Intranasal Delivery System Research Articles

Exploring the Intranasal Medication Delivery Methods for the Management of Hypertension

Intranasal drug delivery systems (INDS) have attracted interest as a possible tactic to enhance the bioavailability and absorption of medications. The use of INDS to treat hypertension (HTN), a prevalent cardiovascular ailment, is examined in this review study. The paper describes the ability for medication to cross the nasal barrier and gives a summary of the cellular and structural makeup of the nasal cavity. It talks about many options and strategies to improve the way nasal drugs are delivered, with an emphasis on devices that make use of nanotechnology. The paper also includes a thorough analysis of the various approaches to treating HTN and a discussion of how INDS can enhance medication efficacy and lessen systemic side effects. This review compiles available literature on formulation strategies, relevant in vivo, ex vivo, and in vitro assessment technologies, as well as the advancement of studies concerning the role of the nasal epithelium in the systemic circulation of antihypertensive medications. With intranasal delivery, the first-pass impact is removed, doses are lowered, and drug bioavailability is enhanced. Future research in this area may lead to more effective and patient-friendly HTN therapies.

Chitosan-coated nanoemulsion for intranasal administration increases temozolomide mucosal permeation, cellular uptake, and In vitro cytotoxicity in glioblastoma multiforme cells

Glioblastoma multiforme (GBM) is the most prevalent and aggressive type of brain cancer in adults. Temozolomide (TMZ) is the chemotherapeutic agent used to treat primary central nervous system tumors. However, TMZ's clinical effectiveness faces several challenges due to its physical-chemical properties and biological features of GBM, such as the blood-brain barrier (BBB). Mucoadhesive nanosystems such as those coated with chitosan represent a promising alternative for optimizing the delivery of therapeutic agents to the central nervous system, as they possess ideal characteristics that enhance their interaction with the intranasal mucosa. We aimed to develop a chitosan-coated nanoemulsion containing temozolomide (CS-NE-TMZ) for nose-to-brain delivery and characterize its physical-chemical and in vitro biological properties. CS-NE-TMZ were obtained by emulsification followed by sonication. The optimized CS-NE-TMZ presented droplet size of 123,4 ± 2,3 nm, polydispersity index of 0.273 ± 0.028, zeta potential of +21,5 ± 0,81 mV, entrapment efficiency of 100 ± 1,91 % and drug loading of 2 ± 0,007 %. An in vitro release study of CS-NE-TMZ showed sustained release for up to 24 h following the Korsmeyer-Peppas model with Fickian diffusion. CS-NE-TMZ demonstrated significantly enhanced ex vivo mucosal permeation, compared to free TMZ, and showed enhanced in vitro cellular uptake, selectively increasing cytotoxicity in U-87MG glioma cells but not in healthy L929 fibroblasts, reinforcing the potential of mucoadhesive nanoemulsions as effective intranasal drug delivery systems for future brain cancer therapies.

Prospects for the use of intranasal nanoscale polymer delivery systems for drugs and antidotes in extreme medicine

Introduction. The development of improved formulations of antidotes and remedies, which can be used not only by qualified medical personnel, but also in self- and mutual assistance, is an urgent task for extreme medicine.Objective. Evaluation of the possibility of using nanoscale polymer delivery systems for medicines and antidotes intended for intranasal administration (into the nasal cavity) in extreme medicine.Discussion. The main submicron-sized polymer carriers which are promising as the basis for the creation of an intranasal form of antidotes are identified. The bioavailability of the substance delivered is dependent on the physico-chemical properties of the carrier, the conditions for its production, as well as physiological and anatomical factors. Data is presented regarding possible ways of correcting these factors in order to increase bioavailability. Examples of the use of polymer nanocarriers in the treatment of poisoning with heavy metals and rocket fuel components, as well as lesions caused by radioactive substances, are presented. It is shown that carriers (dendrimers, cyclodextrins) can act as antidotes in certain cases. The study presents a list of antidotes approved for use within the territory of the Russian Federation, for which the development of intranasal forms is possible, taking their physico-chemical and pharmacokinetic properties into account.Conclusions. Following a review of literature sources, the most promising submicron-sized polymer carriers for the intensification of intranasal delivery of drugs and antidotes are herein proposed: dendrimers, liposomes, nanocapsules, nanoparticles, and cyclodextrins. Using the list of antidotes approved for use in the Russian Federation as an example, promising drugs that can be potentially developed on the basis of these carriers are proposed.

Review of Intranasal Active Pharmaceutical Ingredient Delivery Systems.

In recent decades, there has been an increased interest in the development of intranasal delivery systems for active pharmaceutical ingredients (APIs) not only for treating local nasal diseases but also for treating systemic diseases, central nervous system (CNS) disorders, and vaccine delivery. The nasal cavity possesses a unique set of anatomical characteristics for delivering active pharmaceutical ingredients, but there are several limitations that recent research in the field of the intranasal administration of APIs aims to overcome. For the effective delivery of nasal preparations, active pharmaceutical ingredients are incorporated into various micro- and nanosystems. Some of the most commonly encountered API delivery systems in the scientific literature include liposomal systems, polymer particles with mucoadhesive properties, in situ gels, nano- and microemulsions, and solid lipid particles. This article provides a review of research on the development of nasal preparations for treating local nasal cavity diseases (in particular, for antibiotic delivery), systemic diseases (analgesics, drugs for cardiovascular diseases, antiviral and antiemetic drugs), CNS disorders (Alzheimer's disease, Parkinson's disease, epilepsy, schizophrenia, depression), and vaccine delivery. The literature data show that active research is underway to reformulate drugs of various pharmacotherapeutic groups into a nasal form.

First Biodistribution Study of [68Ga]Ga-NOTA-Insulin Following Intranasal Administration in Adult Vervet Monkeys.

Intranasal insulin (INI) is being explored as a treatment for Alzheimer's disease (AD). Improved memory, functional ability, and cerebrospinal fluid (CSF) AD biomarker profiles have been observed following INI administration. However, the method of intranasal delivery may significantly affect outcomes. To show reliable delivery of insulin to the brain using the Aptar Cartridge Pump System (CPS) intranasal delivery system. To visualize INI biodistribution, we developed a novel PET radiotracer, Gallium 68-radiolabeled (NOTA-conjugated) insulin, [68Ga]Ga-NOTA-insulin. We used the Aptar CPS to administer [68Ga]Ga-NOTA-insulin to anesthetized healthy adult vervet monkeys and measured brain regional activity and whole-body dosimetry following PET/CT scans. We observed brain penetration of [68Ga]Ga-NOTA-insulin following intranasal administration with the Aptar CPS. Radioactive uptake was seen in multiple regions, including the amygdala, putamen, hypothalamus, hippocampus, and choroid plexus. A safety profile and whole-body dosimetry were also established in a second cohort of vervets. Safety was confirmed: vitals remained stable, blood glucose levels were unchanged, and no organ was exposed to more than 2.5 mSv of radioactivity. Extrapolations from vervet organ distribution allowed for estimation of the [68Ga]Ga-NOTA-insulin absorbed dose in humans, and the maximum dose of [68Ga]Ga-NOTA-insulin that can be safely administered to humans was determined to be 185 MBq. The use of [68Ga]Ga-NOTA-insulin as a PET radiotracer is safe and effective for observing brain uptake in vervet monkeys. Further, the Aptar CPS successfully targets [68Ga]Ga-NOTA-insulin to the brain. The data will be essential in guiding future studies of intranasal [68Ga]Ga-NOTA-insulin administration in humans.

A Comprehensive Review on the Nanotechnology-based Intranasal Drug Delivery Systems for Brain Targeting

A Comprehensive Review on the Nanotechnology-based Intranasal Drug Delivery Systems for Brain Targeting

Construction of an intranasal drug delivery system with hypothalamus‐targeting nanoparticles

AbstractDysfunction of the hypothalamus is associated with endocrine imbalances, growth abnormalities, and reproductive disorders. However, there is a lack of targeted treatment strategies focused on the hypothalamus. In this study, we constructed a multifunctional nanocarrier system (S@ANP) to directly target the hypothalamic neurokinin receptor 3 (NK3R) via an intranasal delivery strategy. This system could overcome the primary obstacles in drug delivery for hypothalamus‐related diseases. Under the guidance of a modified (Trp7, β‐Ala8)‐neurokinin A (4‐10) peptide with cysteine, nanoparticles encapsulated with SB222200, an NK3R inhibitor, were found to readily penetrate hypothalamic cells with substantial loading capacity, encapsulation efficiency, and sustained release in vitro. Moreover, intranasal delivery represents an optimal delivery strategy that allows for a significant reduction in oral dosage and enables nanoparticles to bypass the blood‒brain barrier and target relevant parts of the brain. The mucolytic agent N‐acetyl‐L‐cysteine (NAC) was loaded into the nanoparticles (S@ANP + NAC) to increase mucosal solubility and intranasal delivery efficiency. In vivo evaluations showed that S@ANP + NAC could effectively target the hypothalamus and modulate NK3R‐regulated hypothalamic functions in mice. Due to its high hypothalamic targeting efficiency and low toxicity, this intranasal nanoparticle drug delivery system may serve as a potential strategy for precision therapy of hypothalamic disorders.

Chitosan-Based Nanocarriers for Pulmonary and Intranasal Drug Delivery Systems: A Comprehensive Overview of their Applications.

The optimization of respiratory health is important, and one avenue for achieving this is through the application of both Pulmonary Drug Delivery System (PDDS) and Intranasal Delivery (IND). PDDS offers immediate delivery of medication to the respiratory system, providing advantages, such as sustained regional drug concentration, tunable drug release, extended duration of action, and enhanced patient compliance. IND, renowned for its non-invasive nature and swift onset of action, presents a promising path for advancement. Modern PDDS and IND utilize various polymers, among which chitosan (CS) stands out. CS is a biocompatible and biodegradable polysaccharide with unique physicochemical properties, making it well-suited for medical and pharmaceutical applications. The multiple positively charged amino groups present in CS facilitate its interaction with negatively charged mucous membranes, allowing CS to adsorb easily onto the mucosal surface. In addition, CS-based nanocarriers have been an important topic of research. Polymeric Nanoparticles (NPs), liposomes, dendrimers, microspheres, nanoemulsions, Solid Lipid Nanoparticles (SLNs), carbon nanotubes, and modified effective targeting systems compete as important ways of increasing pulmonary drug delivery with chitosan. This review covers the latest findings on CS-based nanocarriers and their applications.

Nanotechnology-based Intranasal Drug Delivery Systems: A Review

An experimental study has focused on developing a different approach to systemic oral along with parenteral administration in order to overcome their common drawbacks, including hepatic first-pass, which reduces drug bioavailability following oral administration, off-target effects, low patient compliance, along with a slow onset of pharmacological action through first-aid cases. Novel drug delivery systems (DDS), mostly composed of polymers and biocompatible lipid materials, have significantly boosted this sector in recent years. The previously intranasal (IN) method of delivery is an acceptable non-invasive option. It is ideal for self-administration since the medication quickly enters the circulation, eliminating the initial pass effect, and it may additionally reach the brain’s cortex directly by crossing the blood-brain barrier (BBB). The combination of the IN route alongside DDS can, therefore, become a successful method for regulated drug administration, particularly when a rapid impact is sought or required. This study seeks to analyze the scientific literature on IN-DDS and its various routes for consumption (systemic, topical, pulmonary, and nose-to-brain). In this regard, the intranasal route offers a viable pathway for medication delivery reaching the brain because of its distinct anatomical characteristics. Nanoparticle-based technologies, in particular, have proven a remarkable ability to overcome the limitations of the intranasal route to induce drug accumulation throughout the brain despite avoiding systemic dissemination

Recent advances in biopolymer based electrospun nanomaterials for drug delivery systems

AbstractDrug delivery systems, including liposomes, gels, prodrugs, and so forth, are used to enhance the tissue benefit of a pharmaceutical drug or conventional substance at a specific diseased site with little toxicological impact. Nanotechnology can be a rapidly developing multidisciplinary science that enables the production of polymers at the manometer scale for different medical applications. The use of biopolymers in drug delivery systems provides compatibility, biodegradability and low immunogenicity biologically. Large‐scale and smaller‐than‐expected medication particles can be delivered using biopolymers such as silk fibroins, collagen, gelatine, and others that are easily formed into suspensions. These drug carrier systems are functional at improving drug delivery and can be used in intranasal, transdermal, dental, and ocular delivery systems. This study discusses the latest developments in drug delivery methods based on nanomaterials, mainly using biopolymers like proteins and polysaccharides.

Nose-to-brain delivery of nanotherapeutics: Transport mechanisms and applications.

The blood-brain barrier presents a key limitation to the administration of therapeutic molecules for the treatment of brain disease. While drugs administered orally or intravenously must cross this barrier to reach brain targets, the unique anatomical structure of the olfactory system provides a route to deliver drugs directly to the brain. Entering the brain via receptor, carrier, and adsorption-mediated transcytosis in the nasal olfactory and trigeminal regions has the potential to increase drug delivery. In this review, we introduce the physiological and anatomical structures of the nasal cavity, and summarize the possible modes of transport and the relevant receptors and carriers in the nose-to-brain pathway. Additionally, we provide examples of nanotherapeutics developed for intranasal drug delivery to the brain. Further development of nanoparticles that can be applied to intranasal delivery systems promises to improve drug efficacy and reduce drug resistance and adverse effects by increasing molecular access to the brain. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease.

Polymeric Nanoparticles as Oral and Intranasal Peptide Vaccine Delivery Systems: The Role of Shape and Conjugation.

Mucosal vaccines are highly attractive due to high patient compliance and their suitability for mass immunizations. However, all currently licensed mucosal vaccines are composed of attenuated/inactive whole microbes, which are associated with a variety of safety concerns. In contrast, modern subunit vaccines use minimal pathogenic components (antigens) that are safe but typically poorly immunogenic when delivered via mucosal administration. In this study, we demonstrated the utility of various functional polymer-based nanostructures as vaccine carriers. A Group A Streptococcus (GAS)-derived peptide antigen (PJ8) was selected in light of the recent global spread of invasive GAS infection. The vaccine candidates were prepared by either conjugation or physical mixing of PJ8 with rod-, sphere-, worm-, and tadpole-shaped polymeric nanoparticles. The roles of nanoparticle shape and antigen conjugation in vaccine immunogenicity were demonstrated through the comparison of three distinct immunization pathways (subcutaneous, intranasal, and oral). No additional adjuvant or carrier was required to induce bactericidal immune responses even upon oral vaccine administration.

Research progress in brain-targeted nasal drug delivery.

The unique anatomical and physiological connections between the nasal cavity and brain provide a pathway for bypassing the blood-brain barrier to allow for direct brain-targeted drug delivery through nasal administration. There are several advantages of nasal administration compared with other routes; for example, the first-pass effect that leads to the metabolism of orally administered drugs can be bypassed, and the poor compliance associated with injections can be minimized. Nasal administration can also help maximize brain-targeted drug delivery, allowing for high pharmacological activity at lower drug dosages, thereby minimizing the likelihood of adverse effects and providing a highly promising drug delivery pathway for the treatment of central nervous system diseases. The aim of this review article was to briefly describe the physiological structures of the nasal cavity and brain, the pathways through which drugs can enter the brain through the nose, the factors affecting brain-targeted nasal drug delivery, methods to improve brain-targeted nasal drug delivery systems through the application of related biomaterials, common experimental methods used in intranasal drug delivery research, and the current limitations of such approaches, providing a solid foundation for further in-depth research on intranasal brain-targeted drug delivery systems (see Graphical Abstract).

Intranasal Drug Delivery by Nanotechnology: Advances in and Challenges for Alzheimer's Disease Management.

Alzheimer's disease, a progressive neurodegenerative condition, is characterized by a gradual decline in cognitive functions. Current treatment approaches primarily involve the administration of medications through oral, parenteral, and transdermal routes, aiming to improve cognitive function and alleviate symptoms. However, these treatments face limitations, such as low bioavailability and inadequate permeation. Alternative invasive methods, while explored, often entail discomfort and require specialized assistance. Therefore, the development of a non-invasive and efficient delivery system is crucial. Intranasal delivery has emerged as a potential solution, although it is constrained by the unique conditions of the nasal cavity. An innovative approach involves the use of nano-carriers based on nanotechnology for intranasal delivery. This strategy has the potential to overcome current limitations by providing enhanced bioavailability, improved permeation, effective traversal of the blood-brain barrier, extended retention within the body, and precise targeting of the brain. The comprehensive review focuses on the advancements in designing various types of nano-carriers, including polymeric nanoparticles, metal nanoparticles, lipid nanoparticles, liposomes, nanoemulsions, Quantum dots, and dendrimers. These nano-carriers are specifically tailored for the intranasal delivery of therapeutic agents aimed at combatting Alzheimer's disease. In summary, the development and utilization of intranasal delivery systems based on nanotechnology show significant potential in surmounting the constraints of current Alzheimer's disease treatment strategies. Nevertheless, it is essential to acknowledge regulatory as well as toxicity concerns associated with this route; meticulous consideration is required when engineering a carrier. This comprehensive review underscores the potential to revolutionize Alzheimer's disease management and highlights the importance of addressing regulatory considerations for safe and effective implementations. Embracing this strategy could lead to substantial advancements in the field of Alzheimer's disease treatment.

In silico exploration of venlafaxine, a potential non-tricyclic antidepressant in a liposomal formulation for nose-to-brain drug delivery

Objective Non-tricyclic antidepressants (non-TCAs) work by preventing the intake of norepinephrine and serotonin. Therefore, the aim of this study was to identify a potent non-TCAs and to develop liposomal formulation, characterize and to determine the drug release study across model of dialysis membrane via in vitro and in silico techniques. Methods The in silico docking analysis identified venlafaxine (VLF) as the best non-TCAs with the depressant targets (PDB ID: 3PBL and 4BVN). VLF-loaded liposomal formulation was prepared by the thin-film hydration technique and characterized by physicochemical properties, including entrapment efficacy, in vitro drug release, particle size analysis, and FTIR. Moreover, this article also compares VLF and VLF-loaded with liposome carriers (LPs) based on nose-to-brain drug delivery approaches to treating depression. Results Drug release profiles of the optimal liposomal formulation of VLF-LPs were examined in the high entrapment efficiency 94.13 ± 1.20% was attained at 224 nm, composed of spherical particles having a mean particle size of 191 ± 2.0 nm, a polydispersity index of 0.281 ± 0.06 and zeta potential of −20.3 mV. The best formulation of VLF-LPs was more effective than oral VLF treatment, as shown by the in vitro drug release data. Conclusion The results show that the VLF-LPs formulation is a promising potential platform for application in nose-to-brain drug delivery. Thus, highlighting the robustness of the intranasal drug delivery system with enhanced pharmaceutical properties, efficacy, and bioavailability for the anti-depression effect.

Evaluation of nasal delivery systems of olanzapine by desorption electrospray ionization mass spectrometry imaging

Nose-to-brain delivery presents an attractive administration route for neuroactive drugs that suffer from compromised bioavailability or fail to pass the blood–brain barrier. However, the conventional gauge of effectiveness for intranasal delivery platforms primarily involves detecting the presence of the administered drug within the brain, with little insight into its precise localization within brain structures. This may undermine the therapeutic efficacy of drugs and hinder the design of systems that target specific brain regions. In this study, we designed two intranasal delivery systems for the antipsychotic drug, olanzapine, and evaluated its distribution in the rat brain following intranasal administration. The first evaluated system was an olanzapine-loaded microemulsion and the second one was nanoparticulate aqueous dispersion of olanzapine. Both systems exhibited characteristics that render them compatible for intranasal administration, and successfully delivered olanzapine to the brain. We further employed an ambient mass spectrometry imaging method, called desorption electrospray ionization mass spectrometry imaging, to visualize the signal intensity of olanzapine in different brain regions following the intranasal administration of these two systems. Substantial variations in the distribution patterns of olanzapine across various brain structures were revealed, potentially highlighting the importance of mass spectrometry imaging in designing and evaluating intranasal drug delivery platforms.

Transmucosal Delivery of Nasal Nanovaccines Enhancing Mucosal and Systemic Immunity.

Intranasal vaccines can induce protective immune responses at the mucosa surface entrance, preventing the invasion of respiratory pathogens. However, the nasal barrier remains a major challenge in the development of intranasal vaccines. Herein, a transmucosal nanovaccine based on cationic fluorocarbon modified chitosan (FCS) is developed to induce mucosal immunity. In our system, FCS can self-assemble with the model antigen ovalbumin and TLR9 agonist CpG, effectively promoting the maturation and cross-presentation of dendritic cells. More importantly, it can enhance the production of secretory immunoglobin A (sIgA) at mucosal surfaces for those intranasally vaccinated mice, which in the meantime showed effective production of immunoglobulin G (IgG) systemically. As a proof-of-concept study, such a mucosal vaccine inhibits ovalbumin-expressing B16-OVA melanoma, especially its lung metastases. Our work presents a unique intranasal delivery system to deliver antigen across mucosal epithelia and promote mucosal and systemic immunity.

Brain photobiomodulation therapy on neurological and psychological diseases.

Photobiomodulation (PBM) therapy is an innovative treatment for neurological and psychological conditions. Complex IV of the mitochondrial respiratory chain can be stimulated by red light, which increases ATP synthesis. In addition, the ion channels' light absorption causes the release of Ca2+, which activates transcription factors and changes gene expression. Neuronal metabolism is improved by brain PBM therapy, which also promotes synaptogenesis and neurogenesis as well as anti-inflammatory. Its depression-treating potential is attracting attention for other conditions, including Parkinson's disease and dementia. Giving enough dosage for optimum stimulation using the transcranial PBM technique is challenging because of the rapidly increasing attenuation of light transmission in tissue. Different strategies like intranasal and intracranial light delivery systems have been proposed to overcome this restriction. The most recent preclinical and clinical data on the effectiveness of brain PBM therapy are studied in this review article.

Design and development of donepezil hydrochloride loaded nanostructured lipid carriers for efficient management of Alzheimer’s disease

Objective The primary objective of this study was to develop nanostructured lipid carriers of donepezil hydrochloride (DNZ HCl) for effective management of Alzheimer’s disease (AD). Significance Intranasal administration of DNZ NLC containing Nigella sativa (NS) oil as a liquid lipid may significantly improve nasal penetration and deliver the drug directly to the brain avoiding blood brain barrier (BBB). Method High pressure homogenization was used to prepare nanostructured lipid carriers (NLCs), followed by ultrasonication. Glyceryl monostearate (GMS), Tween 80, and Poloxamer 407 were used as solid lipid, surfactant and co-surfactant respectively, whereas, Nigella sativa oil was used as a liquid lipid. Result The particle size, polydispersity index and zeta potential were found to be 107.4 ± 2.64 nm, 0.25 ± 0.04 and −41.7 mV. The entrapment efficiency and drug content were found to be 70.20% and 89.05% respectively. After intranasal administration of Donepezil hydrochloride (DNZ HCl) loaded NLC’s, the maximum concentrations (Cmax) of 4.597 µg/mL in brain and 2.2583 µg/mL in blood was achieved after 1 h (Tmax). Conclusion The formulated DNZ HCl loaded NLCs significantly improved nasal penetration and enhanced drug distribution in brain resulting in a potentially effective intranasal drug delivery system for the effective management of Alzheimer’s disease.

Intranasal nanoparticulate delivery systems for neurodegenerative disorders: a review.

Neurodegenerative diseases are a significant cause of mortality worldwide, and the blood-brain barrier (BBB) poses a significant challenge for drug delivery. An intranasal route is a prominent approach among the various methods to bypass the BBB. There aredifferent pathways involved in intranasal drug delivery. The drawbacks of this method include mucociliary clearance, enzymatic degradationand poor drug permeation. Novel nanoformulations and intranasal drug-delivery devices offer promising solutions to overcome these challenges. Nanoformulations include polymeric nanoparticles, lipid-based nanoparticles, microspheres, liposomes and noisomes. Additionally, intranasal devices could be utilized to enhance drug-delivery efficacy. Therefore, intranasal drug-delivery systems showpotential for treating neurodegenerative diseases through trigeminal or olfactory pathways, which can significantly improve patient outcomes.