5 % intranasal gel with controlled releasing of captopril substance in Zaporizhzhia State Medical University. The aim of the research was to study the pharmacodynamics of captopril gel in patients with arterial hypertension with uncomplicated hypertensive crises. Materials and methods. 58 outpatients with stage 2 arterial hypertension with uncomplicated cardiac crises were surveyed, an experienced group had 30 patients aged from 38 to 69 years (average age 52.60 ± 5.03 years) with average duration of disease 11.50 ± 2.72 years, obtained the intranasal application into two nasal routes 0.5 ml 2.5 % captopril gel with a dose syringe. Comparison group had 28 patients with stage 2 arterial hypertension with uncomplicated cardiac crises aged from 37 to 65 years with duration of arterial hypertension 10.8 ± 2.63 years, obtained peroral captopril in equivalent dose. Captopril tablets 0.025 g were used as a reference drug. In the course of treatment, the indicators of office blood pressure and heart rate in the crisis state were determined after 60, 120 and 240 minutes after the use of captopril. Because of asymmetric distribution, the non-parametric method – the Wilcoxon signed-rank test – was used. Results. There has been a significant reduction in systolic and diastolic arterial pressure one hour after the gel’s intranasal application by 19.9 % and 23.8 % respectively, whereas, after the use of captopril in tablets, there is only a tendency to decrease systolic and diastolic pressures by 8.8 % and 11.6 % respectively. Two hours after the use of the gel, systolic and diastolic blood pressure decreased by 23.5 % and 23.5 % respectively, reaching the level recommended by the leading cardiologists of Ukraine. After oral administration of the captopril tablets, systolic arterial pressure decreased by 13 %, diastolic arterial pressure, and heart rate showed only a downward trend. Four hours after the use of the captopril gel, there was a gradual increase in systolic arterial pressure, and the level of diastolic arterial pressure remained almost the same. After application of captopril gel, the heart rate in the treatment dynamics remained unchanged, with a trend of acceleration in the first time of treatment, and decreased by 4 hours by 12.4 %. Conclusions. A randomized, controlled study of nasal captopril pharmacodynamics in the form of 2.5 % hydrophilic gel compared to its tableted dosage form in patients with arterial hypertension with uncomplicated hypertensive crises was carried out. It has been established that the nasal dosage form of captopril provides for the reduction of the arterial pressure to the level recommended in the case of uncomplicated hypertensive crises for 4 hours more efficiently than the oral agent. Captopril nasal gel has been shown to have good tolerance and there are practically no side effects from its use.

Insulin-dependent maturation of newly generated olfactory sensory neurons after injury

Loss of olfactory sensory neurons (OSNs) after injury to the olfactory epithelium (OE) triggers the generation of OSNs that are incorporated into olfactory circuits to restore olfactory sensory perception. This study addresses how insulin receptor-mediated signaling affects the functional recovery of OSNs after OE injury. Insulin levels were reduced in mice by ablating the pancreatic beta cells via streptozotocin injections. These streptozotocin-induced diabetic and control mice were then intraperitoneally injected with the olfactotoxic drug methimazole to selectively ablate OSNs. The OE of diabetic and control mice regenerated similarly until day 14 after injury. Thereafter, the OE of diabetic mice contained fewer mature and more apoptotic OSNs than control mice. Functionally, diabetic mice showed reduced electro-olfactogram responses and their olfactory bulbs had fewer c-Fos-active cells following odor stimulation, as well as performed worse in an odor-guided task compared to control mice. Insulin administered intranasally during day 8 to 13 after injury was sufficient to rescue recovery of OSNs in diabetic mice compared to control levels, while insulin administration between days 1 – 6 did not. During this critical time window on day 8 – 13 after injury, insulin receptors are highly expressed and intranasal application of insulin receptor antagonist inhibits regeneration. Furthermore, an insulin-enriched environment could facilitate regeneration even in non-diabetic mice. These results indicate that insulin facilitates the regeneration of OSNs after injury and suggest a critical stage during recovery (8 – 13 days after injury) during which the maturation of newly generated OSNs is highly dependent on and promoted by insulin.Significance StatementAlthough insulin receptor signaling is known to influence on cellular processes such as proliferation and apoptosis, it is poorly understood whether the insulin influences the regeneration of olfactory sensory neurons (OSNs) after injury. We compared the maturation processes of new OSNs after the methimazole-induced loss of pre-existing OSNs between diabetic and control mice. The results show that the regeneration of new OSNs depend on sufficient insulin levels during a specific temporal window, when insulin receptor expression is highly upregulated. Furthermore, an insulin-enriched environment via nasal insulin application during the critical period facilitates OSNs regeneration even in non-diabetic mice. The present results have implications for intranasal application of insulin as potential clinical therapeutics to facilitate OSNs regeneration after the injury.