Table 1.
Summary of studies on antidepressant active ingredients and new dosage forms for intranasal administration.
| Types | Ingredients | Dosage Form | Characterization | Ex Vivo/In Vivo Studies | Relevant Outcomes | Ref. |
|---|---|---|---|---|---|---|
| Antidepressants | Venlafaxine | Poly lactic-co-glycolic acid nanoparticles (PLGA-NPs); Peptide-modified nanoparticles |
PS = 206.3 ± 3.7 nm; PI = 0.041 ± 0.017; ZP = −26.5 ± 0.5 mV; around 200 nm after lyophilization process; DL = 10–12%; EE = 48–50%. |
In vitro cell viability and cellular uptake (hCMEC/D3 cells); Permeability assay and transport studies; Biodistribution studies (C57/bl6 mice). |
Cell viability of h-CMEC/D3 cells is more than 85% in the MTT assay. In vivo biodistribution studies showed higher concentrations of plain fluorescent NPs than functionalized NPs in the brain after 30 min of administration. | [107] |
| Chitosan nanoparticles (CN-NPs) | PS = 167 ± 6.5 nm; PI = 0.367 ± 0.045; ZP = +23.83 ± 1.76 mV; DL = 32.25 ± 1.63%; EE = 79.3 ± 2.6%; Yield = 71.42 ± 3.24%. |
Ex vivo permeation studies using porcine nasal mucosal membrane (Franz cells); Pharmacodynamic studies in Wistar rats (modified forced swim test, locomotor activity test); Qualitative localization and biodistribution studies by confocal laser scanning microscopy; Pharmacokinetic analysis. |
The cumulative drug permeability after 24 h in VLF CN-NPs was nearly 3 times compared with VLF solution. VLF CN-NPs showed a more significant antidepressant effect than VLF solution on chronic depression rats by forced swimming method. DTE (%)/DTP (%): NPs = 508.59/80.34 |
[108] | ||
| Desvenlafaxine | Chitosan-coated poly lactic-co-glycolic acid nanoparticles (PLGA-CN-NPs) | PS = 172.5 ± 10.2 nm; PI = 0.254 ± 0.02; ZP = +35.63 ± 8.25 mV; DL = 30.8 ± 3.1%; EE = 76.4 ± 4.2%; Release (24 h) = 77.21 ± 3.87% (pH 7.4) and 76.32 ± 3.54% (pH 6.0). |
Ex vivo permeation studies on porcine nasal mucosa; Pharmacodynamic studies (Wistar rats); Stress-induced model (forced swimming test); Drug-induced model (reserpine reversal test); Biochemical estimation of serotonin, noradrenaline, and dopamine; Blood and brain pharmacokinetic studies. |
In a rodent model of depression, compared with intranasal DVF solution and oral administration, increased levels of 5-HT and NE in the brain showed a more pronounced antidepressant effect. Pharmacokinetic parameters such as concentration, half-life, and AUC in the brain after intranasal administration were higher than those of through intravenous. DTE (%)/DTP (%) = 544.23/81.62 (DVF-NP s) DTE (%)/DTP (%) = 202.41/50.59 (DVF) |
[111] | |
| Agomelatine | Nanoemulsion thermosensitive in situ gel + 0.5% Chitosan | Gelling point = 28 ± 1 °C; Mucoadhesive strength = 6246.27 dynes/cm2; NEs: PS = 206.3 ± 3.7 nm; Micelles of P-407: PS = 142.58 ± 4.21 nm; Ago-NE-gel + 0.5%chitosan: Viscosity = 2439 ± 23 cP (35 ± 1 °C); pH = 5.8 ± 0.2. |
In vitro gel erosion study; Ex vivo drug permeation through the bovine nasal mucosa; Nasal toxicity study; Pharmacokinetic analysis: DTE (%) and DTP (%); Pharmacodynamic studies (Behavioral test; modified forced swim test and tail suspension test). |
Pharmacokinetic study in Wistar rats showed plasma concentration in the brain was 2.82 times higher than that of the intravenous suspension via the intranasal route. DTE (%)/DTP (%) = 344.9/71.0 |
[112] | |
| Solid lipid nanoparticles (SLNs) | PS = 167.70 ± 0.42 nm; PI = 0.12 ± 0.10; ZP = −17.90 ± 2.70 mV; EE = 91.25 ± 1.70%; Release (1 h)/(8 h) = 35.40 ± 1.13%/80.87 ± 5.16%. |
Pharmacokinetic study (rats): assay of agM in plasma and brain; Pharmacokinetic analysis: DTE (%) and DTP (%). |
The nasal solid lipid nanoparticles prepared by Ahmed et al. were superior to the oral suspension in brain concentration, AUC0–360min, and absolute bioavailability (44.44%) DTE (%)/DTP (%) = 190.02/47.37 |
[113] | ||
| Duloxetine | Nanostructured lipid carriers (NLCs) | PS = 137.2 ± 2.88 nm; ZP = -31.53 ± 11.21 mV; DL = 9.73 ± 3.22%; EE = 79.15 ± 4.17%. |
Biodistribution studies (Wistar rats); Pharmacokinetic study; Gamma-imaging study. |
Intranasal DLX-NLCs showed higher concentrations in blood and brain compared with DLX solution and oral route, which showed the same results in behavioral tests in mice. Intranasal NLCs were 8-fold higher in brain concentrations than intravenous DLX. DTE (%)/DTP (%) = 757.74/86.80 (DLX-NLC) DTE (%)/DTP (%) = 287.34/65.12 (DLX) |
[116,117] | |
| Thiomer gel loaded with proniosomes | 20% w/v PF127, 5% w/v PF68; 3.76 lipid ratio; PS = 265.13 ± 9.85 nm; GT = 32 ± 0.05 °C; EE = 98.13 ± 0.50%; Release (3 h) = 33%. |
Pharmacokinetic analysis: DTE (%) and DTP (%); Stability study. |
Thiomer gel loaded with duloxetine proniosomes increased the retention time and sustained release and penetration of DLX in the nasal mucosa (1.96 times that of duloxetine proniosomes). DTE (%)/DTP (%) = 137.77/10.5 |
[118] | ||
| Paroxetine | Nanoemulsion (NEs) | PS = 58.47 ± 3.02 nm; PDI = 0.339 ± 0.007; ZP = −33 mV; Transmittance = 100.60 ± 0.577%; Refractive index = 1.412 ± 0.003. |
Ex vivo permeation studies using porcine nasal mucosal membrane (Franz cells); Pharmacodynamic studies (Wistar rats; forced swimming test, locomotor activity test); Biochemical estimation: GSH and TBARS. |
The permeability of paroxetine NEs was 2.57 times higher than that of its suspension via permeation studies. Results of behavioral studies in rats showed that intranasal administration of paroxetine NEs significantly improved behavioral activity in depressed rats compared with the oral suspension of paroxetine. | [121] | |
| Trazodone | Microemulsion | labelling yield = 91.23 ± 2.12%; In vitro stability of 131I-TZ = 6 h; Droplet size = 16.4 ± 2.5 nm; PDI = 0.11 ± 0.02; ZP = 3.83 ± 0.36; Viscosity (25 °C) = 261.7 ± 3.0; Viscosity (37 °C) = 157.3 ± 7.5. |
Biodistribution of 131I-TZ; The 131I-TZ uptake in organs and body fluids. |
Sayyed et al. radiolabeled trazodone and compared the pharmacokinetic parameters of intranasal delivery of 131I-TZ solution, 131I-TZ microemulsion, and intravenous injection of 131I-TZ solution. Intranasal 131I-TZ microemulsion had sustained and higher brain uptake at any time tested than the other two formulations and routes. In addition, the blood exposure of intranasal 131I-TZ microemulsion was lower than that of intravenous injection, reducing systemic toxicity. | [123] | |
| Quetiapine fumarate | Microemulsion Chitosan microemulsion (CH-ME) methyl-β-cyclodextrin microemulsion (MeβCD-ME) |
PS: QF-ME = 29.75 ± 0.99 nm; CH-ME = 35.31 ± 1.71 nm; MeβCD-ME = 46.55 ± 1.9 nm with; PDI: QF-ME = 0.221 ± 0.01; CH-ME = 0.249 ± 0.03; MeβCD-ME = 0.233 ± 0.02; ZP: QF-ME = 2.77 ± 0.51; CH-ME = 20.29 ± 1.23 MeβCD-ME = 8.43 ± 0.7; Viscosity: QF-ME = 17.5 ± 0.69 cP; CH-ME = 38.5 ± 1.26 cP; MeβCD-ME = 33.3 ± 0.93 cP. |
Ex vivo mucoadhesive strength; Ex vivo nasal and intestinal diffusion study (goat nasal mucosa and small intestine); Nasal mucosal toxicity test; Pharmacokinetic analysis: DTE (%) and DTP (%). |
The brain bioavailability of quetiapine fumarate of chitosan-coated microemulsion was 3.8-fold and 2.7-fold higher than that of drug solution and chitosan-free microemulsion, respectively. DTE (%)/DTP (%) = 371.20 ± 12.02/ 68.66 ± 6.84 (QF-ME) DTE (%)/DTP (%) = 453.69 ± 10.17/80.51 ± 6.46 (CH-ME) |
[125] | |
| Doxepin hydrochloride | Thermoreversible biogels | Gelation temperature = 37.4 °C; Gelation time = 7.32 min pH = 6.93. |
In vitro penetration test on sheep nasal mucosa; Stress-induced model (forced swimming test). |
Compared with doxepin hydrochloride solution, the thermoreversible biogel showed more advantages in immobility time and swimming activity count in mice after 13 days of drug administration. | [126] | |
| Off-label drugs | Ketamine/Esketamine | Nasal spray | N/A | N/A | Ketamine, whether administered intravenously or intranasally, has a higher bioavailability than the oral route, and has a more rapid and significant effect than traditional antidepressants with delayed onset of action. Due to the plasma elimination half-life of ketamine of 2–4 h and the discomfort associated with invasive administration, delivery of ketamine directly to the brain via the nasal cavity is a more advantageous strategy. | [127,128] |
| Amisulpride | Lipid-based poloxamer-gellan gum nanoemulgel AMS nanoemulsion (AMS-NE) AMS in situ nanoemulgel (AMS-NG) |
AMS-NE: PS = 92.15 ± 0.42 nm; PI = 0.46 ± 0.03; ZP = −18.22 mV; Transmittance = 99.57%; Mucoadhesive strength = 1.24 g; Release (4 h) = 99.99%; AMS-NG: PS = 106.11 ± 0.26 nm; PI = 0.51 ± 0.01; ZP = −16.01 mV; Transmittance = 98.47%; Mucoadhesive strength = 8.90 g; Release (4 h) = 98.96%. |
Ex vivo drug permeation study on freshly isolated sheep nasal mucosa; In vivo animal experiments (pharmacokinetic study, AMS in brain and blood plasma samples); Animal behavioral studies (induced locomotor activity test, paw test); In vivo safety assessment. |
Pharmacokinetic studies in Wister rats showed that the intranasal C(max) of the brain was 3.39 times higher than that of the intravenous administration and intranasal administration within one month did not affect blood leukocyte and granulocyte counts. DTE (%)/DTP (%) = 314.08/76.13 (AMS-NE) DTE (%)/DTP (%) = 1821.72/275.09 (AMS-NG) |
[139] | |
| Aripiprazole | Mucoadhesive nanoemulsion | PS = 121.8 ± 1.5 nm; PI = 0.248 ± 0.05; ZP = −18.89 ± 3.47 mV; Viscosity = 187.79 ± 5.35 cP (25% Carbopol); Viscosity = 626.32 ± 8.63 cP (1% Carbopol); Release (8 h) = 84.92%. |
Ex vivo permeation test and nasal ciliotoxicity on sheep nasal mucosa; In vitro cytotoxicity study (Vero cells, PC12 cells); In vivo pharmacokinetic study (DTE (%) and DTP (%)); Locomotor activity study. |
Pharmacokinetic studies with single-dose administration showed that the plasma concentration in the brain of intranasal ARP-MNE was 1.44 and 6.03 times higher than that of intranasal and intravenous ARP-NE, respectively, and the Tmax was smaller than that of intravenously administered ARP-NE. DTE (%)/ DTP (%) = 96.90/89.73 |
[144] | |
| Poly(caprolactone) nanoparticles | PS = 199.2 ± 5.65 nm; ZP = -21.4 ± 4.6 mV; EE = 69.2 ± 2.34%; Release (8 h) = 90 ± 2.69%. |
Ex vivo diffusion studies on goat nasal mucosa; Nasal toxicity study (goat nasal mucosa); In vivo pharmacokinetics study (DTE (%) and DTP (%)). |
The AUC0–8h of Aripiprazole in the rat brain administered by the intranasal route of APNPs was approximately twice that of the intravenous route. DTE (%)/DTP (%) = 64.11/74.34 |
[145] | ||
| Selegiline | Chitosan nanoparticle | PS = 341.6 ± 56.91 nm; PI = 0.317 ± 0.29; ZP = −13.4 ± 0.04 mV; EE = 92.20 ± 7.15%; Release (8 h) = 90 ± 2.69%. |
Ex vivo drug diffusion on sheep nasal mucosa; Pharmacokinetics and pharmacodynamics studies; Behavioral testing; Biochemical analyses: dopamine level, catalase activity, reduced glutathione (GSH) content. |
The Cmax of plain solution of selegiline in the brain and plasma by intranasal administration (Tmax = 5 min) was 20 and 12 times higher, respectively, compared with oral administration (Tmax = 15 min). Furthermore, intranasal administration of selegiline-loaded CN-NPs and mucoadhesive thermosensitive gel showed superior formulation advantages compared with the AUC0–24h of plain solution. | [148,149] | |
| Peptides | Insulin | N/A | N/A | Pharmacokinetics study (insulin concentrations in brain and plasma via different delivery routes); AUCbrain: plasma ratio; Repeated in insulin administration. |
The study found intranasal delivery of insulin showed a 2000-fold increased AUCbrain: plasma ratio compared with subcutaneous administration, with no apparent effect on blood glucose levels. | [158] |
| Lixisenatide | N/A | N/A | Chronic unpredictable mild stress depression model (rats); Behavioral studies (forced swim test, tail suspension test, open field test); Cells were labeled with BrdU and neurogenesis in the olfactory bulb and hippocampus was observed. |
Intranasal lixisenatide not only improved depressive and anxious behaviors in a chronic unpredictable mild stress model, but also improved olfactory system function. In addition, intranasal lixisenatide was demonstrated to play an antidepressant role by regulating cyclic-AMP response binding protein (CREB)-mediated neurogenesis. | [159] | |
| GLP-2 | PAS-CPPs-GLP-2 | N/A | Behavioral studies (forced swim test, tail suspension test, open field test); Distribution test (rats’ brain). |
Studies have found that intranasal PAS-CPP-GLP-2 exhibited antidepressant effects similar to intracerebroventricular injection in mouse models, but not intravenous injection. | [56,160] | |
| BDNF | BDNF-HA2TAT/AAV | Each step was qualified by specific restriction enzyme reactions and AGE; High expression of BDNF in infected Hela cells. |
Chronic unpredictable mild stress depression model (rats); Behavioral assessment (forced swim test, sucrose preference test, open field test); Body weight; Western-blotting analysis; Expression of BDNF mRNA. |
Western-blotting analysis showed that the content of BDNF in the hippocampus increased via intranasal administration. Compared with the control group and the AVV group, the BDNF-HA2TAT/AAV group significantly reversed the depressive behavior of the rats. | [169,170] | |
| NAP | NT4-NAP/AAV | Each step was qualified by specific restriction enzyme reactions and AGE; Expression of BDNF in infected PC12 cells. |
Behavioral assessment (forced swim test, sucrose preference test, open field test); Effect on plasma CORT; Expression of 5-HT and BNDF in hippocampus. |
Experiments have shown that the depressive symptoms of female mice are improved after ten days of administration. Although the effect is not significant, it also proves that intranasal administration from different targets, such as microtubules, provide new ideas for the treatment of depression. | [171,172] | |
| NPY/LCG-17/MCH/CST-14/NGF | N/A | N/A | Behavioral assessment (forced swim test, sucrose preference test, open field test); Biochemical studies. |
These peptides bypass the blood–brain barrier via a non-invasive intranasal route of administration, improving bioavailability and brain targeting. The peptides both improve anxiety and depression behavior in animal models. The peptides also promote neuroplasticity in the central nervous system, especially the hippocampus and prefrontal cortex. | [173,174,175,176] | |
| Natural active ingredients | Albiflorin | Alginate nanogels | PS = 45.6 ± 5.2 nm; PI < 0.20; ZP = −19.8 ± 0.9 mV; EE = ±7.15%; Release (12 h) = 99%; Gelling temperature = 28 °C. |
In vivo fluorescence distribution analysis of alginate nanogels (rats); Pharmacodynamic study; Antidepressant behavioral studies: tail suspension test; Transcriptome studies: cAMP, calcium ion, and cGMP PKG signal pathway. |
Fluorescent labeling showed that albiflorin could quickly reach the brain for distribution after intranasal administration (≤30 min). The authors observed through tail suspension experiments in mice that low-dose intranasal administration significantly shortened the chronic unpredictable mild stress model of mice compared with intragastric gavage and intravenous injection of albiflorin solution. Do not move time. The reduction of pro-inflammatory cytokine levels and the repair of neuronal damage in CUMS rats further suggest that albiflorin has an excellent potential for rapid antidepressant effects. | [186] |
| Berberine | Cyclodextrin + thermosensitive hydrogel | The berberine /HP-β-CD inclusion complex (1H-NMR-NMR showed good degree of inclusion); Gelling temperature = 30 °C; Release (6 h) = 83.29 ± 3.98%; Loading efficiency = 22.86%. |
Brain targeting of berberine study (Radioactive tracer of 125I); Pharmacokinetic analysis: berberine in hippocampus; Monoamine neurotransmitters in rats (reserpine-induced model). |
The relative intracerebral bioavailability of berberine showed that the intranasal formulation of berberine was 110 times higher than the oral inclusion complex of berberine–cyclodextrin. Pharmacological studies have found that the intranasal route, in addition to increasing the levels of monoamine neurotransmitters in the hippocampus compared with oral administration, exhibits a potential antidepressant mechanism by restoring sphingolipid and phospholipid abnormalities and mitochondrial dysfunction. | [190] | |
| Berberine and Evodiamine | Thermosensitive in situ hydrogels | P407/P188/HP-β-CD/PEG 8000 = 20/0/8/1; Release = 93% (berberine); Release = 43% (evodiamine); Gelling temperature = 28 °C. |
Pharmacokinetic study (plasma and hippocampus); Antidepressant behavioral studies (open field test, tail suspension test); Monoamine neurotransmitters studies in rats. |
The bioavailability of intranasal hydrogels was more than 135- and 112-fold higher than that of gavage berberine and evodiamine solutions. The intranasal formulation significantly improved behavioral despair by modulating monoamine levels and related metabolic pathways in mice. | [191] | |
| Cang-ai volatile oil | Intranasal inhaler | N/A | Chronic unpredictable mild stress depression model (rats); Behavioral studies (open field test, forced swim test, and sucrose preference test); Expression of pro-inflammatory cytokines and monoamine neurotransmitters studies in prefrontal cortex. |
Studies have shown that Cang-ai volatile oil can inhibit microglia activation and kynurenine pathway to regulate 5-HT and play an antidepressant effect. The forced swim test, open field test, sucrose preference test, etc. confirmed that intranasal delivery of Cang-ai volatile oil can effectively regulate the metabolism of dopamine and 5-HT in the brain of CUMS rats and improve depressive behavior. | [192,193] | |
| Icariin | Nanogel loaded thermosensitive hydrogel (NGSTH) | PS = 73.80 ± 2.34 nm; PI < 0.15; ZP = −19.2 ± 1.14 mV; Loading efficiency = 2.03%; Release (36 h) = 70% (nanogel); Gelling temperature = 30 °C; Release (36 h) = 100% (NGSTH). |
In vivo distribution fluorescently labeled nanogels Behavioral testing (tail suspension test, forced swim test); Expression of pro-inflammatory cytokines and morphological changes in the hippocampus. |
ICA-NGSTH could be distributed in the brain in about half an hour and showed zero order kinetic release within 10 h. By comparing the oral route of ICA, intranasal ICA-NGSTH showed better behavior improvement ability in an animal model of depression. | [196] | |
| White tea | N/A | N/A | Chronic unpredictable mild stress depression model (rats); Behavioral testing (open-field test, sucrose preference test, buried food pellet test); Olfactory sensitivity test. |
High and low levels of white tea extracts could effectively reverse depressive behavior in mice. Olfactory avoidance tests and olfactory sensitivity tests showed its relief of olfactory dysfunction. Pharmacological studies found that white tea reduced mitochondrial and synaptic damage in the olfactory bulb and enhanced the content of BDNF. | [197] |
Abbreviations: PS, globule size; ZP, zeta potential; PI, polydispersity index; DTE (%), drug targeting efficiency; DTP (%), nose-to-brain direct transport percentage; BDNF, brain-derived neurotrophic factor; CORT, corticosterone; P407, poloxamer 407; P188, poloxamer 188.