scholarly journals Intranasal Nanoemulsions for Direct Nose-to-Brain Delivery of Actives for CNS Disorders

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1230
Author(s):  
Shiv Bahadur ◽  
Dinesh M. Pardhi ◽  
Jarkko Rautio ◽  
Jessica M. Rosenholm ◽  
Kamla Pathak
Keyword(s):  
Rapid Development ◽  
Brain Targeting ◽  
Nasal Administration ◽  
Future Research ◽  
Brain Delivery ◽  
Olfactory Pathway ◽  
Nasal Drug Delivery ◽  
Cns Diseases ◽  
Biodistribution Studies ◽  
The Brain

The treatment of various central nervous system (CNS) diseases has been challenging, despite the rapid development of several novel treatment approaches. The blood–brain barrier (BBB) is one of the major issues in the treatment of CNS diseases, having major role in the protection of the brain but simultaneously constituting the main limiting hurdle for drugs targeting the brain. Nasal drug delivery has gained significant interest for brain targeting over the past decades, wherein the drug is directly delivered to the brain by the trigeminal and olfactory pathway. Various novel and promising formulation approaches have been explored for drug targeting to the brain by nasal administration. Nanoemulsions have the potential to avoid problems, including low solubility, poor bioavailability, slow onset of action, and enzymatic degradation. The present review highlights research scenarios of nanoemulsions for nose-to-brain delivery for the management of CNS ailments classified on the basis of brain disorders and further identifies the areas that remain unexplored. The significance of the total dose delivered to the target region, biodistribution studies, and long-term toxicity studies have been identified as the key areas of future research.

scholarly journals Ion-Triggered In Situ Gelling Nanoemulgel as a Platform for Nose-to-Brain Delivery of Small Lipophilic Molecules

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1216
Author(s):  
Sreeharsha Nagaraja ◽  
Girish Meravanige Basavarajappa ◽  
Ranjith Kumar Karnati ◽  
Esam Mohamed Bakir ◽  
Swati Pund
Keyword(s):  
Neurodegenerative Diseases ◽  
Nasal Mucosa ◽  
Systemic Exposure ◽  
Brain Diseases ◽  
Brain Targeting ◽  
Nasal Administration ◽  
Brain Delivery ◽  
Biodistribution Studies ◽  
In Situ Gelling

Background: Intranasal route offers a direct nose-to-brain delivery via olfactory and trigeminal nerves and minimizes the systemic exposure of the drug. Although reliable and non-invasive, intranasal administration of lipophilic neuroprotective agents for brain targeting is still challenging. Literature focuses on naturally-derived compounds as a promising therapeutics for chronic brain diseases. Naringin, a natural flavonoid obtained from citrus fruits possesses neuroprotective effects. By regulating multiple crucial cellular signaling pathways, naringin acts on several therapeutic targets that make it suitable for the treatment of neurodegenerative diseases like Alzheimer’s disease and making it a suitable candidate for nasal administration. However, the hydrophobicity of naringin is the primary challenge to formulate it in an aqueous system for nasal administration. Method: We designed a lipid-based nanoemulsifying drug delivery system of naringin using Acrysol K140 as an oil, Tween 80 as a surfactant and Transcutol HP as a cosolvent, to improve solubility and harness the benefits of nanosizing like improved cellular penetration. Intranasal instillations of therapeutic agents have limited efficacy due to drug washout and inadequate adherence to the nasal mucosa. Therefore, we reconstituted the naringin self-emulsifying system in a smart, biodegradable, ion-triggered in situ gelling hydrogel and optimized for desirable gel characteristics. The naringin-loaded composition was optimized and characterized for various physicochemical and rheological properties. Results: The formulation showed a mean droplet size 152.03 ± 4.6 nm with a polydispersity index <0.23. Ex vivo transmucosal permeation kinetics of the developed formulation through sheep nasal mucosa showed sustained diffusion and enhanced steady-state flux and permeability coefficient. Scanning and transmission electron microscopy revealed the spherical shape of emulsion droplets and entrapment of droplets in a gel structure. The formulation showed excellent biocompatibility as analyzed from the viability of L929 fibroblast cells and nasal mucosa histopathology after treatment. In vivo biodistribution studies revealed significantly higher drug transport and brain targeting efficiency. Conclusion: In situ gelling system with nanoemulsified naringin demonstrated a safe nasal delivery providing a new dimension to the treatment of chronic neurodegenerative diseases using small hydrophobic phytoconstituents with minimization of dose and related systemic adverse effects.

scholarly journals Crocetin as New Cross-Linker for Bioactive Sericin Nanoparticles

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 680
Author(s):  
Sara Perteghella ◽  
Giovanna Rassu ◽  
Elisabetta Gavini ◽  
Antonella Obinu ◽  
Elia Bari ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Human Fibroblasts ◽  
Brain Targeting ◽  
Brain Delivery ◽  
Ros Scavenging ◽  
Freeze Dried ◽  
Cross Linker ◽  
The Brain ◽  
Natural Cross

The nose-to-brain delivery route is used to bypass the blood–brain barrier and deliver drugs directly into the brain. Over the years, significant signs of progress have been made in developing nano-drug delivery systems to address the very low drug transfer levels seen with conventional formulations (e.g., nasal solutions). In this paper, sericin nanoparticles were prepared using crocetin as a new bioactive natural cross-linker (NPc) and compared to sericin nanoparticles prepared with glutaraldehyde (NPg). The mean diameter of NPc and NPg was about 248 and 225 nm, respectively, and suitable for nose-to-brain delivery. The morphological investigation revealed that NPc are spherical-like particles with a smooth surface, whereas NPg seem small and rough. NPc remained stable at 4 °C for 28 days, and when freeze-dried with 0.1% w/v of trehalose, the aggregation was prevented. The use of crocetin as a natural cross-linker significantly improved the in vitro ROS-scavenging ability of NPc with respect to NPg. Both formulations were cytocompatible at all the concentrations tested on human fibroblasts and Caco-2 cells and protected them against oxidative stress damage. In detail, for NPc, the concentration of 400 µg/mL resulted in the most promising to maintain the cell metabolic activity of fibroblasts higher than 90%. Overall, the results reported in this paper support the employment of NPc as a nose-to-brain drug delivery system, as the brain targeting of antioxidants is a potential tool for the therapy of neurological diseases.

scholarly journals Nanoemulsions for “Nose-to-Brain” Drug Delivery

Pharmaceutics ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 84 ◽  
Author(s):  
Maria Bonferoni ◽  
Silvia Rossi ◽  
Giuseppina Sandri ◽  
Franca Ferrari ◽  
Elisabetta Gavini ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Neurological Diseases ◽  
High Surface ◽  
High Surface Area ◽  
Brain Targeting ◽  
Nasal Administration ◽  
Toxic Substances ◽  
Onset Of Action ◽  
Brain Drug Delivery ◽  
The Brain

The blood–brain barrier (BBB) plays a fundamental role in protecting the brain from toxic substances and therefore also controls and restricts the entry of therapeutic agents. The nasal administration of drugs using the nose-to-brain pathway allows direct drug targeting into the brain, avoiding the first-pass effect and bypassing the BBB. Through the nasal route, the drug can access the brain directly along the trigeminal and olfactory nerves, which are located in the upper part of the nasal cavity. Nanoemulsions are formulations belonging to the field of nanomedicine. They consist of emulsions (commonly oil in water) stabilized by one or more surfactants—and eventually co-surfactants—delivered in droplets of small dimensions (sizes of 100–300 nm or less) with a high surface area. A mucoadhesive polymer such as chitosan can be added to the formulation to impair rapid nasal clearance. Nanoemulsions represent promising formulations to deliver drugs directly into the brain through the intranasal route. Therefore, they can be used as a possible alternative to oral administration, avoiding problems such as low solubility in water, poor bioavailability, enzymatic degradation and slow onset of action. This review focuses the present situation in literature regarding the use of nanoemulsions for nose-to-brain targeting, with particular attention to recent publications. Nasal nanoemulsions appear to be effective, non-invasive and safe drug delivery systems to achieve brain targeting for the treatment of neurological diseases.

scholarly journals Brain Targeting Through Intranasal Route: An Overview

2021 ◽  
pp. 112-124
Author(s):  
Sorakayala Venkata Anusha ◽  
Jonnala Ratna ◽  
Srirama Swarnalatha ◽  
Maruvajala Vidyavathi
Keyword(s):  
Drug Delivery ◽  
Small Molecules ◽  
Local Treatment ◽  
Systemic Circulation ◽  
Brain Targeting ◽  
Nasal Administration ◽  
Toxic Substances ◽  
Large Molecules ◽  
Nasal Route ◽  
The Brain

Brain targeting has always been challenging due to the presence of physiological barriers by Changing the integrity of these barriers, so as to allow the toxic substances, bacteria and viruses into the brain, Which may severely damage the central nervous system .This problem can be reduced by delivering drugs through the intra nasal route, which by passes the blood brain barrier and reaches into the brain. Nasal route is a non-invasive type, widely used for the local treatment as well as used for systemic therapy as drug delivery directly goes in to systemic circulation. Nasal route provides good absorption of small molecules compared to that of large molecules, absorption of small molecules and large molecules can be increased by absorption promoters. Different drug delivery devices are developed for nasal administration like liquids, semi-solid and solid formulation are consider to deliver the drugs to treat most of  the CNS diseases (i.e. Parkinson’s, Alzheimer’s disease) because it requires specific targeting of drugs to the brain. This review highlighted the challenges, approaches for brain targeting and various drug delivery systems developed with different drugs targeting to brain through nasal administration.

scholarly journals Tailoring Midazolam-Loaded Chitosan Nanoparticulate Formulation for Enhanced Brain Delivery via Intranasal Route

Polymers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 2589
Author(s):  
Nikesh Shrestha ◽  
Saba Khan ◽  
Yub Raj Neupane ◽  
Shweta Dang ◽  
Shadab Md ◽  
...  
Keyword(s):  
Particle Size ◽  
Drug Loading ◽  
Chitosan Nanoparticles ◽  
In Vitro Release ◽  
Area Under The Curve ◽  
Brain Targeting ◽  
Brain Delivery ◽  
Nanoparticle Formulation ◽  
The Brain

In the present study, midazolam (MDZ)-loaded chitosan nanoparticle formulation was investigated for enhanced transport to the brain through the intranasal (IN) route. These days, IN MDZ is very much in demand for treating life-threatening seizure emergencies; therefore, its nanoparticle formulation was formulated in the present work because it could substantially improve its brain targeting via the IN route. MDZ-loaded chitosan nanoparticles (MDZ-CSNPs) were formulated and optimized by the ionic gelation method and then evaluated for particle size, particle size distribution (PDI), drug loading (DL), encapsulation efficiency (EE), and in vitro release as well as in vitro permeation. The concentration of MDZ in the brain after the intranasal administration of MDZ-CSNPs (Cmax 423.41 ± 10.23 ng/mL, tmax 2 h, and area under the curve from 0 to 480 min (AUC0-480) of 1920.87 ng.min/mL) was found to be comparatively higher to that achieved following intravenous (IV) administration of MDZ solution (Cmax 245.44 ± 12.83 ng/mL, tmax 1 h, and AUC0-480 1208.94 ng.min/mL) and IN administration of MDZ solution (Cmax 211.67 ± 12.82, tmax 2 h, and AUC0-480 1036.78 ng.min/mL). The brain–blood ratio of MDZ-CSNPs (IN) were significantly greater at all sampling time points when compared to that of MDZ solution (IV) and MDZ (IN), which indicate that direct nose-to-brain delivery by bypassing the blood–brain barrier demonstrates superiority in brain delivery. The drug-targeting efficiency (DTE%) as well as nose-to-brain direct transport percentage (DTP%) of MDZ-CSNPs (IN) was found to be comparatively higher than that for other formulations, suggesting better brain targeting potential. Thus, the obtained results demonstrated that IN MDZ-CSNP has come up as a promising approach, which exhibits tremendous potential to mark a new landscape for the treatment of status epilepticus.

Efficient brain targeting and therapeutic intracranial activity of bortezomib through intranasal co-delivery with NEO100 in rodent glioblastoma models

2020 ◽  
Vol 132 (3) ◽  
pp. 959-967 ◽  
Author(s):  
Weijun Wang ◽  
Steve Swenson ◽  
Hee-Yeon Cho ◽  
Florence M. Hofman ◽  
Axel H. Schönthal ◽  
...  
Keyword(s):  
Brain Lesion ◽  
Systemic Exposure ◽  
Brain Targeting ◽  
Brain Delivery ◽  
Intranasal Delivery ◽  
Systemic Delivery ◽  
Pharmaceutical Agent ◽  
The Central Nervous System ◽  
Pharmaceutical Agents ◽  
The Brain

OBJECTIVEMany pharmaceutical agents are highly potent but are unable to exert therapeutic activity against disorders of the central nervous system (CNS), because the blood-brain barrier (BBB) impedes their brain entry. One such agent is bortezomib (BZM), a proteasome inhibitor that is approved for the treatment of multiple myeloma. Preclinical studies established that BZM can be effective against glioblastoma (GBM), but only when the drug is delivered via catheter directly into the brain lesion, not after intravenous systemic delivery. The authors therefore explored alternative options of BZM delivery to the brain that would avoid invasive procedures and minimize systemic exposure.METHODSUsing mouse and rat GBM models, the authors applied intranasal drug delivery, where they co-administered BZM together with NEO100, a highly purified, GMP-manufactured version of perillyl alcohol that is used in clinical trials for intranasal therapy of GBM patients.RESULTSThe authors found that intranasal delivery of BZM combined with NEO100 significantly prolonged survival of tumor-bearing animals over those that received vehicle alone and also over those that received BZM alone or NEO100 alone. Moreover, BZM concentrations in the brain were higher after intranasal co-delivery with NEO100 as compared to delivery in the absence of NEO100.CONCLUSIONSThis study demonstrates that intranasal delivery with a NEO100-based formulation enables noninvasive, therapeutically effective brain delivery of a pharmaceutical agent that otherwise does not efficiently cross the BBB.

Intranasal Lipid Particulate Drug Delivery Systems: An Update on Clinical Challenges and Biodistribution Studies of Cerebroactive Drugs in Alzheimer’s disease

2020 ◽  
Vol 26 (27) ◽  
pp. 3281-3299
Author(s):  
Deepshi Arora ◽  
Shailendra Bhatt ◽  
Manish Kumar ◽  
Hari D.C. Vattikonda ◽  
Yugam Taneja ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Drug Delivery ◽  
Drug Delivery Systems ◽  
Lipid Nanoparticles ◽  
Delivery Systems ◽  
Brain Delivery ◽  
Cns Disorders ◽  
Biodistribution Studies ◽  
The Brain

Background: Alzheimer is the primary cause of death in the various countries that affects wide strata of the population. The treatment of it is restricted to a few conventional oral medications that act only superficially. It is evident that the delivery of a drug to the brain across the blood-brain barrier is challenging as the BBB is armed with several efflux transporters like the P-glycoprotein as well as nasal mucociliary clearance adds up leading to decreased concentration and reduced therapeutic efficacy. Considering these, the intranasal IN route of drug administration is emerging as an alternative route for systemic delivery of a drug to the brain. The intranasal (IN) administration of lipid nanoparticles loaded with cerebroactive drugs showed promise in treating various neurodegenerative diseases, since the nasal route allows the direct nose to brain delivery by means of solid lipid nanoparticles (SLN’s). The tailoring of intranasal lipid particulate drug delivery systems is a pleasing approach to facilitate uptake of therapeutic agents at the desired site of action, particularly when a free drug has poor pharmacokinetics/ biodistribution (PK/BD) or significant off-site toxicities. Objectives: 1) In this review, key challenges and physiological mechanisms regulating intranasal brain delivery in Alzheimer’s disease, ex vivo studies, pharmacokinetics parameters including brain uptake and histopathological studies are thoroughly discussed. : 2) A thorough understanding of the in vivo behaviour of the intranasal drug carriers will be the elusive goal. : 3) The article emphasizes to drag the attention of the research community working in the intranasal field towards the challenges and hurdles of the practical applicability of intranasal delivery of cerebroactive drugs. Method: Various electronic databases, journals like nanotechnology and nanoscience, dove press are reviewed for the collection and compilation of data. Results: From in vivo biodistribution studies, pharmacokinetics parameters, and gamma scintigraphy images of various drugs, it is speculated that intranasal lipid particulates drug delivery system shows better brain targeting efficiency for various CNS disorders in comparison to other routes. Conclusion: Various routes are explored for the delivery of drugs to increase bioavailability in the brain for CNS disorders but the intranasal route shows better results that pave the way for success in the future if properly explored.

scholarly journals Targeting Systems to the Brain Obtained by Merging Prodrugs, Nanoparticles, and Nasal Administration

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1144
Author(s):  
Giada Botti ◽  
Alessandro Dalpiaz ◽  
Barbara Pavan
Keyword(s):  
Blood Brain Barrier ◽  
Brain Targeting ◽  
Nasal Administration ◽  
Efflux Transporter ◽  
Active Efflux ◽  
Valuable Alternative ◽  
Hydrophilic Drugs ◽  
Neuroactive Drugs ◽  
The Brain ◽  
Nanoparticulate Systems

About 40 years ago the lipidization of hydrophilic drugs was proposed to induce their brain targeting by transforming them into lipophilic prodrugs. Unfortunately, lipidization often transforms a hydrophilic neuroactive agent into an active efflux transporter (AET) substrate, with consequent rejection from the brain after permeation across the blood brain barrier (BBB). Currently, the prodrug approach has greatly evolved in comparison to lipidization. This review describes the evolution of the prodrug approach for brain targeting considering the design of prodrugs as active influx substrates or molecules able to inhibit or elude AETs. Moreover, the prodrug approach appears strategic in optimization of the encapsulation of neuroactive drugs in nanoparticulate systems that can be designed to induce their receptor-mediated transport (RMT) across the BBB by appropriate decorations on their surface. Nasal administration is described as a valuable alternative to obtain the brain targeting of drugs, evidencing that the prodrug approach can allow the optimization of micro or nanoparticulate nasal formulations of neuroactive agents in order to obtain this goal. Furthermore, nasal administration is also proposed for prodrugs characterized by peripheral instability but potentially able to induce their targeting inside cells of the brain.

scholarly journals Mucoadhesive microemulsion of ibuprofen: design and evaluation for brain targeting efficiency through intranasal route

2015 ◽  
Vol 51 (3) ◽  
pp. 721-731 ◽  
Author(s):  
Surjyanarayan Mandal ◽  
Snigdha Das Mandal ◽  
Krishna Chuttani ◽  
Bharat Bhushan Subudhi
Keyword(s):  
Brain Targeting ◽  
Nasal Administration ◽  
Albino Rats ◽  
Brain Uptake ◽  
Intranasal Route ◽  
Transmission Electron ◽  
Globule Size ◽  
Capmul Mcm ◽  
The Brain ◽  
Microemulsion Gel

This study aimed at designing mucoadhesive microemulsion gel to enhance the brain uptake of Ibuprofen through intranasal route. Ibuprofen loaded mucoadhesive microemulsion (MMEI) was developed by incorporating polycarbophil as mucoadhesive polymer into Capmul MCM based optimal microemulsion (MEI) and was subjected to characterization, stability, mucoadhesion and naso-ciliotoxicity study. Brain uptake of ibuprofen via nasal route was studied by performing biodistribution study in Swiss albino rats. MEI was found to be transparent, stable and non ciliotoxic with 66.29 ± 4.15 nm, -20.9 ± 3.98 mV and 98.66 ± 1.01% as average globule size, zeta potential and drug content respectively. Transmission Electron Microscopy (TEM) study revealed the narrow globule size distribution of MEI. Following single intranasal administration of MMEI and MEI at a dose of 2.86 mg/kg, uptake of ibuprofen in the olfactory bulb was around 3.0 and 1.7 folds compared with intravenous injection of ibuprofen solution (IDS). The ratios of AUC in brain tissues to that in plasma obtained after nasal administration of MMEI were significantly higher than those after intravenous administration of IDS. Findings of the present investigation revealed that the developed mucoadhesive microemulsion gel could be a promising approach for brain targeting of ibuprofen through intranasal route.

scholarly journals Nose-to-Brain Delivery of Antioxidants as a Potential Tool for the Therapy of Neurological Diseases

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1246
Author(s):  
Maria Cristina Bonferoni ◽  
Giovanna Rassu ◽  
Elisabetta Gavini ◽  
Milena Sorrenti ◽  
Laura Catenacci ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neurological Diseases ◽  
Olfactory Nerve ◽  
Brain Targeting ◽  
Brain Delivery ◽  
Oxygen Species ◽  
Neuroprotective Effects ◽  
The Central Nervous System ◽  
The Brain ◽  
Potential Tool

Oxidative stress has a key role in the pathogenesis of neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases and can be an important cause of the damages in cerebral ischemia. Oxidative stress arises from high levels of reactive oxygen species (ROS). Consequently, on this rational base, antioxidants (many of natural origin) are proposed as potential drugs to prevent ROS noxious actions because they can protect the target tissues from the oxidative stress. However, the potential of antioxidants is limited, owing to the presence of the blood–brain barrier (BBB), which is difficult to cross with a consequent low bioavailability of the drug into the brain after systemic (intravenous, intraperitoneal, oral) administrations. One strategy to improve the delivery of antioxidants to the brain involves the use of the so-called nose-to-brain route, with the administration of the antioxidant in specific nasal formulations and its passage to the central nervous system (CNS) mainly through the olfactory nerve way. In the current literature, many examples show encouraging results in studies carried out in cell cultures and in animal models about the potential neuroprotective effects of antioxidants when administered through the nose. This review concerns the nose-to-brain route for the brain targeting of antioxidants as a potential tool for the therapy of neurological diseases.

Sign in / Sign up

Export Citation Format

Share Document