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The present study aimed to formulate and characterize an intranasal mucoadhesive gel of loratadine to enhance its bioavailability. Loratadine, an antihistamine, is commonly used for the treatment of allergic conditions, but its low bioavailability due to extensive first-pass metabolism can limit its effectiveness. To address this issue, an in situ gel formulation was developed using Poloxamer 407 and Carbopol 934 as excipients. The gel's physicochemical properties, including pH, drug content, viscosity, gel strength, gelation temperature, and drug release profile, were evaluated. FT-IR analysis revealed no significant chemical interaction between the drug and excipients, confirming the stability of the formulation. The gel exhibited shear-thinning behavior and gelation temperatures suitable for nasal administration. In vitro drug release studies showed a sustained release profile, with higher Carbopol concentrations resulting in slower drug release. The mucoadhesion time increased with Carbopol 934 concentration, ensuring prolonged retention at the nasal site. Stability studies demonstrated that the formulations remained stable under standard storage conditions. The results suggest that the loratadine-loaded mucoadhesive gel has the potential to improve the bioavailability of loratadine through intranasal delivery, offering a promising alternative to conventional oral dosage forms. [ABSTRACT FROM AUTHOR]

Introduction. In the pharmaceutical technology field there is great interest in polymers with mucoadhesive properties, as they increase the drug retention time on the mucosal surface and increase the bioavailability of the drug. There are various mucoadhesive drug delivery systems: tablets, films, gels, suspensions of micro- and nanoparticles, etc. The ability to adhesion depends on the excipients, especially on their chemical structure. Molecular weight, surface charge, flexibility of the polymer chain and the presence of various functional groups play an important role. Polymers under the trade name Eudragit®, produced by the German concern Evonik Nutrition & Care GmbH, have been used in the pharmaceutical field for several decades to produce controlled-release oral dosage forms. Eudragit® EPO (EPO) is a ternary copolymer based on methacrylic acid derivatives and has mucoadhesive properties due to the presence of dimethylamino groups in its structure. The proposed chemical modification of Eudragit® EPO with a phenylboronic acid derivative, due to the presence of hydroxyl groups in their structure, leads to additional interaction with mucin oligosaccharides, providing enhanced mucoadhesive properties of this polymer.Aim. Synthesis and study of a chemically modified Eudragit® EPO using 4-bromophenylboronic acid in order to increase the mucoadhesive properties of the copolymer for use in transmucosal drug delivery systems.Materials and methods. The synthesis of chemically modified Eudragit® EPO (BEPO) was carried out for 24 hours at 50 °C, followed by purification by dialysis using a dialysis membrane (MMO = 12–14 kDa; Medicell International Ltd, UK) for 7 days and freeze drying at –50 °C and 0.05 mbar using Heto Power Dry LL 3000 (Thermo Electron Corporation, USA) for 5 days. Confirmation of the formation of ВЕРО was carried out by ATR-FTIR spectroscopy on a Nicolet iS5 spectrometer (Thеrmо Fisher Sciеntific, USA) and 1H-NMR spectroscopy on a DPX 400 MHz device (Bruker, Germany). Thermogravimetric analysis (TGA) and modulated differential scanning calorimetry (mDSC) were performed using Discovery TGA™ and Discovery DSC™ (TA Instruments, USA), respectively. The study of mucoadhesive properties was performed by the ability to retain the copolymer on the isolated sheep nasal mucosa at 37.0 ± 0.5 °C for 30 minutes.Results and discussion. BEPO was prepared with a substitution degree of dimethylamino groups with phenylboronic acid of 25 % (BEPO25) and 50 % (BEPO50). The yields of BEPO25 and BEPO50 were 40.70 and 30.79 %. The new characteristic band appears at 1605 cm–1 in the IR spectrum of BEPO, which indicates the attachment of phenylboronic acid to EPO. In the 1H-NMR spectrum of BEPO, the formation of additional peaks in the range of 7.8 and 7.5 ppm is observed, which are absent in the EPO spectrum, which indicates the presence of phenylboronic acid. According to TGA results the samples of boronated EPO have the thermal stability similar to the original EPO. The results of DSC analysis show that the glass transition temperature (Tg) of BEPO samples is somehow higher than the original EPO, which is probably associated with a decrease in the amount of free dimethylamino groups in the terpolymer structure. BEPO50 is retained on the surface of isolated sheep nasal mucosa for 30 minutes, while EPO is washed off with artificial nasal fluid in 5 minutes.Conclusion. The development and study of BEPO is a promising direction for further use in transmucosal drug delivery systems.

Background/Objectives: Due to the high frequency and severity of upper respiratory bacterial infections, probiotics could offer a new medical approach. We explored the antibacterial and anti-inflammatory properties of the new strain Lactiplantibacillus plantarum BIA and formulated a nasal spray. Methods: L. plantarum BIA was isolated from orange peel and taxonomically identified through 16S rRNA gene sequencing. Its antibacterial activity was tested against Pseudomonas aeruginosa, Streptococcus pyogenes, Bacillus subtilis, Escherichia coli, and Staphylococcus aureus, while anti-inflammatory potential was evaluated by Griess assay. BIA genome was fully sequenced and analyzed to assess its safety. BIA was formulated in a freeze-dried matrix, containing prebiotics and cryoprotectants, to be reconstituted with a polymer solution. Solutions containing two types of hydroxypropyl methylcellulose (HPMC) and hyaluronic acid were evaluated as resuspending media and compared in terms of pH, viscosity, and mucoadhesion ability. The biological activity of BIA formulated as nasal spray was verified together with the stability of the selected formulations. Results: L. plantarum BIA inhibited human pathogens' growth and showed anti-inflammatory activity and a safe profile. In the best-performing formulation, the probiotic is lyophilized in 10% fructooligosaccharides, 0.1% ascorbic acid, and 0.5% lactose and reconstituted with HPMC high viscosity 1% w/v. This composition ensured the probiotic's viability for up to six months in its dried form and one week after reconstitution. It also allowed interaction with the nasal mucosa, preserving its antimicrobial and anti-inflammatory activities. Conclusion: The developed nasal spray could become a promising formulation in the field of nasal infectious and inflammatory diseases. [ABSTRACT FROM AUTHOR]

The application of serum albumin in various types of formulations has emerged as a valuable option in biomedical research, especially in the field of nasal drug delivery systems. A serum albumin-based carrier system has been employed due to several benefits, such as enhancing drug solubility and stability, generating the desired controlled release profile, and developing favorable properties with respect to the challenges in nasal conditions, which, in this case, involves hindering rapid elimination due to nasal mucociliary clearance. Accordingly, considering the important role of serum albumin, in-depth knowledge related to its utilization in preparing nasal drug formulation is highly encouraged. This review aimed to explore the potential application of serum albumin in fabricating nasal drug formulations and its crucial role and functionality regarding the binding interaction with nasal mucin, which significantly determines the successful administration of nasal drug formulations. [ABSTRACT FROM AUTHOR]

Objective(s): ”Quality by Design” (QbD) is a novel approach to product development that involves understanding the product and process, as well as the relationship between critical quality attributes (CQA) and critical process parameters (CPP). This study aimed to optimize the gabapentin-loaded solid lipid nanoparticle formulation (GP-SLN) using a QbD approach and evaluate in vitro and ex vivo performance.Materials and Methods: The GP-SLN formulation was created using the microemulsion method by combining Gelucire 48/16, Tween 80, and Plurol Oleique CC 497. The Box-Behnken experimental design was adopted to investigate the effects of independent factors on dependent factors. The GP-SLN formulation was assessed based on particle size and distribution, zeta potential, morphology, entrapment efficiency, release kinetics, permeation parameters, stability, and nasal toxicity.Results: The nanoparticles had a cubical shape with a particle size of 185.3±45.6 nm, a zeta potential of -24±3.53 mV, and an entrapment efficiency of 82.57±4.02%. The particle size and zeta potential of the GP-SLNs remained consistent for 3 months and followed Weibull kinetics with a significantly higher ex vivo permeability (1.7 fold) than a gabapentin solution (GP-SOL). Histopathology studies showed that intranasal administration of the GP-SLN formulation had no harmful effects.Conclusion: The current study reports the successful development of a GP-SLN formulation using QbD. A sustained release of GP was achieved and its nasal permeability was increased. Solid lipid nanoparticles with optimum particle size and high entrapment efficiency may offer a promising approach for the intranasal delivery of drugs.

The nasal administration of therapeutic fluids and vaccines is used to treat allergic rhinitis, sinusitis, congestion, coronaviruses and even Alzheimer's disease. In the latter, the drug must reach the olfactory region, so it finds its way into the central nervous system. Effective administration techniques able to reach the olfactory region are challenging due to the tortuous anatomy of the nasal cavity, and are frequently evaluated in vitro using transparent anatomical models. Here, the liquid distribution inside a 3D printed human nasal cavity is quantified for model fluids resulting from the discharge of a 1-mL syringe with either a spray-generating nozzle, and a straight tip emitting a collimated fluid stream. Experiments using two model fluids with different viscosities suggest that a simple, correctly positioned straight tip attached to a syringe is able to efficiently deliver most of a therapeutic fluid in the human olfactory region in the side-laying position, avoiding the adoption of head-back and head-down positions that can be difficult for patients in the age range typical of Alzheimer's disease. Furthermore, we demonstrate by computer simulations that the conclusion is valid within a wide range of parameters. A collimated liquid jet efficiently reaches the olfactory zone in a human nasal cavity model. Left panel: Experimental set up. Middle panel: Poor delivery of liquid to the olfactory zone (region 2) by a spray-producing cone. Right panel: efficient delivery to the olfactory zone by a collimated stream of fluid generated by a straight duct [Display omitted] [ABSTRACT FROM AUTHOR]

Objective(s): ”Quality by Design” (QbD) is a novel approach to product development that involves understanding the product and process, as well as the relationship between critical quality attributes (CQA) and critical process parameters (CPP). This study aimed to optimize the gabapentin-loaded solid lipid nanoparticle formulation (GP-SLN) using a QbD approach and evaluate in vitro and ex vivo performance. Materials and Methods: The GP-SLN formulation was created using the microemulsion method by combining Gelucire 48/16, Tween 80, and Plurol Oleique CC 497. The Box-Behnken experimental design was adopted to investigate the effects of independent factors on dependent factors. The GPSLN formulation was assessed based on particle size and distribution, zeta potential, morphology, entrapment efficiency, release kinetics, permeation parameters, stability, and nasal toxicity. Results: The nanoparticles had a cubical shape with a particle size of 185.3±45.6 nm, a zeta potential of -24±3.53 mV, and an entrapment efficiency of 82.57±4.02%. The particle size and zeta potential of the GP-SLNs remained consistent for 3 months and followed Weibull kinetics with a significantly higher ex vivo permeability (1.7 fold) than a gabapentin solution (GP-SOL). Histopathology studies showed that intranasal administration of the GP-SLN formulation had no harmful effects. Conclusion: The current study reports the successful development of a GP-SLN formulation using QbD. A sustained release of GP was achieved and its nasal permeability was increased. Solid lipid nanoparticles with optimum particle size and high entrapment efficiency may offer a promising approach for the intranasal delivery of drugs. [ABSTRACT FROM AUTHOR]

This comprehensive review delves into the potential of intranasal insulin delivery for managing Alzheimer's Disease (AD) while exploring the connection between AD and diabetes mellitus (DM). Both conditions share features of insulin signalling dysregulation and oxidative stress that accelerate inflammatory response. Given the physiological barriers to brain drug delivery, including the blood-brain barrier, intranasal administration emerges as a non-invasive alternative. Notably, intranasal insulin has shown neuroprotective effects, impacting Aβ clearance, tau phosphorylation, and synaptic plasticity. In preclinical studies and clinical trials, intranasally administered insulin achieved rapid and extensive distribution throughout the brain, with optimal formulations exhibiting minimal systemic circulation. The detailed mechanism of insulin transport through the nose-to-brain pathway is elucidated in the review, emphasizing the role of olfactory and trigeminal nerves. Despite promising prospects, challenges in delivering protein drugs from the nasal cavity to the brain remain, including enzymes, tight junctions, mucociliary clearance, and precise drug deposition, which hinder its translation to clinical settings. The review encompasses a discussion of the strategies to enhance the intranasal delivery of therapeutic proteins, such as tight junction modulators, cell-penetrating peptides, and nano-drug carrier systems. Moreover, successful translation of nose-to-brain drug delivery necessitates a holistic understanding of drug transport mechanisms, brain anatomy, and nasal formulation optimization. To date, no intranasal insulin formulation has received regulatory approval for AD treatment. Future research should address challenges related to drug absorption, nasal deposition, and the long-term effects of intranasal insulin. In this context, the evaluation of administration devices for nose-to-brain drug delivery becomes crucial in ensuring precise drug deposition patterns and enhancing bioavailability. Drug transport mechanism through the nose-to-brain pathway using the olfactory and trigeminal nerves (major pathway) and from the bloodstream through BBB (minor pathway). [ABSTRACT FROM AUTHOR]

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The current research aims to develop thermosensitive polymeric micelles loaded with risperidone for nasal administration, emphasizing the added benefits of their thermosensitive behavior under nasal conditions. An initial risk assessment facilitated the advanced development process, confirming that the key indicators of thermosensitivity were suitable for nasal application. The polymeric micelles exhibited an average size of 118.4 ± 3.1 nm at ambient temperature and a size of 20.47 ± 1.2 nm at 36.5 °C, in both cases in monodisperse distribution. Factors such as pH and viscosity did not significantly impact these parameters, demonstrating appropriate nasal applicability. The model formulations showed a rapid, burst-like drug release profile in vitro, accompanied by a quick and high permeation rate at nasal conditions. Overall, the Quality by Design-based risk assessment process led to the development of an advanced drug delivery system capable of administering risperidone through the nasal cavity. [ABSTRACT FROM AUTHOR]

This comprehensive review aims to explore the future potential of nasopulmonary drug delivery systems for the administration of drugs through the nasal route. Nasal drug delivery has gained significant attention due to its numerous advantages, including rapid absorption, avoidance of first-pass metabolism, and non-invasive administration. This review provides an overview of the nasal anatomy and physiology, highlighting the factors influencing drug absorption and bioavailability. Additionally, it discusses the various types of nasopulmonary drug delivery systems, such as nasal sprays, powders, and gels, along with their advantages and limitations. Furthermore, the review delves into the challenges associated with nasal drug delivery, including mucociliary clearance, nasal irritation, and formulation issues. The potential applications of nasopulmonary drug delivery systems in the treatment of various diseases, such as allergies, respiratory disorders, and systemic conditions, are also discussed. Finally, the review concludes with an outlook on the future prospects of nasopulmonary drug delivery systems, emphasising the need for further research and development to optimise their efficacy and safety. [ABSTRACT FROM AUTHOR]

In recent years, there have been a growing number of small and large molecules that could be used to treat diseases of the central nervous system (CNS). Nose-to-brain delivery can be a potential option for the direct transport of molecules from the nasal cavity to different brain areas. This review aims to provide a compilation of current approaches regarding drug delivery to the CNS via the nose, with a focus on biologics. The review also includes a discussion on the key benefits of nasal delivery as a promising alternative route for drug administration and the involved pathways or mechanisms. This article reviews how the application of various auxiliary agents, such as permeation enhancers, mucolytics, in situ gelling/mucoadhesive agents, enzyme inhibitors, and polymeric and lipid-based systems, can promote the delivery of large molecules in the CNS. The article also includes a discussion on the current state of intranasal formulation development and summarizes the biologics currently in clinical trials. It was noted that significant progress has been made in this field, and these are currently being applied to successfully transport large molecules to the CNS via the nose. However, a deep mechanistic understanding of this route, along with the intimate knowledge of various excipients and their interactions with the drug and nasal physiology, is still necessary to bring us one step closer to developing effective formulations for nasal–brain drug delivery. [ABSTRACT FROM AUTHOR]

Objectives: It has previously been shown that the peptide (34Pro,35Phe)CGRP27–37 is a potent calcitonin gene-related peptide, CGRP receptor antagonist, and in this project we aimed to improve the antagonist potency through the structural modification of truncated C-terminal CGRP peptides. Methods: Six peptide analogues were synthesized and the anti-CGRP activity confirmed using both in vitro and in vivo studies. Key findings: A 10 amino acid-containing peptide VPTDVGPFAF-NH2 (P006) was identified as a key candidate to take forward for in vivo evaluation, where it was shown to be an effective antagonist after intraperitoneal injection into mice. P006 was formulated as a preparation suitable for nasal administration by spray drying with chitosan to form mucoadhesive microcarriers (9.55 ± 0.91 mm diameter) and a loading of 0.2 mg peptide per 20 mg dose. Conclusions: The project has demonstrated the potential of these novel small peptide CGRP antagonists, to undergo future preclinical evaluation as anti-migraine therapeutics. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders occur through progressive loss of function or structure of neurons, with loss of sensation and cognition values. The lack of successful therapeutic approaches to solve neurologic disorders causes physical disability and paralysis and has a significant socioeconomic impact on patients. In recent years, nanocarriers and stem cells have attracted tremendous attention as a reliable approach to treating neurodegenerative disorders. In this regard, nanoparticle‐based labeling combined with imaging technologies has enabled researchers to survey transplanted stem cells and fully understand their fate by monitoring their survival, migration, and differentiation. For the practical implementation of stem cell therapies in the clinical setting, it is necessary to accurately label and follow stem cells after administration. Several approaches to labeling and tracking stem cells using nanotechnology have been proposed as potential treatment strategies for neurological diseases. Considering the limitations of intravenous or direct stem cell administration, intranasal delivery of nanoparticle‐labeled stem cells in neurological disorders is a new method of delivering stem cells to the central nervous system (CNS). This review describes the challenges and limitations of stem cell‐based nanotechnology methods for labeling/tracking, intranasal delivery of cells, and cell fate regulation as theragnostic labeling. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease [ABSTRACT FROM AUTHOR]

In this present formulation study, vinpocetine-loaded nano-spray-dried polymeric micelles were developed via nano-spray-drying. Three different mucoadhesive excipients were applied in the studies, namely chitosan, hyaluronic acid and hydroxypropyl methylcellulose. In all cases, the formulations had a proper particle size and drug content after drying with spherical morphology and amorphous structure. After rapid dissolution in water, the polymeric micelles had a particle size around 100–130 nm, in monodisperse size distribution. The high encapsulation efficiency (>80%) and high solubilization (approx. 300-fold increase in thermodynamic solubility) contributed to rapid drug release (>80% in the first 15 min) and fast passive diffusion at simulated nasal conditions. The formulated prototype preparations fulfilled the demands of a low-viscosity, moderately mucoadhesive nasal drug delivery system, which may be capable of increasing the overall bioavailability of drugs administered via the auspicious nasal drug delivery route. [ABSTRACT FROM AUTHOR]

Sino-nasal disease is appropriately treated with topical treatment, where the nasal mucosa acts as a barrier to systemic absorption. Non-invasive nasal delivery of drugs has produced some small molecule products with good bioavailability. With the recent COVID pandemic and the need for nasal mucosal immunity becoming more appreciated, more interest has become focused on the nasal cavity for vaccine delivery. In parallel, it has been recognized that drug delivery to different parts of the nose can have different results and for "nose-to-brain" delivery, deposition on the olfactory epithelium of the upper nasal space is desirable. Here the non-motile cilia and reduced mucociliary clearance lead to longer residence time that permits enhanced absorption, either into the systemic circulation or directly into the CNS. Many of the developments in nasal delivery have been to add bioadhesives and absorption/permeation enhancers, creating more complicated formulations and development pathways, but other projects have shown that the delivery device itself may allow more differential targeting of the upper nasal space without these additions and that could allow faster and more efficient programs to bring a wider range of drugs—and vaccines—to market. [ABSTRACT FROM AUTHOR]

Abstract Background Dysbiosis or imbalance of gut microbiota in Alzheimer's disease (AD) affects the production of short-chain fatty acids (SCFAs), whereas exogenous SCFAs supplementation exacerbates brain Aβ burden in APP/PS1 mice. Bifidobacterium is the main producer of SCFAs in the gut flora, but oral administration of Bifidobacterium is ineffective due to strong acids and bile salts in the gastrointestinal tract. Therefore, regulating the levels of SCFAs in the gut is of great significance for AD treatment. Methods We investigated the feasibility of intranasal delivery of MSNs-Bifidobacterium (MSNs-Bi) to the gut and their effect on behavior and brain pathology in APP/PS1 mice. Results Mesoporous silica nanospheres (MSNs) were efficiently immobilized on the surface of Bifidobacterium. After intranasal administration, fluorescence imaging of MSNs-Bi in the abdominal cavity and gastrointestinal tract revealed that intranasally delivered MSNs-Bi could be transported through the brain to the peripheral intestine. Intranasal administration of MSNs-Bi not only inhibited intestinal inflammation and reduced brain Aβ burden but also improved olfactory sensitivity in APP/PS1 mice. Conclusions These findings suggested that restoring the balance of the gut microbiome contributes to ameliorating cognitive impairment in AD, and that intranasal administration of MSNs-Bi may be an effective therapeutic strategy for the prevention of AD and intestinal disease.

Oral delivery of olanzapine suffers from low oral bioavailability and there has been reports of metabolic side effects. This study aimed to prepare a nanoemulsion of olanzapine and incorporate it into an in situ gel for nasal delivery. Such nasal delivery of olanzapine could provide prolonged contact time with the nasal mucosa and a potential enhanced action with lower side effects. Several formulations of nanoemulsions were prepared and characterized through the measurements of conductivity, transmittance, pH, viscosity, hydrodynamic diameter, polydispersity index, Zeta potential, entrapment efficiency, and release profiles. In addition, a pharmacodynamics study was conducted through animal studies. The selected formulation showed excellent nanoemulsion with a size in the nanometre range, a good polydispersity index with acceptable stability as indicated by the thermodynamic stability test. The cumulative percentage of olanzapine released from the nanoemulsion showed a good release profile. Pharmacodynamics study on rats using Paw test demonstrated a very clear enhancement in the antipsychotic efficacy of olanzapine in the following order: Nanoemulsion-based in situ gel (with HPMC)>nanoemulsion-based in situ gel >nanoemulsion>solution. Interestingly, olanzapine from the nanoemulsion-based in situ gel showed comparable antipsychotic efficacy to haloperidol, when given intraperitoneally. Nanoemulsion-based nasal in situ gel is a promising drug delivery system for olanzapine for achieving a targeted delivery. However, further investigations on olanzapine accumulation in the brain after such delivery are recommended. [ABSTRACT FROM AUTHOR]

Purpose: The main aim of the present study was to formulate Donepezil Hydrochloride (DH)–loaded ethosomal intranasal gel to increase the transport of the drug through the blood–brain barrier (BBB), thus decreasing plasma fluctuation and also decreasing the oral side effects associated with the drug. Methods: DH-loaded ethosomes were prepared by ethanol injection method. Nine ethosomal formulations were prepared containing three different concentrations of Phospholipon 90G and ethanol in combination and were evaluated for vesicle size, %entrapment efficiency, and drug content. The optimized ethosomal formulation was incorporated into the gelling base containing Poloxamer 407 (18%) and Poloxamer 188 (6%) as thermosensitive polymers and Carbopol 934 (0.1–0.5%) as mucoadhesive polymer. The prepared gels were further evaluated for gelation temperature, gelation time, drug content, mucoadhesive strength, viscosity, in vitro drug release, and ex vivo drug permeation study through the sheep nasal mucosa. Results: The optimized ethosomal formulation F4 showed a vesicle size of 110.06 ± 1.910 and a % entrapment efficiency of 70.02 ± 0.353. The mucoadhesive strength and gelation temperature were found to be 3332 ± 4.314 and 31.7 ± 0.033 in the case of optimized gel formulation. The in vitro and ex vivo drug permeation from the optimized gel formulation was almost 100% after a period of 24 h. Conclusion: Formulated DH-loaded ethosomal intranasal gel could serve as the better alternative for the brain targeting via the intranasal route. [ABSTRACT FROM AUTHOR]

Abstract Parkinson’s disease (PD), a neurodegenerative disease that shows a high incidence in older individuals, is becoming increasingly prevalent. Unfortunately, there is no clinical cure for PD, and novel anti-PD drugs are therefore urgently required. However, the selective permeability of the blood–brain barrier (BBB) poses a huge challenge in the development of such drugs. Fortunately, through strategies based on the physiological characteristics of the BBB and other modifications, including enhancement of BBB permeability, nanotechnology can offer a solution to this problem and facilitate drug delivery across the BBB. Although nanomaterials are often used as carriers for PD treatment, their biological activity is ignored. Several studies in recent years have shown that nanomaterials can improve PD symptoms via their own nano-bio effects. In this review, we first summarize the physiological features of the BBB and then discuss the design of appropriate brain-targeted delivery nanoplatforms for PD treatment. Subsequently, we highlight the emerging strategies for crossing the BBB and the development of novel nanomaterials with anti-PD nano-biological effects. Finally, we discuss the current challenges in nanomaterial-based PD treatment and the future trends in this field. Our review emphasizes the clinical value of nanotechnology in PD treatment based on recent patents and could guide researchers working in this area in the future.

Multiple daily injections via subcutaneous route are the primary modes of insulin delivery for patients with Diabetes Mellitus. While this process is invasive, painful and may cause patients to develop lipohypertrophy at injection site, the perception of fear surrounding this process causes patients to delay in initiation and remain persistent with insulin therapy over time. Moreover, poor glycemic control may often lead to acute complications, such as severe hypoglycemia and nocturnal hypoglycemia, especially in older patients with diabetes. To address the imperative need for a patient-convenient non-invasive insulin therapy, an insulin-loaded arginine-coated self-emulsifying nanoglobule system (INS-LANano) was developed for nasal delivery of insulin with a biodegradable cationic surfactant—Lauroyl Ethyl Arginate (LAE). Incorporation of LAE resulted in formation of positively charged nanoglobules with L-arginine oriented on the surface. LANano enabled binding of insulin molecules on the surface of nanoglobules via an electrostatic interaction between negatively charged α-helix and LAE molecules at physiological pH. INS-LANano showed a hydrodynamic diameter of 23.38 nm with a surface charge of +0.118 mV. The binding efficiency of insulin on LANano globules was confirmed by zeta potential, circular dichroism (CD) spectroscopy and centrifugal ultrafiltration studies. The attachment of insulin with permeation-enhancing nanoglobules demonstrated significantly higher in vitro permeability of insulin of 15.2% compared to insulin solution across human airway epithelial cell (Calu-3) monolayer. Upon intranasal administration of INS-LANano to diabetic rats at 2 IU/kg insulin dose, a rapid absorption of insulin with significantly higher Cmax of 14.3 mU/L and relative bioavailability (BA) of 23.3% was observed. Therefore, the INS-LANano formulation significant translational potential for intranasal delivery of insulin [ABSTRACT FROM AUTHOR]

Nanotechnology-based drug delivery platforms have shown great potential in overcoming the limitations of conventional therapy for glioblastoma (GBM). However, permeation across the blood–brain barrier (BBB), physiological complexity of the brain, and glioma targeting strategies cannot entirely meet the challenging requirements of distinctive therapeutic delivery stages. The objective of this research is to fabricate lipid nanoparticles (LNPs) for the co-delivery of paclitaxel (PTX) and miltefosine (HePc) a proapoptotic agent decorated with transferrin (Tf-PTX-LNPs) and investigate its anti-glioma activity both in vitro and in vivo orthotopic NOD/SCID GBM mouse model. The present study demonstrates the anti-glioma effect of the dual drug combination of PTX and proapoptotic HePc lipid-based transferrin receptor (TfR) targeted alternative delivery (direct nose to brain transportation) of the nanoparticulate system (Tf-PTX-LNPs, 364 ± 5 nm, −43 ± 9 mV) to overcome the O6-methylguanine-DNA methyltransferase induce drug-resistant for improving the effectiveness of GBM therapy. The resulting nasally targeted LNPs present good biocompatibility, stability, high BBB transcytosis through selective TfR-mediated uptake by tumor cells, and effective tumor penetration in the brain of GBM induced mice. We observed markedly enhanced anti-proliferative efficacy of the targeted LNPs in U87MG cells compared to free drug. Nasal targeted LNPs had shown significantly improved brain concentration (Cmax fivefold and AUC0-24 4.9 fold) with early tmax (0.5 h) than the free drug. In vivo intracranial GBM-bearing targeted LNPs treated mice exhibited significantly prolonged survival with improved anti-tumor efficacy accompanied by reduced toxicity compared to systemic Taxol® and nasal free drug. These findings indicate that the nasal delivery of targeted synergistic nanocarrier holds great promise as a non-invasive adjuvant chemotherapy therapy of GBM. [ABSTRACT FROM AUTHOR]

Oral tablets account for the majority of medications used to acutely treat migraine, but relief can be limited by their rates of dissolution and absorption. The nose is an attractive alternative route of drug delivery since it provides patient convenience of at-home use, gastrointestinal (GI) avoidance, and rapid absorption of drugs into systemic circulation because of its large surface area. However, the site of drug deposition within the nasal cavity should be considered since it can influence drug absorption. Traditional nasal devices have been shown to target drug delivery to the lower nasal space where epithelium is not best-suited for drug absorption and where there is an increased likelihood of drug clearance due to nasal drip, swallowing, or mucociliary clearance, potentially resulting in variable absorption and suboptimal efficacy. Alternatively, the upper nasal space (UNS) offers a permeable, richly vascularized epithelium with a decreased likelihood of drug loss or clearance due to the anatomy of this area. Traditional nasal pumps deposit <5% of active drug into the UNS because of the nasal cavity's complex architecture. A new technology, Precision Olfactory Delivery (POD®), is a handheld, manually actuated, propellant-powered, administration device that delivers drug specifically to the UNS. A dihydroergotamine (DHE) mesylate product, INP104, utilizes POD technology to deliver drug to the UNS for the acute treatment of migraine. Results from clinical studies of INP104 demonstrate a favorable pharmacokinetic profile, consistent and predictable dosing, rapid systemic levels known to be effective (similar to other DHE mesylate clinical programs), safety and tolerability on the upper nasal mucosa, and high patient acceptance. POD technology may have the potential to overcome the limitations of traditional nasal delivery systems, while utilizing the nasal delivery benefits of GI tract avoidance, rapid onset, patient convenience, and ease of use. [ABSTRACT FROM AUTHOR]

Pulmonary, nasal, and nose-to-brain diseases involve clinical approaches, such as bronchodilators, inhaled steroids, oxygen therapy, antibiotics, antihistamines, nasal steroids, decongestants, intranasal drug delivery, neurostimulation, and surgery to treat patients. However, systemic medicines have serious adverse effects, necessitating the development of inhaled formulations that allow precise drug delivery to the airways with minimum systemic drug exposure. Particle size, surface charge, biocompatibility, drug capacity, and mucoadhesive are unique chemical and physical features that must be considered for pulmonary and nasal delivery routes due to anatomical and permeability considerations. The traditional management of numerous chronic diseases has a variety of drawbacks. As a result, targeted medicine delivery systems that employ nanotechnology enhancer drug efficiency and optimize the overall outcome are created. The pulmonary route is one of the most essential targeted drug delivery systems because it allows the administering of drugs locally and systemically to the lungs, nasal cavity, and brain. Furthermore, the lungs' beneficial characteristics, such as their ability to inhibit first-pass metabolism and their thin epithelial layer, help treat several health complications. The potential to serve as noninvasive self-administration delivery sites of the lung and nasal routes is discussed in this script. New methods for treating respiratory and some systemic diseases with inhalation have been explored and highlight particular attention to using specialized nanocarriers for delivering various drugs via the nasal and pulmonary pathways. The design and development of inhaled nanomedicine for pulmonary, nasal, and respiratory medicine applications is a potential approach for clinical translation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Abstract Background The ongoing COVID-19 pandemic has resulted in 185 million recorded cases and over 4 million deaths worldwide. Several COVID-19 vaccines have been approved for emergency use in humans and are being used in many countries. However, all the approved vaccines are administered by intramuscular injection and this may not prevent upper airway infection or viral transmission. Results Here, we describe a novel, intranasally delivered COVID-19 vaccine based on a helper-dependent adenoviral (HD-Ad) vector. The vaccine (HD-Ad_RBD) produces a soluble secreted form of the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and we show it induced robust mucosal and systemic immunity. Moreover, intranasal immunization of K18-hACE2 mice with HD-Ad_RBD using a prime-boost regimen, resulted in complete protection of the upper respiratory tract against SARS-CoV-2 infection. Conclusion Our approaches provide a powerful platform for constructing highly effective vaccines targeting SARS-CoV-2 and its emerging variants.

Background: Dysbiosis or imbalance of gut microbiota in Alzheimer's disease (AD) affects the production of short-chain fatty acids (SCFAs), whereas exogenous SCFAs supplementation exacerbates brain Aβ burden in APP/PS1 mice. Bifidobacterium is the main producer of SCFAs in the gut flora, but oral administration of Bifidobacterium is ineffective due to strong acids and bile salts in the gastrointestinal tract. Therefore, regulating the levels of SCFAs in the gut is of great significance for AD treatment. Methods: We investigated the feasibility of intranasal delivery of MSNs-Bifidobacterium (MSNs-Bi) to the gut and their effect on behavior and brain pathology in APP/PS1 mice. Results: Mesoporous silica nanospheres (MSNs) were efficiently immobilized on the surface of Bifidobacterium. After intranasal administration, fluorescence imaging of MSNs-Bi in the abdominal cavity and gastrointestinal tract revealed that intranasally delivered MSNs-Bi could be transported through the brain to the peripheral intestine. Intranasal administration of MSNs-Bi not only inhibited intestinal inflammation and reduced brain Aβ burden but also improved olfactory sensitivity in APP/PS1 mice. Conclusions: These findings suggested that restoring the balance of the gut microbiome contributes to ameliorating cognitive impairment in AD, and that intranasal administration of MSNs-Bi may be an effective therapeutic strategy for the prevention of AD and intestinal disease. [ABSTRACT FROM AUTHOR]

The objective of the present research was to formulate diammonium glycyrrhizinate (DG) into phytosomes (DG-P) to induce nasal immune responses and enhance absorption. Plackett- Burman design was used for process optimization, incorporating specific formulation and process variables to obtain the optimal parameters. Fourier transform infrared spectroscopy (FTIR), X-ray power diffraction (P-XRD), and transmission electron microscopy (TEM) were used for characterization. The adjuvant activity of the DG-P was evaluated by using bone marrow dendritic cells. In vitro nasal mucosal permeation and in situ nasal perfusion were also investigated to evaluate nasal absorption. The DG phytosomes were in the size range of 20~30 nm and zeta-potential range of −30~−40 mV. DG-P demonstrated 4.2-fold increased solubility in n-octanol. Coculturing bone marrow dendritic cells with DG-P led to enhanced dendritic cell maturation. Apparent permeability coefficient of the phytosomal formulation was almost four times higher than that of free DG determined by ex vivo permeation studies on excised porcine mucosa. In situ nasal perfusion studies in rats demonstrated that the nasal absorption of DG-P was significantly higher than that of free DG. Conclusively, the results confirmed that DG-P have potential for use as an adjuvant for nasal vaccine. [ABSTRACT FROM AUTHOR]

[Display omitted] It is always a challenge to encapsulate water-soluble peptides in polymer nanoparticle (NP) systems. We establish and validate our newly developed non-aqueous nanoprecipitation method to encapsulate neuro-peptides drugs such as oxytocin and Luteinizing hormone-releasing hormone (LHRH) in poly(sebacic anhydride) (PSA) NPs. NPs were prepared by a solvent-antisolvent process under a strict anhydrous environment to obtain high drug loading and to avoid premature PSA degradation and drug release. Dynamic light scattering (DLS) and Scanning Electron Microscopy (SEM) reveal the size for both drug loaded PSA NPs to ∼ 300 nm. The drug loaded NPs were dispersible and spherical in shape with uniform morphology. The in vitro release profile of oxytocin from PSA NPs occurs with the burst release of ∼ 50% within the first hour in the aqueous release medium, whereas LHRH release is comparatively slow. Thus, looking into the fast degrading properties of PSA and drug release behavior, the developed NPs can be used for direct delivery of the neuropeptides to the olfactory epithelium using a refillable nasal atomizer that deposits mist onto the olfactory neuro-epithelium. We also applied our developed method to prepare NPs of poly(lactic- co -glycolic acid) (PLGA), polylactic acid (PLA), and poly(ε-caprolactone) (PCL). A Thyrotropin releasing hormone (TRH) was used as the sample neuropeptide drug to validate our non-aqueous method. The results reveal the formation of TRH loaded PLGA, PLA and PCL NPs with 100% drug loading. TEM analysis shows the formation of spherical NPs, having similar release properties as those of PSA NPs. Overall, we report that our developed method is suitable for co-encapsulating hydrophilic drugs in polymer NPs with high drug loading and release properties. [ABSTRACT FROM AUTHOR]

Pramipexole hydrochloride (PPX) is a dopamine receptor agonist for the treatment of Parkinson's disease. It does not penetrate easily into the brain due to the presence of the blood-brain barrier (BBB), which hinders the treatment of the disease. The nasal mucosal drug delivery system is an effective method to deliver drugs to the brain bypassing the blood-brain barrier and the concentration of drugs targeted to the brain by intranasal administration is quite low due to the limitation of the permeability of the nasal mucosa and the nasal environment. Therefore, this study innovatively encapsulates prepared PPX microcapsules in a temperature-sensitive in situ gel for intranasal drug delivery to increase the target concentration of the drug in the brain and prolong the duration of treatment. The gel formulation containing 24% poloxamer 407 and 6% poloxamer 188 and 0.3% ice chips as absorption enhancers formed a hard gel at 30.44-31.36°C and allowed a slow release within 12 hours. A pharmacokinetic comparison of the developed PPX microencapsulated temperature-sensitive in situ gel (PPX-MTISG) with PPX temperature-sensitive in situ gel (PPXTISG) revealed that the microencapsulated nasal mucosal in situ gel was a more effective PPX brain-targeted drug delivery system. [ABSTRACT FROM AUTHOR]

Background: The management of central nervous system diseases is extremely challenging due to the numerous obstacles that stand against the successful delivery of drugs to their target site in the brain. Defeating the blood-brain barrier is considered the most significant challenge in this delivery. Different alternative routes of administration have been investigated. Nasal delivery is one of the possible ways for direct brain targeting. The nasal mucosa is the only part of the body at which the external environment become in straight connection with the central nervous system which takes place through the olfactory portion of the nasal mucosa. Different mechanisms have been suggested to describe the pathway for straight nasal to brain transport of medications, however, the precise route is still vague. The most important proposed pathways include nerve pathways (olfactory and trigeminal nerve), vascular, lymphatic, and cerebrospinal fluid mediated pathways. Among these mechanisms, the olfactory intra-neuronal delivery is the dominant one. Various particulate systems have been investigated for nasal delivery with the intention of direct transport to the brain. The most frequently studied delivery systems are polymeric nanosystems, lipid based nanosystems, and nanometric emulsions. In conclusion, direct nasal-to-brain delivery is a very fertile research area and any achievements in this area are running side by side with the progressions that occur in the particulate systems.

• In situ nasal gel of amoxicillin trihydrate appears promising for local delivery. • Adequate mucoadhesive properties facilitate prolonged nasal residence time. • Ex vivo penetration studies on human nasal tissue confirm localized drug retention. • Raman chemical mapping can be employed to explore nasal mucosal retention profile. Orally administered amoxicillin is recommended as the first-line treatment of acute bacterial rhinosinusitis (ABR) and given in a high-dose regimen. However, the risk of various systemic adverse reactions and low oral bioavailability are unbearable, increasing the threat of antibiotic resistance. Therefore, nasal delivery of amoxicillin can be a potential approach for effectively treating ABR locally, as well as overcoming those drawbacks. In a way to guarantee the effectiveness for local therapy in nasal cavity, the permeation and retention properties are of significant importance considerations. Accordingly, the present work aimed to investigate the characteristics with respect to the nasal applicability of the in situ gelling amoxicillin trihydrate (AMT) and further evaluate its permeability and retention properties through human nasal mucosa. The lyophilized formulations were characterized utilizing the Differential Scanning Calorimetry (DSC) and X-ray Powder Diffraction (XRPD), and also evaluated for its polarity, reconstitution time, droplet size distribution, mucoadhesive properties, and ex vivo permeability and retention studies. The results confirmed that the in situ gelling AMT formulations possess adequate mucoadhesive behavior, especially the formulation containing 0.3 % of gellan gum. Substantially, the in situ gelling AMT formulations were able to retain the drug on the surface of nasal mucosa instead of permeating across the membrane; thus, suitable for treating nasal infections locally. Altogether, the in situ gelling systems demonstrates promising abilities as a delivery platform to enhance local application of AMT within the nasal cavity. [Display omitted] [ABSTRACT FROM AUTHOR]

Dimethyl fumarate (DMF) is a drug that is orally administered for the treatment of relapsing-remitting multiple sclerosis. However, DMF causes gastrointestinal side effects and flushing in 43 % of patients, which significantly contributes to treatment discontinuation. To reduce side effects and increase patient compliance, the aim of this study was to develop a thermosensitive chitosan/glycerophosphate hydrogel for the nasal administration of DMF. A binary system of DMF with hydroxypropyl-β-cyclodextrin (HP-β-CD) was made and included in the hydrogel precursor solution. The precursor solution (drug content, DMF stability, thermogelling properties, viscosity), and the resulting thermosensitive hydrogel (mucoadhesion, in vitro DMF permeation) were characterized. HP-β-CD was able to interact with DMF and improve its water solubility. The leader thermosensitive nasal solution, G1 solution, was loaded with approximately 92 % DMF, which remained stable for 21 days. The G1 solution formed a hydrogel in approximately 2–1 min; it had a pH of 6.8 ± 0.06 and caused no significant change in the osmolality of the simulated nasal medium. The G1 hydrogel showed good mucoadhesive properties and released DMF that permeated in vitro in a controlled manner. As a result, G1 is a potential new approach to exploit the intranasal administration of DMF for treating multiple sclerosis. [Display omitted] [ABSTRACT FROM AUTHOR]

The objective and novelty of the present study is the development and optimization of innovative nasal film of Donepezil hydrochloride (DH) for potential use in Alzheimer's disease. Hydroxypropyl-methyl-cellulose E50 (factor A) nasal films, with Polyethylene glycol 400 as plasticizer (factor B), and Methyl-β-Cyclodextrin, as permeation enhancer (factor C), were prepared and characterized in vitro and ex vivo. An experimental design was used to determine the effects of the selected factors on permeation profile of DH through rabbit nasal mucosa (response 1), and on film flexibility/foldability (response 2). A face centered central composite design with three levels was applied and 17 experiments were performed in triplicate. The prepared films exhibited good uniformity of DH content (90.0 ± 1.6%–99.8 ± 4.9%) and thickness (19.6 ± 1.9–170.8 ± 11.5 μm), storage stability characteristics, and % residual humidity (<3%), as well as favourable swelling and mucoadhesive properties. Response surface methodology determined the optimum composition for flexible nasal film with maximized DH permeation. All selected factors interacted with each other and the effect of these interactions on responses is strongly related to the factor's concentration ratios. Based on these encouraging results, in vivo serum and brain pharmacokinetic study of the optimized nasal film, in comparison to DH oral administration, is ongoing in an animal model. [ABSTRACT FROM AUTHOR]

Based on the MRI, cell therapy was not able to significantly reduce the infarct size; however, treatment with MSCs provided protection from MBP degradation indicating attenuation of white matter loss 28 days after ischemia. Although reports on this method of cell delivery are mainly centered around the therapeutic consequences of the cell therapy, few studies focused on the pathways by which intranasally applied cells enter the brain. At day 28 post-stroke, the cell therapy had increased the number of EdU and BrdU-positive cells in the ipsilateral striatum, near the ischemic boundary zone, indicating an enhancement of endogenous cell proliferation. Beneficial potential of neural stem cells (NSCs) in cell therapy after ischemia Although MSCs are considered the most commonly employed stem cell type for cell-based therapies in general, and the field of cerebral hypoxia/ischemia in particular, the curative potential of NSC is gaining interest. Keywords: conditioned medium; hypoxic brain; ischemic brain; nasal delivery; secretome; stem cell EN conditioned medium hypoxic brain ischemic brain nasal delivery secretome stem cell 583 606 24 08/09/22 20220801 NES 220801 Introduction Cerebral ischemia and hypoxic brain damage are devastating conditions that are considered as major global problems. [Extracted from the article]

A brain tumor (BT) is a condition in which there is growth or uncontrolled development of the brain cells, which usually goes unrecognized or is diagnosed at the later stages. Since the mechanism behind BT is not clear, and the various physiological conditions are difficult to diagnose, the success rate of BT is not very high. This is the central issue faced during drug development and clinical trials with almost all types of neurodegenerative disorders. In the first part of this review, we focus on the concept of brain tumors, their barriers, and the types of delivery possible to target the brain cells. Although various treatment methods are available, they all have side effects or toxic effects. Hence, in the second part, a correlation was made between the use of resveratrol, a potent antioxidant, and its advantages for brain diseases. The relationship between brain disease and the blood–brain barrier, multi-drug resistance, and the use of nanomedicine for treating brain disorders is also mentioned. In short, a hypothetical concept is given with a background investigation into the use of combination therapy with resveratrol as an active ingredient, the possible drug delivery, and its formulation-based approach. [ABSTRACT FROM AUTHOR]

Highlights: Strategies for crossing the blood–brain barrier and the nano-biological effects of nanomaterials used for anti-Parkinsonian therapy are summarized. Patents related to nanotechnology-based anti-Parkinsonian therapy are reviewed, and the status of progress in this field are discussed. Current challenges in nanotechnology-based Parkinson's disease treatment are discussed, with insights into the future trends in this field. Parkinson's disease (PD), a neurodegenerative disease that shows a high incidence in older individuals, is becoming increasingly prevalent. Unfortunately, there is no clinical cure for PD, and novel anti-PD drugs are therefore urgently required. However, the selective permeability of the blood–brain barrier (BBB) poses a huge challenge in the development of such drugs. Fortunately, through strategies based on the physiological characteristics of the BBB and other modifications, including enhancement of BBB permeability, nanotechnology can offer a solution to this problem and facilitate drug delivery across the BBB. Although nanomaterials are often used as carriers for PD treatment, their biological activity is ignored. Several studies in recent years have shown that nanomaterials can improve PD symptoms via their own nano-bio effects. In this review, we first summarize the physiological features of the BBB and then discuss the design of appropriate brain-targeted delivery nanoplatforms for PD treatment. Subsequently, we highlight the emerging strategies for crossing the BBB and the development of novel nanomaterials with anti-PD nano-biological effects. Finally, we discuss the current challenges in nanomaterial-based PD treatment and the future trends in this field. Our review emphasizes the clinical value of nanotechnology in PD treatment based on recent patents and could guide researchers working in this area in the future. [ABSTRACT FROM AUTHOR]