Summary
The blood-brain barrier (BBB) is a critical obstacle in treating central nervous system (CNS) disorders, as it regulates the influx of substances to the brain and maintains CNS homeostasis. Its selective permeability significantly limits the brain exposure of many phytochemicals due to tight junctions, rapid metabolism, low solubility, and transporter-mediated efflux. These factors hinder clinical translation and justify the development of lipid-based nanocarrier strategies to enhance drug delivery. Moreover, many phytochemicals suffer from unfavorable pharmacokinetic profiles, and nanocarriers have been described as vehicles capable of improving bioavailability, stability, and delivery, leading to the design of oral systems that stabilize and solubilize lipophilic cargo.
This review critically evaluates data suggesting that lipid-based nanoformulations (e.g., nanoemulsions, SEDDS/SNEDDS, SLN/NLC, liposomes, and phospholipid complexes) can enhance systemic and/or brain exposure to botanicals. It also highlights areas where more direct evidence is required, such as measuring brain concentrations or using BBB models. It pays particular attention to liquid-filled hard capsules (LFHC) technology as a platform for delivering oil-surfactant-cosurfactant mixtures (SEDDS), which are stable formulations administrable in soft or hard gelatin capsules. Additionally, data on self-nanoemulsifying granules in hard capsules that enhance release and intestinal absorption of lipophilic drugs are discussed.
Examples of improved bioavailability (e.g., nanoemulsion of curcuminoids: total curcuminoids bioavailability 46% vs 8.7% in dispersion, or oral curcumin NLC: 11.93-fold increase in brain AUC) and increased permeability in BBB models (e.g., 1.8-fold increase by ApoE-functionalized resveratrol-SLN through hCMEC/D3 monolayers) are summarized. Moreover, the neuropharmacological section emphasizes the “catecholamine paradox”: catecholamines generally do not cross the mature BBB (except in periventricular areas). Thus, orally administered botanicals achieve "catecholamine homeostasis" indirectly (e.g., modulation of signaling, enzymes, neurotrophins) rather than directly delivering dopamine or norepinephrine to the brain.
Conclusions emphasize (i) the improved systemic exposure following lipid-based formulations, (ii) the presence of preclinical evidence for increased brain exposure of selected compounds (e.g., curcumin, α-asarone, andrographolide, Ginkgo TTL), and (iii) the necessity for cautious extrapolation to nootropic products, as some data involve intravenous administration or in vitro models rather than oral LFHC in human populations.
Key Words
This review focuses on the blood-brain barrier, nanoemulsions, SEDDS/SNEDDS, lipid nanoparticles (SLN/NLC), liquid-filled hard capsules, and botanical compounds with limited bioavailability and restricted access to the brain.
1. Introduction
The most significant barrier to CNS disease therapy is drug penetration through the blood-brain barrier (BBB), which regulates the influx of substances into the brain and ensures CNS homeostasis. In the case of phytochemicals, this barrier poses dual challenges of limited systemic availability and restricted brain exposure. The BBB effectively excludes most native phytochemicals due to tight junctions, rapid metabolism, low solubility, and transporter-mediated efflux. These unique features of the BBB significantly limit the access of phytochemicals to target tissues, thereby constraining clinical translation and necessitating nanodelivery platforms to optimize drug transport into the brain.
Many botanicals share unfavorable pharmacokinetic profiles, which impede their pharmacological activity. Nanotechnology is increasingly recognized as a tool to enhance the delivery, bioavailability, biocompatibility, and stability of phytochemicals. Reviews on nanomedicine in neurology highlight lipid carriers as a biomimetic approach to bypass the BBB, improve neurological disorder therapy, and minimize toxicity, including in the case of natural compounds like resveratrol or curcumin.
In this context, lipid platforms that maintain the drug in solubilized states and form micro-/nanoemulsions within the gastrointestinal tract hold particular promise. Self-emulsifying drug delivery systems (SEDDS), composed of oils, surfactants, and co-surfactants, enable stable emulsions at the target site, enhancing drug absorption and stabilizing labile lipophilic compounds. These findings support developing LFHC as a dosage form for liquid lipid mixtures in pharmaceutical and nutraceutical applications.
2. Blood-Brain Barrier (BBB)
The BBB is a physical barrier regulating molecular entry into the brain and maintaining CNS homeostasis, rendering drug delivery to the CNS particularly challenging. For phytochemicals, the BBB directly limits access to most native plant-derived molecules due to tight junction selectivity, rapid metabolism, low solubility, and transporter-mediated efflux. These phenomena comprise the primary barriers at the level of the brain endothelium and perivascular environment.
Experimental evidence indicates that BBB integrity is dynamic and modulated by factors like inflammation and endogenous signaling. For instance, cortistatin deficiency predisposes to endothelial weakening, increased permeability, and tight junction breakdown, while cortistatin administration can reverse hyperpermeability and reduce BBB leakage in vivo. Mechanistic insights into these processes suggest that metabolic and stress pathways, such as labile iron pools and stress regulators like HIF2α, are tightly coupled to barrier integrity, providing a potential framework for novel interventions.
The Catecholamine Paradox
A major limitation of "catecholamine homeostasis" claims is that catecholamines generally cannot penetrate the mature BBB, except in periventricular regions where the barrier is absent or defective. Additionally, in rodent models, it has been shown that the BBB forms in stages postnatally, with early development of physical and ion-restrictive elements, followed by later enzymatic development. Consequently, the permeability of catecholaminergic molecules is influenced by both molecular properties and the barrier's developmental stage.
Interestingly, dopamine itself can modulate BBB properties. Under oxidative stress (e.g., with H2O2), dopamine and the agonist A68930 reduce hyperpermeability of endothelial monolayers, preserve the integrity of tight junctions, and support actin cytoskeletal assembly. This protective mechanism involves inhibition of the NLRP3 inflammasome rather than direct mitigation of increased ROS production. From a nootropic perspective, this highlights the necessity of separating (i) direct central delivery of catecholamines (usually ineffective due to the BBB) and (ii) indirect modulation of the CNS and endothelium to influence neuroinflammatory and neurotrophic balance.
Pharmacological Modulation of Permeability
Approaches such as reversible and non-toxic BBB modulation by compounds like NEO100 have shown promise in increasing brain ingress of therapies. Mechanistically, these strategies affect various BBB transport pathways and can alter the localization of tight junction proteins from membranes to the cytoplasm in brain endothelial cells. However, such approaches qualitatively differ from lipid-based formulations that focus on solubilization and enhanced systemic exposure, and their application requires rigorous safety evaluation due to the potential risks associated with temporarily increased BBB permeability.
Additional Data on SLN Surface Modification
Additional data suggests that surface modification of SLNs (quaternized chitosan, TMC-SLCN) provided controlled release in simulated intestinal fluids and "significantly higher" oral bioavailability and brain distribution of curcumin compared to free curcumin, chitosan, and uncoated SLCN. This connects the mechanisms of stability, release, and CNS distribution into a single preclinical outcome [45].
Curcumin
In a zebrafish model, a curcumin microemulsion in turmeric oil, designed for "brain-targeting," achieved a twofold improvement in plasma pharmacokinetics (PK), a 1.87-fold improvement in brain PK, improved spatial memory, and reduced oxidative stress. This suggests that enhanced brain exposure via a lipid system may correlate with measurable functional effects in a neurodegeneration model [46].
In clinical data, lipid formulations of curcumin can provide rapid and measurable absorption. For instance, in the CRM-LF study, a dose of 750 mg reported a Tmax of approximately 0.18 h (12 min), T1/2 of 0.60 ± 0.05 h, and Cmax of 183.35 ± 37.54 ng/mL, with an AUC0–∞ of 321.12 ± 25.55 ng·h/mL. These results indicate a rapid absorption phase and significant systemic exposure (without measuring CNS uptake) [47].
In the AQUATURM® study, >7-fold improvement in AUC0–12h was demonstrated, with detectable curcumin levels maintained for the full 12 hours (while a comparator formulation dropped below the limit of quantification after 4 hours in most participants). This provides clinical evidence for the potential of specific formulations to prolong systemic exposure, even though it utilizes a "water-soluble" rather than a classic lipid nanoemulsion approach [48].
Phospholipid-based formulations (phytosomes) represent a distinct paradigm. In a cross-over human study, Meriva (a lecithin-based formulation of curcuminoid mixture) resulted in ~29-fold higher total curcuminoid absorption compared to the unformulated mix. However, only phase II metabolites were detected, and plasma concentrations were still significantly below levels required for inhibition of most anti-inflammatory targets for curcumin, limiting overinterpretation of the "multiple-fold bioavailability enhancement" as an automatic improvement in CNS effects [38].
Resveratrol
Resveratrol requires formulation strategies due to its poor solubility and chemical instability, which constrain bioavailability and biological benefits. Reviews indicate a trend toward resveratrol encapsulation strategies targeting the brain and justify the role of nanotechnology in enabling BBB penetration through masking physicochemical properties and extending half-life [27].
In an in vitro BBB model, functionalizing SLNs with apolipoprotein E increased permeability across hCMEC/D3 monolayers, with permeability 1.8-fold higher for SLN-ApoE compared to non-functionalized versions. This constitutes direct evidence of improved transport across the BBB model via "liganding" of the lipid nanocarrier [14].
In vivo studies have further supported the hypothesis of improved neural targeting using resveratrol-loaded SLNs in a rat model of Alzheimers disease. These SLNs enhanced HSP70 expression by fourfold, reduced IL-1b levels, and improved passive avoidance memory in behavioral tests, suggesting functional benefits for resveratrol delivery to the CNS. However, no direct measurements of brain concentrations were reported in the cited study [49].
Other in vivo studies, such as those using lipid-core nanocapsules, demonstrated that resveratrol could "rescue" the deleterious effects of A 3b13 infusion in a mouse model of neurodegeneration. This was attributed to a "substantial increase" in resveratrol concentration in brain tissue facilitated by nanocapsules, supporting the mechanism of brain exposure-based efficacy [50].
More targeted liposomal strategies have simultaneously reported improved transport and neurotrophic effects. Liposomal resveratrol conjugated with an ANG ligand increased resveratrol's ability to cross the BBB and achieve neuronal uptake in cellular experiments. In a mouse aging model, it improved cognitive function by reducing oxidative stress and inflammation in the brain while increasing BDNF levels. These findings link technological advancements in BBB penetration with improved neurotrophic biomarkers and cognitive outcomes [51].
Bacopa monnieri
Bacopa monnieri's active component, bacoside A, has low aqueous solubility and limited BBB penetration, which restrict its bioavailability and clinical efficacy for neurodegenerative diseases. This justifies the use of carrier strategies such as niosomes [52].
A niosomal formulation of a fraction rich in bacoside A (Fort-BAF) was evaluated for its in vivo pro-cognitive properties compared to the fraction alone. The authors concluded that niosomes significantly improved Fort-BAF's stability and bioavailability, supporting that vesicular systems can facilitate CNS-directed delivery [52].
Research into self-nanoemulsifying drug delivery systems (SNEDDS) has been conducted to enhance the solubility and bioavailability of poorly soluble bacosides. These systems, incorporating various oils/surfactants/co-surfactants, were assessed for brain penetration and pharmacokinetic profiles in rats, linking Bacopa with the paradigm of lipid nanosystems for CNS exposure, although specific PK data were not provided in the cited segment [53].
In terms of nootropic mechanisms, reviews suggest Bacopa operates, in part, by modulating neurotransmitter systems including norepinephrine and dopamine. This directly ties Bacopa9s effects to catecholaminergic homeostasis without the need for direct catecholamine delivery across the BBB [15, 54].
Withania somnifera
Preclinical studies suggest that withanolides may promote neurogenesis, protect against neurodegenerative diseases, and reduce oxidative stress and inflammation. Advances in delivery methods (such as liposomal and nanoemulsion systems) show improvements in their bioavailability [55].
On the cellular level, MPEG-PCL nanoparticles containing Withania somnifera extract (WSE) were found to be efficiently taken up by U251 cells and provided greater protection from oxidative damage (95.1%) compared to PCL with WSE (56.4%) and free WSE (39.0%). This supports the concept that encapsulation increases functional efficacy under oxidative stress, although no direct evidence of BBB penetration is provided [56].
Ginkgo biloba
In a study on rats, single oral administration of 600 mg/kg standardized extract EGb 761® demonstrated significant concentrations of ginkgolide A (GA), ginkgolide B (GB), and bilobalide (Bb) in both plasma and CNS tissues. Brain concentrations rose quickly to 55 ng/g (GA), 40 ng/g (GB), and 98 ng/g (Bb), providing direct evidence that specific terpene trilactones cross the BBB after oral administration in an animal model [18].
Review data also confirm significant levels of Ginkgo biloba's TTLs and flavonoids in the CNS of rats after oral administration of GBE, supporting the general observation of CNS penetration, though without precise PK parameters [57].
However, in vitro transport models suggest limitations in absorption and efflux. For example, a MDR-MDCK model reported low permeability in the absorptive direction (Papp 0.27;0.39;106;6 cm/s) but much higher flux in the secretory direction (Papp 2.97;3.69;106;6 cm/s), consistent with inhibited net absorption due to efflux mechanisms. Lipid formulations that reduce efflux or improve solubilization may be beneficial in this context [32, 58]. Moreover, co-administration of Ginkgo biloba extract with a mixture of sesame extract and turmeric oil resulted in increased brain levels of ginkgolide A in mice, suggesting that oil-based co-formulations can enhance brain exposure of TTLs [59].
Preclinical and Review Evidence Supporting Lipid Nanocarriers
Review and preclinical evidence support the hypothesis that lipid nanocarriers (nanoemulsions, SEDDS/SNEDDS, SLN/NLC, liposomes) can enhance the stability and bioavailability of phytochemicals while facilitating their passage through the blood-brain barrier (BBB) and accumulation in the brain compared to free-form compounds. This provides scientific justification for designing "lipophilic botanical encapsulation" for nootropics [6, 29].
The strongest evidence of "brain exposure" in the presented material includes a 11.93-fold increase in brain AUC for oral curcumin-loaded NLC, detection of SLN beyond the vascular barrier in the brain for andrographolide post-IV administration, and measurable concentrations of GA/GB/Bb in the brain after oral EGb 761® intake. These findings demonstrate that selected botanical or natural lipophilic compounds can achieve measurable central nervous system (CNS) exposure when distribution barriers and pharmacokinetics (PK) are appropriately addressed during formulation design and/or compound selection [13, 17, 18].
Technological Arguments for LFHC Dosage Forms
From a technological perspective, arguments in favor of LFHC (lipid-based formulations for highly lipophilic compounds) as practical dosage forms arise from the fact that SEDDS are mixtures suitable for soft or hard gelatin capsules. Examples of Self-Nanoemulsifying Granules (SNEGs) in hard capsules demonstrate a 2–3-fold increase in release and a 2-fold increase in intestinal permeability in models, supporting the hypothesis that encapsulated self-emulsifying systems can enhance the oral absorption phase for lipophilic molecules [10, 11].
Considerations for Catecholamine Homeostasis
At the same time, "catecholamine homeostasis" should be carefully formulated as catecholamines typically do not cross the mature BBB. Therefore, the plausible mechanisms of action for botanicals and their formulations in the CNS are likely to be indirect (e.g., modulation of neurotransmission or neurotrophy, as seen in data involving Bacopa or BDNF following targeted resveratrol liposomes), rather than based on direct delivery of dopamine or noradrenaline to the brain [15, 51, 54].
Future Directions for Pharmaceutical Development
Future research aiming to qualify as "pharmaceutical" BBB-penetration technology for nootropics should combine:
- Rigorous pharmacokinetic (PK) methods: including differentiation of free form and metabolites.
- Direct CNS exposure measurements: to assess penetration and activity.
- Advanced lipid system design: focusing on controlled precipitation/dispersion and potential ligand conjugation.
These considerations are directly informed by observations regarding the limitations in assessing free curcumin, the dependence of absorption on dispersion, and the functionalization benefits observed in BBB models [14, 28, 42].
