Intranasal Nanoemulsions for Direct Nose-to-Brain Delivery of Actives for CNS Disorders
Abstract
:1. Introduction
2. Pathways for Brain Delivery through the Intranasal Route
2.1. Olfactory Pathway
2.2. Trigeminal Pathway
2.3. Lymphatic Pathway
2.4. Systemic Pathway
3. Nanoemulsions
3.1. Overview of Nanoemulsion Components
3.1.1. Oils
3.1.2. Surfactants
3.1.3. Cosurfactants
3.2. Significant Factors of Nanoemulsions for Nose-to-Brain Delivery
3.2.1. Globule Size
3.2.2. Zeta Potential
4. Intranasal NEs for Brain Disorders
4.1. NEs for Alzheimer’s Disease
4.2. NE for Parkinson’s Disease
4.3. NE for Migraines
4.4. NE for Epilepsy
4.5. NE for Psychosis
4.6. NE for CNS Infection
4.7. NE for Senile Dementia and Cerebrovascular Spasms
4.8. NE for Depression
4.9. NE for Brain Tumors
4.10. NE for Neuroprotection
4.11. NE for Multiple Sclerosis and Amyotrophic Lateral Sclerosis
4.12. NE for Cerebral Ischemia
5. Current Challenges and Future Prospects
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Drug | Therapy for | Characterization Parameters | Study Model (s) | Relevant Therapeutic Outcomes | Ref. |
---|---|---|---|---|---|
Donepezil | Alzheimer’s disease | GS = 127.13 ± 4.14 nm PDI = 0.182 ± 0.011 | In vitro drug diffusion study. Ex vivo drug permeation study. Tolerability study through in vitro and in vivo models. | The permeation of donepezil was found to be significant through intranasal NE. The polymers can be used as an effective strategy to improve the bioadhesion and drug penetration through nasal mucosa, which enhances the bioavailability of donepezil. | [47] |
Rivastigmine | Alzheimer’s disease | GS = 35.75 ± 0.21 nm PDI = 0.247 ± 0.04 ZP = −24.4 ± 0.67 mV | In vitro drug release study. Ex vivo diffusion study. In vivo pharmacokinetic and biodistribution study in rat. Nasal ciliotoxicity studies in goat nasal mucosa. | Rivastigmine-loaded NE showed significantly higher drug concentration in brain than the solution. The optimized formulation was devoid of nasal ciliotoxicity. | [48] |
Resveratrol | Parkinson’s disease | GS = 176.3 ± 3.5 nm PDI = 0.17 ± 0.03 ZP = 18.5 ± 1.77 mV | In vitro drug release study. Ex vivo diffusion study. In vivo drug biodistribution study in Wistar rat’s brain. | Diffusion controlled release of resveratrol was for 6 h with flux of 2.86 mg/cm2 h through sheep nasal mucosa. The drug level in the brain from intranasal resveratrol mucoadhesive NE was higher than the resveratrol solution. Bioavailability was seven times higher through this approach. | [49] |
Selegiline | Parkinson’s disease | GS = 61.43 ± 4.10 nm PDI = 0.203 ± 0.005 ZP = −34.00 ± 0.17 mV | In vitro drug release study. Ex vivo diffusion study. Behavioral activities of Parkinson’s disease in Wistar rats. | Selegiline NE showed 3.7-fold more penetration than the drug solution. Haloperidol-induced Parkinson’s disease in animals with selegiline intranasal NE showed significant improvement in behavioral activities in comparison to conventional drug delivery. | [50] |
Letrozole | Epilepsy | GS = 95.59 ± 2.34nm PDI = 0.162 ± 0.012 ZP = −7.12 ± 0.12 mV | In vitro and ex vivo drug release study. A behavioral seizure; biochemical and histopathological studies were performed. | Intranasal administration of NE showed the prolonged drug release profile as compared to suspension. High concentration of drug was found in brain. | [51] |
Amiloride | Antiepileptic | GS = 89.36 ± 11.18 nm PDI = 0.231 ± 0.018 ZP = −9.83 ± 0.12 mV | In vitro drug release study. Ex vivo diffusion study. In vivo pharmacodynamic and pharmacokinetic study in Wistar rats. | Bioavailability and brain-targeting efficiency with efficacy of developed amiloride NE was enhanced though nasal administration. | [52] |
Zolmitriptan | Migraine | GS = 54.63 ± 3.24 nm ZP = −0.086 ± 0.014 mV PDI = 0.17 ± 0.01 | In vitro mucoadhesion study. Ex vivo drug permeation studies. In vivo pharmacokinetic and biodistribution studies. | Zolmitriptan mucoadhesive NE showed higher permeability coefficients than the solution through the nasal mucosa. In vivo study of zolmitriptan mucoadhesive NE showed higher AUC0–8 and shorter Tmax in the brain in comparison to intravenous and nasal solutions. | [53] |
Rizatriptan | Migraine | GS = 20–120 nm | In vitro drug diffusion study. Nasal irritation study on sheep nasal mucosa. In vivo brain-targeting potential. | Ex vivo drug diffusion-defined controlled release with 86% in 4 h. Brain targeting through intranasal NE (AUC = 302.52 μg min/g) was more than intranasal gel (AUC = 115 μg min/g) and intravenous route (AUC = 109.63 μg min/g). | [54] |
Cyclosporine-A | Neuroprotective | GS = 158.47 ± 3.02 nm ZP = −30 mV | In vitro drug diffusion study. In vivo brain uptake study. | The brain/blood ratios of cyclosporine-A by intranasal and intravenous was found to be 4.49 and 0.01, respectively. Cyclosporine-A NE can be used for direct nose-to-brain delivery, bypassing the BBB. | [55] |
Kaempferol | Neuroprotective and anti-tumor | GS = 170.4 ± 4.1 nm PDI = 0.155 ± 0.015 ZP = −18.71 ± 1.72 | Ex vivo diffusion study. In vivo drug biodistribution study in Wistar rats. | The drug concentration through intranasal NE was found to be 4 to 5-fold higher than the solution. Ex vivo permeation and in vivo biodistribution studies showed higher drug concentrations in the brain with chitosan NE through intranasal administration in compared to NE and the kaempferol solution. | [56] |
Ziprasidone hydrochloride | Antipsychotic | GS = 145.24 ± 4.75 nm PDI = 0.186 ± 0.40 ZP = −30.2 ± 3.21 mV DC = 0.3418 ± 0.03 CM2/min | Ex vivo diffusion study. In vivo pharmacodynamic study in Wistar rats. Nasal ciliotoxicity studies in goat nasal mucosa. | Higher drug diffusion of ziprasidone NE than the solution was found. Pharmacodynamic study revealed the superiority of mucoadhesive NE than NE in the locomotor activity and paw test. Formulation was devoid of acute nasal ciliotoxicity. | [57] |
Quetiapine | Antipsychotic | GS = 144 ± 0.5 nm | In vitro dissolution study. In vivo drug distribution study in Wistar rats. | Higher drug transport efficiency (DTE%) via intranasal NE. | [58] |
Drug | Method of Preparation | GS and ZP | In Vivo Model | Ref. |
---|---|---|---|---|
Ecto-50-nucleotidase (CD73) | Microfluidization | 262.7 ± 12.8 nm +3.5 ± 3.0 | C6 rat glioma | [111] |
Kaempferol | High-pressure homogenization | 180.53 ± 4.90 nm (coated) +26.09 ± 2.67 (coated) 145.07 ± 4.91 nm (uncoated) −18.10 ± 2.55 (uncoated) | N/A | [112] |
Temozolomide | High-pressure homogenization | 134 nm −13.11 | N/A | [113] |
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Bahadur, S.; Pardhi, D.M.; Rautio, J.; Rosenholm, J.M.; Pathak, K. Intranasal Nanoemulsions for Direct Nose-to-Brain Delivery of Actives for CNS Disorders. Pharmaceutics 2020, 12, 1230. https://doi.org/10.3390/pharmaceutics12121230
Bahadur S, Pardhi DM, Rautio J, Rosenholm JM, Pathak K. Intranasal Nanoemulsions for Direct Nose-to-Brain Delivery of Actives for CNS Disorders. Pharmaceutics. 2020; 12(12):1230. https://doi.org/10.3390/pharmaceutics12121230
Chicago/Turabian StyleBahadur, Shiv, Dinesh M. Pardhi, Jarkko Rautio, Jessica M. Rosenholm, and Kamla Pathak. 2020. "Intranasal Nanoemulsions for Direct Nose-to-Brain Delivery of Actives for CNS Disorders" Pharmaceutics 12, no. 12: 1230. https://doi.org/10.3390/pharmaceutics12121230