Lipid Nanoformulations of Botanicals in Liquid-Filled Hard Capsules (LFHC) as a Strategy for Delivering Lipophilic Molecules to the Central Nervous System: A Critical Review of Pharmacokinetic Principles, Blood–Brain Barrier Transport Mechanisms, and Implications for Nootropic Catecholaminergic System Support
Abstract
The blood-brain barrier (BBB) represents a crucial obstacle in the treatment of central nervous system (CNS) diseases, as it regulates the influx of substances into the brain and maintains CNS homeostasis, with many compounds experiencing restricted passage across it.[1–3] In practice, the BBB limits cerebral exposure of numerous phytochemicals, among other reasons, due to tight junction selectivity, rapid metabolism, low solubility, and transporter efflux, which reduces clinical translation and justifies “enabling” strategies based on lipid nanocarriers.[4, 5] Simultaneously, many phytochemicals suffer from an unfavorable pharmacokinetic profile, and nanocarriers are described as vehicles that increase bioavailability, stability, and delivery, serving as a starting point for designing oral systems that stabilize and solubilize a lipophilic payload.[6] The aim of this review is a critical synthesis of data indicating that lipid nanoforms (nanoemulsions, SEDDS/SNEDDS, SLN/NLC, liposomes, and phospholipid complexes) can increase systemic and/or brain exposure of botanicals, and to indicate where evidence remains indirect (increase in plasma AUC) rather than direct (measurement of concentration in the brain or in BBB models).[7–9] Specifically, the technology of liquid-filled hard capsules (LFHC) is discussed as a platform for administering oil–surfactant–co-surfactant mixtures (SEDDS), which are stable mixtures administrable in soft or hard gelatin capsules, along with data on self-nanoemulsifying granules in hard capsules that increase the release and permeation of a lipophilic drug in intestinal models.[10, 11] The review compiles quantitative examples of increased bioavailability (e.g., curcuminoid nanoemulsion: total curcuminoid bioavailability 46% vs 8.7% in dispersion; or oral curcumin NLC: 11.93-fold increase in brain AUC) and examples of increased permeability in BBB models (e.g., 1.8-fold increase in permeability of ApoE-functionalized resveratrol-SLN across hCMEC/D3 monolayers).[12–14] In the neuropharmacological section, the “catecholamine paradox” is highlighted: catecholamines typically do not cross the mature BBB (outside periventricular areas), so “catecholamine homeostasis” achieved by oral botanicals is indirect (modulation of signaling, enzymes, neurotrophy) rather than through direct delivery of dopamine or norepinephrine to the brain.[15] Conclusions indicate that the most well-established findings are: (i) improved systemic exposure after lipid formulations, (ii) the presence of preclinical evidence of increased brain exposure for selected compounds (curcumin, α-asarone, andrographolide, Ginkgo TTL), and (iii) the necessity for cautious extrapolation to nootropic products, as some data relate to intravenous administration or in vitro models, not oral LFHC in the human population.[13, 16–18]
Keywords
The review focuses on the blood-brain barrier, nanoemulsions, SEDDS/SNEDDS, solid lipid nanoparticles (SLN/NLC), liquid-filled hard capsules, and botanical compounds with limited bioavailability and brain access.[4, 7, 9, 19]
1. Introduction
The biggest obstacle in the therapy of CNS diseases is the passage of drugs across the BBB, which, as a physical barrier, regulates the influx of substances and ensures CNS homeostasis.[1, 2] In the context of phytochemicals, the problem is twofold: limited systemic availability and limited brain exposure, because the BBB "in practice" restricts most native phytochemicals due to tight junction selectivity, rapid metabolism, low solubility, and transporter efflux.[4] Review literature emphasizes that the unique characteristics of the BBB significantly limit the access of phytochemicals to the target tissue and thus limit clinical translation, providing a direct justification for nanodelivery platforms that enable "optimization" of delivery for impermeable compounds to the brain.[5]
A common denominator for many botanicals is an unfavorable pharmacokinetic profile that limits pharmacological activity, and nanotechnology is indicated as a tool to improve the delivery, bioavailability, biocompatibility, and stability of phytochemicals.[6] Simultaneously, nanomedicine reviews in neurology describe lipid carriers as an approach aimed at crossing the BBB to improve therapies for neurological conditions and minimize toxicity in a biomimetic way, including for compounds of natural origin such as resveratrol or curcumin.[20]
In this context, lipid platforms that, after oral administration, keep the payload in a solubilized state and form micro-/nanoemulsions in the gastrointestinal environment are particularly attractive, as SEDDS keep the drug in a dissolved form, facilitate the formation of stable emulsions at the target site, and increase absorption.[8] It is also important that SEDDS are described as mixtures of oil, surfactant, and co-surfactant with a dissolved active substance, which are physically stable and can be administered orally in soft or hard gelatin capsules, providing a direct premise for the concept of LFHC as a dosage form for liquid lipid mixtures in supplementation and pharmaceutical practice.[10]
2. Blood-Brain Barrier
The BBB is described as a physical barrier regulating the entry of substances into the brain and ensuring CNS homeostasis, which makes delivering therapies to the CNS particularly difficult.[1, 2] In the context of phytochemicals, reviews explicitly state that the BBB restricts most native plant molecules through tight junction selectivity, rapid metabolism, low solubility, and transporter efflux, which is a synthetic description of the main barriers at the level of the cerebral endothelium and the perivascular environment.[4]
Experimental evidence indicates that barrier integrity is dynamic and can be weakened or strengthened depending on inflammation and endogenous factors, as cortistatin deficiency predisposes to endothelial weakening with increased permeability and tight junction breakdown, while cortistatin administration reverses hyperpermeability and reduces BBB leakage in vivo in an LPS model.[21] From a mechanistic perspective, it is also important that in a human BBB damage model (in vitro co-culture), insults increase the "labile iron pool" (LIP) and disrupt stress pathways (HIF2α), and an iron chelator (Desferal, DFO) rescues endothelial survival, which is interpreted as a signal that metabolic-stress pathways are coupled with barrier integrity and may provide an additional dimension in designing interventions supporting stable brain exposure.[22]
Catecholamine Paradox
A key limitation for the promise of "catecholamine homeostasis" is the fact that catecholamines are generally unable to penetrate the mature BBB and gain entry into the brain, with the exception of periventricular sites where the BBB is absent or defective.[15] In a rat model, it was also shown that the BBB in different brain regions forms sequentially after birth, with early formation of physical and ion-restrictive elements and later development of enzymatic elements, emphasizing that permeability to catecholamine-like molecules is a function not only of the molecule's properties but also of the barrier's state/stage.[15]
On the other hand, dopamine itself can modulate barrier properties, as under oxidative stress (H2O2) conditions, dopamine and agonist A68930 reduce monolayer hyperpermeability, protect tight junction integrity and actin cytoskeleton assembly, and the protective mechanism is linked to NLRP3 inflammasome inhibition, not direct ROS inhibition.[23] Consequently, in a nootropic context, it is sensible to distinguish between: (i) direct supply of catecholamines to the CNS (usually ineffective via BBB) and (ii) indirect modulation of the CNS environment and endothelium, which can influence neuroinflammatory and neurotrophic "homeostasis" within the brain.[15, 23]
Pharmacological Modulation of Permeability
Strategies for opening the BBB also exist, such as NEO100, which in studies reversibly and non-toxically opens the BBB in vitro and in vivo and increases brain entry of many therapies, mechanistically observing an effect on various BBB transport pathways and translocation of tight junction proteins from the membrane to the cytoplasm in brain endothelial cells.[24] From the perspective of botanical formulations, however, such a strategy is qualitatively different from approaches based on solubilization and increasing systemic exposure, and its application in the field of supplementation would require rigorous safety assessment and a risk-benefit balance arising from temporary increases in BBB permeability.[24]
3. Pharmacokinetic Challenges of Lipophilic Phytochemicals
Phytochemicals often exhibit limited clinical translation in neurology because the BBB restricts their access to target tissue, and the literature emphasizes that the polarity and "large size" of many phytochemicals hinder passage across the selective blood-brain barrier.[5, 25] Additionally, limitations do not end at the BBB: reviews indicate that phytochemicals suffer from a poor pharmacokinetic profile that limits their pharmacological activity, and improving bioavailability and stability is often a necessary condition for achieving measurable biological effects.[6]
Curcumin is an example of a compound with desirable properties (including antioxidant and anti-inflammatory activity) but simultaneously low oral bioavailability due to instability at physiological pH, low water solubility, and rapid metabolism, which motivates the development of formulations improving exposure.[26] Similarly, resveratrol has formulation limitations because it exhibits poor water solubility and chemical instability (degradation by isomerization in response to temperature, pH, UV, or enzymes), resulting in low bioavailability and limited biological benefits.[27]
It is worth noting that even when a formula increases plasma exposure, the interpretation of bioavailability can be complicated by analytical problems, as a review on curcumin indicates that "levels of free, bioactive curcumin in plasma are not determined," despite the existence of many nano-/lipid formulations, which limits the comparability of studies and their translation to "real" exposure to the active form.[28]
4. Lipid Delivery Systems
Lipid nanocarriers are being developed to improve drug delivery across the BBB and increase bioavailability and targeting specificity, and reviews highlight the use of lipid carriers loaded with naturally derived compounds to enhance brain delivery and therapeutic potential in neurological disorders.[3, 20] Simultaneously, literature indicates that encapsulating phytochemicals in lipid nanocarriers improves physiological stability, promotes BBB passage, and increases accumulation in brain tissue compared to the free form, which provides a general premise for "lipophilic encapsulation of botanicals."[25, 29]
Classes of Lipid Systems
SEDDS are defined as mixtures of oils, surfactants, and co-surfactants that, upon dilution with water, form micro- or nanoemulsions capable of carrying large amounts of lipophilic drugs, and their objectives include limiting precipitation at the absorption site, enhancing permeation across absorptive membranes, and improving the stability of labile molecules against enzymatic activity.[30] SNEDDS are described as systems composed of lipids, surfactants, and co-solvents that spontaneously form nanoemulsions upon mixing with water, can be designed as liquid or solid forms, and improve absorption through mechanisms such as increasing the interfacial area, protecting against degradation, and facilitating lymphatic transport.[31] Reviews emphasize that beneficial features of SNEDDS include improved solubility, dissolution rate, and permeability, reduced metabolism in the intestinal wall, reduced P-gp efflux, and bypassing the first-pass effect by stimulating lymphatic transport.[32]
Lipid nanoparticles (including SLN and NLC) are described as one of the effective approaches to "bypass" the BBB and improve brain bioavailability, with SLN and NLC being particularly intensely studied in the context of brain delivery.[9] In the case of resveratrol, it is indicated that the "role of nanotechnology" in neurology arises from the need to mask the physicochemical properties of drugs to prolong their half-life and enable BBB crossing, and resveratrol is often encapsulated in liposomes and lipid nanoparticles, among others.[27]
For nanoemulsions, arguments are made that nanoscale droplets improve intestinal and BBB permeability, leading to increased drug permeation in systemic circulation and the brain, and the typical droplet size range for nanoemulsions is given as 50–500 nm in a review on colloidal delivery systems for lipophilic bioactive substances.[7, 33]
The table below synthesizes selected classes of lipid-based drug delivery systems in terms of composition definition, typical particle/droplet sizes in available data, and exemplary applications related to improving systemic or brain exposure.
| Class of LBDDS | Composition and Behavior upon Dilution | Example Size | Example Application Goal |
|---|---|---|---|
| Nanoemulsion | Nanoscale droplets are intended to improve intestinal and BBB permeability and increase exposure in circulation and the brain.[7] | 50–500 nm in the context of colloidal nanoemulsion systems for lipophilic substances (general range).[33] | Increased bioavailability and stability of lipophilic bioactive substances (e.g., D3) and improved systemic exposure.[33] |
| SEDDS | Isotropic mixtures of oil, surfactant, and co-surfactant that form micro/nanoemulsions upon dilution with water; goals include limiting precipitation, improving permeation, and stability against enzymes.[30] | Not numerically specified in the cited definitions; the end result is a micro/nanoemulsion upon dilution.[30] | Maintaining the drug in a solubilized state in GI fluids and forming a stable emulsion that increases absorption, as well as applications in neurological disorders (argument for BBB crossing ability).[8] |
| SNEDDS | Composition: lipids, surfactants, co-solvents; spontaneous nanoemulsion formation in water; liquid or solid form; mechanisms include, among others, facilitating lymphatic transport and protecting against degradation.[31] | No number in the definition; SNEG (SNEDDS granules) data suggests nanodroplets of approx. 85 nm as an example of an operational formulation.[11] | Improved oral bioavailability through multifactorial mechanisms (e.g., reduced P-gp efflux and bypassing first-pass metabolism via lymphatic absorption).[34] |
| SLN/NLC | Described as an effective approach to improve brain bioavailability by enabling BBB passage; SLN and NLC are intensely studied in brain delivery.[9] | Example of curcumin NLC: particle size 165.9 nm in an optimized formulation.[35] | Increased systemic and/or brain exposure and improved PK profile; e.g., for curcumin, improved BBB crossing ability and increased brain AUC relative to suspension are reported.[13] |
| Phospholipid complex and phytosome | Phospholipid–polyphenol complexes are intended to facilitate transition from a hydrophilic environment to the lipid environment of the cell membrane and increase blood concentrations; a 2–6× increase in polyphenol blood levels is reported in bioavailability comparisons.[36, 37] | No particle size in the cited descriptions; this is a molecular complex, not an emulsion.[36] | Significant increase in absorption (e.g., 29× for Meriva compared to unformulated mixture) with a simultaneous observation that mainly Phase II metabolites are detected and concentrations may remain below levels required for many in vitro anti-inflammatory targets.[38] |
Mechanisms for Increasing Systemic Exposure
Increased systemic exposure is a key "bottleneck" before eventual brain passage, and a review on nanoencapsulation of neuroprotective compounds indicates that gastrointestinal absorption can inhibit the uptake of free and nanoencapsulated compounds into the blood, consequently limiting brain concentration.[2] In this sense, lymphatic absorption mechanisms are particularly important for lipophilic compounds, as lymphatic transport is described as a parallel absorption pathway for lipids and a growing number of lipophilic drugs, where upon absorption, molecules can associate with enterocyte lipoproteins and be secreted into the lymphatic circulation instead of portal circulation, thereby bypassing the metabolically active liver and reducing the first-pass effect.[39] For highly lipophilic compounds, such as CBD, it is indicated that redirection to lymphatic circulation by binding to chylomicrons (in the presence of long-chain triglycerides or fatty acids) can reduce first-pass metabolism, increase bioavailability, and decrease variability in exposure.[40]
Mechanistically, in nanoemulsions, lipid digestion and mixed micelle formation also play a role, as in the small intestine, triglycerides are hydrolyzed into free fatty acids and monoacylglycerols, which, along with bile salts and phospholipids, co-form mixed micelles enabling the migration of lipophilic compounds into the hydrophobic core of the micelles and penetration of the mucous barrier, where absorption occurs via endocytosis or passive diffusion.[41] In the same vein, it is emphasized that indigestible oils (e.g., fragrance/essential oils, mineral oil) are not degraded by lipase, which inhibits the formation of mixed micelles and "traps" lipophilic substances in oil droplets, reducing bioaccessibility.[41] Additionally, it is indicated that long-chain triglycerides in digestible oils are more prone to forming mixed micelles than MCTs, which is relevant when selecting the oil phase in designing lipid formulations for maximum absorption.[41]
5. Liquid-Filled Hard Capsules
SEDDS are described as easy-to-manufacture, physically stable mixtures of oil, surfactant, and co-surfactant that are administered orally in soft or hard gelatin capsules, providing a direct premise for considering LFHC forms as carriers of liquid lipid mixtures in unit doses.[10] Reviews also indicate that lipid formulations in capsules significantly improve the solubility and dissolution rate of poorly soluble drugs compared to non-lipid formulations, and absorption success depends on particle size, emulsification, dispersion rate, and drug precipitation after dispersion, which directly translates to the design of liquid capsule fillings and their behavior upon release in the gastrointestinal tract.[42]
A study on self-nanoemulsifying granules (SNEGs) filled into hard gelatin capsules showed that such a form (encapsulated SNEGs) yielded 2- to 3-fold greater release of a lipophilic molecule (cilostazol) compared to a conventional tablet and pure drug, illustrating the potential of "encapsulating" self-nanoemulsifying systems to improve release.[11] The same material noted that the amount of drug permeating from SNEGs was twice that from a tablet suspension in an ex vivo (non-everted sac) rat intestine model, supporting the thesis that LFHC/encapsulated systems can improve the absorption step even before considering target BBB permeation.[11]
" }6. Evidence for Selected Botanicals
Curcumin
In a rat study, a curcuminoid nanoemulsion prepared with lecithin, Tween 80, and water achieved a particle size of 12.1 nm and an encapsulation efficiency of 98.8%. Pharmacokinetic parameters (Tmax, Cmax, and AUC) after oral administration were higher for the nanoemulsion than for the dispersion at the same dose, providing quantitative confirmation of improved systemic exposure by the nanoemulsion.[12] In the same study, oral bioavailabilities for BDMC, DMC, curcumin, and total curcuminoids in the nanoemulsion versus dispersion were 34.39% vs 4.65%, 39.93% vs 5.49%, 47.82% vs 9.38%, and 46% vs 8.7% respectively, indicating a multi-fold increase in oral bioavailability with the use of the nanoemulsion.[12]
In a mouse model, an oral "practical" curcumin nanoemulsion (up to 20%) resulted in a 10-fold increase in AUC(0–24h) and a >40-fold increase in Cmax compared to a curcumin suspension in 1% methylcellulose, demonstrating the scale of possible improvement in plasma exposure by nanoemulsion formulation.[43] In a rat model with oils (SNO/LSO), nanoemulsification increased transport in intestinal sacs by 79% (SNO) and 437% (LSO) relative to non-emulsified administration. Additionally, it was reported that a "small amount" of curcumin was observed in the brain and heart after nanocurcumin, providing a limited but direct signal of tissue exposure in the CNS following a lipid strategy.[44]
More quantitative evidence for increased brain exposure comes from work on NLCs, as after intragastric administration, nanostructured lipid carriers of curcumin yielded higher Cmax in plasma (564.94 ± 14.98 ng/mL vs 279.43 ± 7.21 ng/mL), a shorter Tmax (0.5 ± 0.01 h vs 1.0 ± 0.12 h), and higher AUC0–∞ (820.36 ± 25.11 mg×h/L vs 344.11 ± 10.01 mg×h/L) compared to a suspension, indicating improved systemic exposure.[13] The same material directly stated that the NLC formulation improved curcumin's ability to cross the BBB, with an 11.93-fold increase in brain AUC compared to a suspension, which is one of the most direct arguments for lipid nanocarriers for CNS exposure via the oral route (animal model).[13]
Additional data indicate that surface modification of SLN (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 SLCNs, linking stability, release, and CNS distribution mechanisms in a single preclinical outcome.[45] In a zebrafish model, a curcumin microemulsion in turmeric oil, designed "for brain targeting," resulted in a 2-fold improvement in plasma PK and a 1.87-fold improvement in brain PK, along with improved spatial memory and reduced oxidative stress, suggesting that improved brain exposure via a lipid system may be associated with measurable functional effects in a neurodegeneration model.[46]
In clinical data (humans), lipid curcumin formulations can provide rapid and measurable absorption, as a CRM-LF study reported a Tlag of approx. 0.18 h (12 min), Tmax of 0.60 ± 0.05 h, Cmax of 183.35 ± 37.54 ng/mL, and AUC0–∞ of 321.12 ± 25.55 ng·h/mL at a 750 mg dose, indicating a rapid absorption phase and significant systemic exposure (without CNS measurement).[47] An AQUATURM® study demonstrated a >7-fold increase in AUC0–12h and maintained detectable curcumin levels for a full 12 h (whereas the comparative preparation fell below the limit of quantification after 4 h in most participants), which is clinical evidence for the possibility of prolonged systemic exposure by the formulation (although this is a "water-soluble" formulation, not a classic lipid nanoemulsion).[48]
Phospholipid formulations (phytosome) represent a distinct paradigm, as a human crossover study showed that Meriva (a lecithin formulation of a curcuminoid mixture) resulted in ~29-fold higher total curcuminoid absorption than an unformulated mixture. However, only phase II metabolites were detectable, and plasma concentrations were still significantly lower than those required to inhibit most anti-inflammatory targets of curcumin, which limits overinterpretation of "multi-fold bioavailability increase" as an automatic improvement in CNS effect.[38]
Resveratrol
Resveratrol requires formulation strategies because its poor solubility and chemical instability limit its bioavailability and biological benefits. Reviews indicate a trend towards encapsulation and brain targeting of resveratrol and justify the role of nanotechnology in enabling BBB crossing by masking physicochemical properties and extending half-life.[27] In an in vitro BBB model, functionalization of SLNs with apolipoprotein E increased permeability through hCMEC/D3 monolayers, with 1.8-fold higher permeability for SLN-ApoE compared to unfunctionalized ones, providing direct evidence of improved transport across the BBB model through "ligandation" of the lipid nanocarrier.[14]
In in vivo studies, SLNs with resveratrol in a rat model with Alzheimer's disease characteristics supported the hypothesis of improved "neural targeting," as SLN/resveratrol increased HSP70 expression fourfold and decreased IL-1β, and behavioral tests showed improved passive avoidance memory in the model, suggesting that the lipid carrier may enhance resveratrol's functional effect in the CNS (although the cited passage itself does not report direct brain concentrations).[49] In another model (Aβ1–42 i.c.v.), lipid-core nanocapsules enabled resveratrol to "rescue" the deleterious effects of Aβ1–42, and the authors link this to a "robust increase" in brain tissue resveratrol concentration achieved by nanocapsules, which represents an interpretation of efficacy mechanism based on brain exposure.[50]
More targeted liposomal strategies report simultaneous "transport" and "neurotrophic" effects, as a resveratrol liposome with an ANG ligand in cellular experiments increased resveratrol's ability to cross the BBB and neuronal uptake, and in a mouse aging model, it improved cognitive function by reducing oxidative stress and inflammation in the brain and increased BDNF.[51] Such data thus combine in a single intervention: (i) technological enhancement of BBB crossing, (ii) improvement of inflammation/oxidative stress biomarkers, and (iii) increase in a neurotrophic factor, which is significant for the narrative of "neurogenesis" and plasticity, although the evidence comes from an animal model and a specific liposomal platform, not from oral LFHC.[51]
Bacopa monnieri
In the case of Bacopa monnieri, it is indicated that bacoside A has low water solubility and "BBB limitation," which restricts its bioavailability and clinical efficacy in neurodegenerative diseases, providing a rationale for carrier strategies such as niosomes.[52] A study of a niosomal formulation of a bacoside A-rich fraction (Fort-BAF) included an in vivo assessment of procognitive properties compared to the fraction, and the authors conclude that niosomes can significantly improve the stability and bioavailability of Fort-BAF, which suggests that vesicular systems may support CNS-directed delivery.[52]
In the area of self-nanoemulsifying systems, it was shown that to increase the solubility and bioavailability of poorly soluble bacosides, SNEDDS with various oils/surfactants/co-surfactants were used, and a "novel lipophilic formulation" was evaluated for brain penetration and pharmacokinetic profile in rats, directly linking Bacopa to the paradigm of lipid nanosystems for CNS exposure (although the cited passage does not contain PK numbers).[53] In terms of nootropic mechanisms, a review indicates that Bacopa acts, among other things, by modulating neurotransmitter systems, including noradrenaline and dopamine, which provides a direct link to the "catecholamine homeostasis" narrative while obviating the need for direct catecholamine supply across the BBB.[15, 54]
Withania somnifera
Regarding neurogenesis, a review indicates that preclinical studies suggest that withanolides can promote neurogenesis, protect against neurodegenerative diseases, and reduce oxidative stress and inflammation, and advances in delivery methods (liposomal and nanoemulsion) improve their bioavailability.[55] At the cellular level, it was shown that MPEG-PCL nanoparticles containing Withania somnifera extract (WSE) are effectively taken up by U251 cells and provide greater protection against oxidative damage (95.1%) than PCL with WSE (56.4%) and free WSE (39.0%), supporting the hypothesis that encapsulation increases the effectiveness of action under oxidative stress conditions (in the absence of direct measurement of BBB crossing).[56]
Ginkgo biloba
In a rat study, after a single oral administration of 600 mg/kg of standardized extract EGb 761®, significant concentrations of ginkgolide A (GA), ginkgolide B (GB), and bilobalide (Bb) were demonstrated in plasma and the CNS, with brain concentrations rapidly increasing to 55 ng/g (GA), 40 ng/g (GB), and 98 ng/g (Bb), providing direct evidence that selected terpene trilactones penetrate the CNS via the oral route in an animal model.[18] In a review, it is stated that significant levels of TTLs and Ginkgo biloba flavonoids cross the BBB and enter the CNS of rats after oral GBE administration, supporting the generality of the observation, although not specifying PK parameters.[57]
At the same time, in vitro transport models suggest the existence of absorption and efflux limitations, as low permeability in the absorptive direction (Papp 0.2–0.3×10−6 cm/s) and significantly higher flux in the secretory direction (Papp 2.9–3.6×10−6 cm/s) were observed in the MDR-MDCK model. This is consistent with inhibition of net absorption by efflux mechanisms and indicates that lipid formulations reducing efflux or improving solubilization may be useful in this context.[32, 58] Conversely, in an animal model, co-administration of Ginkgo biloba extract with a mixture of sesame extract and turmeric oil increased ginkgolide A concentration in the mouse brain compared to GBE alone, suggesting that oil co-formulations may increase brain exposure of TTLs.[59]
α-Asarone
In animal studies, lipid nanoparticles (A-LNPs) provided "prolonged and sustained" release of α-asarone, and after intravenous administration, significantly higher levels of α-asarone were observed in plasma and brain parenchyma fractions compared to free α-asarone, confirming the ability of A-LNPs to maintain therapeutic plasma concentrations and simultaneously transport across the BBB.[16] This result is important for the thesis of "stabilization of exposure profile," but it should be emphasized that it comes from intravenous administration and thus does not directly prove the effectiveness of oral LFHCs in this class of compounds.[16]
Andrographolide
Andrographolide is described as a compound with low bioavailability, poor water solubility, and high chemical and metabolic instability, which justifies its formulation in lipid nanoparticles.[17] In in vitro studies, it was shown that nanoparticles improved andrographolide permeability compared to the free form, and after intravenous administration, fluorescent SLNs were detected in brain parenchyma outside the vascular bed, confirming the ability of this carrier and/or its cargo to "overcome the BBB" in an animal model.[17]
Cannabidiol
In mouse studies and an in vitro BBB model, "cannabinoid-decorated" lipid nanocapsules (LNCs) achieved the highest brain-targeting ability for the smallest sizes, and the enhancement of brain-targeting after CBD conjugation to LNCs surpassed by six-fold the enhancement observed for the clinical "G-Technology" strategy.[60] This result highlights the importance of carrier size and surface functionalization design for BBB transport and brain distribution, although the platform is specialized and not equivalent to classical oral SEDDS in LFHC.[60]
7. Mechanisms of Increased Brain Penetration
Review literature indicates that nanoscale nanoemulsion droplets can improve intestinal and BBB permeability, increasing drug permeability in systemic circulation and the brain, suggesting a simultaneous effect on the absorption and CNS distribution phases.[7] Simultaneously, reviews emphasize that phytochemical delivery by lipid nanoparticles improves physiological stability, promotes BBB crossing, and increases accumulation in brain tissue, providing a general mechanistic framework regardless of the specific cargo chemistry.[29]
For BBB-targeted systems, in vitro evidence suggests a role for transporters and ligandation, as a nanoemulsion functionalized with glucosylceramide (GlcCer) was designed to utilize glucose transporter-dependent (GLUT) uptake, and a 1.6-fold increase in neuronal uptake and a 1.4-fold improvement in endothelial transport were quantitatively observed compared to untargeted controls.[61] Analogously, functionalization of SLNs with apolipoprotein E increased resveratrol permeability across hCMEC/D3 monolayers by 1.8-fold, consistent with the concept that surface functionalization can enhance transendothelial transport in BBB models.[14]
For self-nanoemulsifying systems, the mechanism of maintaining the drug in a solubilized form and the formation of a stable emulsion at the absorption site is crucial, as SEDDS keep the drug dissolved in gastrointestinal fluids and facilitate the formation of stable emulsions that enhance absorption, which is a necessary condition for achieving sufficient systemic exposure for CNS distribution.[8] In the context of SNEDDS, the multi-mechanistic increase in bioavailability is emphasized, including a reduction in intra-enterocyte metabolism (CYP P450), a reduction in P-gp efflux, and bypassing the first-pass effect through lymphatic absorption, which constitutes a logical mechanism for "smoothing" the systemic exposure profile for lipophilic compounds.[34]
Finally, from the perspective of brain exposure, it is important to distinguish between "systemic bioavailability" and "brain bioavailability," because even when a lipid system increases plasma concentrations, the BBB still restricts most native phytochemicals through tight junctions and efflux, and therefore, an increase in plasma AUC is a necessary but not sufficient condition for effective brain exposure.[2, 4]
8. Catecholamines and Neurogenesis
In the nootropic narrative, botanical compounds are often presented as supporting "catecholamine homeostasis" and neuroplasticity, but a fundamental limitation is that catecholamines generally do not penetrate the mature BBB beyond periventricular regions, which necessitates understanding "homeostasis" as an indirect effect within the CNS (e.g., modulation of neurotransmission, neuroinflammation, neurotrophy), rather than as a direct supply of dopamine or noradrenaline to the brain after oral administration.[15]
From the perspective of BBB mechanisms and oxidative stress, dopamine can protect the barrier from H2O2-induced hyperpermeability by preserving tight junction integrity and the cytoskeleton and inhibiting the NLRP3 inflammasome, indicating that catecholamine signaling can affect the BBB microenvironment and potentially indirectly influence the distribution of compounds to the CNS under pathological conditions.[23]
Regarding botanicals, a review of Bacopa monnieri mechanisms indicates that the plant can modulate neurotransmitter systems, including noradrenaline and dopamine, providing a direct link to the catecholaminergic system, even if it does not resolve the question of to what extent these effects depend on BBB penetration by bacosides or their metabolites.[54]
In the area of neurogenesis, there are preclinical data for withanolides, where a review indicates that they can promote neurogenesis and exert neuroprotective effects, and improved bioavailability is supported by advances in liposomal and nanoemulsion formulations.[55] Furthermore, in the Ts65Dn model (Down syndrome), polydatin treatment from P3 to P15 resulted in full restoration of neurogenesis, neuron number, and dendrite development, and treatment until adolescence (~P50) observed full restoration of hippocampus-dependent memory without adverse effects on body and brain weight, providing a strong pro-neurogenesis and pro-cognitive signal for a selected polyphenol (without direct linkage to nanoformulation).[62]
Conversely, in the case of resveratrol, a brain-targeted liposomal system (ANG-RES-LIP) combines increased ability to cross the BBB and neuronal uptake with improved cognitive function and increased BDNF in the mouse brain, consistent with the hypothesis that improved CNS delivery can enhance neurotrophic axes important for plasticity.[51]
9. Limitations
Evidence for improved CNS delivery by lipid nanocarriers is uneven, as much data concerns in vitro models (e.g., permeability through hCMEC/D3) or intravenous administration, which limits direct extrapolation to oral nutraceutical products in capsules.[14, 16] Even when oral data with increased plasma AUC are available, the BBB can still limit penetration through tight junctions, metabolism, and efflux, meaning that increased systemic exposure does not guarantee brain exposure, and conclusions must be drawn cautiously.[2, 4]
In the area of curcumin, interpretive risks are also clearly visible, as despite a 29-fold increase in absorption after phospholipid formulation (Meriva), only phase II metabolites were detectable, and plasma concentrations were still lower than required to inhibit many anti-inflammatory targets in vitro, which undermines the simple narrative of "higher bioavailability, stronger biological effect."[38] Additionally, a review of curcumin points to the problem that levels of free, bioactive curcumin in plasma are not quantified, complicating comparisons between formulations (nanoemulsions, micelles, liposomes, etc.) and making it difficult to infer what fraction is truly available for CNS distribution.[28]
Regarding "bioenhancers" (e.g., piperine), the literature presents divergent pictures: on one hand, it is reported that piperine can effectively penetrate and homogeneously distribute in the brain with brain-to-plasma AUC0→∞ ratios of 0.95 (total) and 1.10 (unbound), supporting its potential for CNS exposure.[63] On the other hand, a review indicates that earlier reports documented poor PK properties of piperine, including BBB permeability, suggesting the need for caution and verification depending on dose, formulation, and analytical methods.[64] Additionally, a safety review of piperine highlights risks and limitations (poor water solubility, dose-dependent toxicity, reproductive and hepatic concerns, and potentially significant drug-drug interactions resulting from CYP3A4 and P-gp inhibition), which is particularly relevant when considering its use in "smart" nootropic formulations that increase exposure to multiple substances simultaneously.[65]
With reference to LFHC technology, it should be noted that the cited evidence for SNEDDS encapsulation pertains to SNEGs granules in hard capsules and shows increased release and permeation in intestinal models but does not yet constitute evidence of increased brain exposure or clinical improvement in cognitive function for specific botanicals in LFHC form.[11]
10. Directions for Future Research
Since the BBB restricts most native phytochemicals through tight junction selectivity, metabolism, low solubility, and transporter efflux, future research should combine formulation development with direct measurements of brain exposure and assessment of transport mechanisms, rather than relying solely on increased plasma AUC.[4] Data on GLUT-targeted systems (GlcCer) and on ApoE or ligand (ANG) functionalization show that surface functionalization can improve transport in BBB models and/or cognitive effects and BDNF, which justifies further work on "ligand-targeted" nanocarriers for highly lipophilic botanicals and/or those with limited BBB penetration.[14, 51, 61]
In parallel, LFHC development should consider dispersion parameters and the risk of precipitation after dilution in the gastrointestinal tract, as the success of absorption from a lipid formulation depends on particles/emulsification, dispersion rate, and precipitation, which constitutes a testable set of critical quality attributes (CQA/CPP) in product development (even if specific encapsulation production parameters are not covered in the cited sources).[42] Since SNEDDS can increase bioavailability by reducing P-gp efflux and bypassing first-pass metabolism through lymphatic absorption, a rational direction is to design formulations that maximize "lymphatic diversion" for lipophilic botanicals, analogous to discussions about CBD and chylomicrons, and then verify whether increased systemic exposure translates into CNS exposure.[34, 40]
Alternative routes of administration (e.g., intranasal) are discussed in the context of SEDDS, as the nasal cavity can allow for partially direct delivery to the brain, bypassing the BBB, and simultaneously avoid hepatic first-pass effect, which can increase the systemic bioavailability of highly metabolized compounds, and combining the advantages of SEDDS and the intranasal route can increase brain targeting and bioavailability.[30, 66] Although this is a different paradigm than oral LFHC, it can serve as a reference point for future research programs in "cognitive performance" when the goal is to maximize brain exposure while limiting GI absorption variability.[30, 66]
11. Conclusions
Review and preclinical evidence supports the thesis that lipid nanocarriers (nanoemulsions, SEDDS/SNEDDS, SLN/NLC, liposomes) can increase the stability and bioavailability of phytochemicals and promote their passage across the BBB and accumulation in the brain compared to free forms, providing scientific justification for the design of "lipophilic encapsulation of botanicals" in nootropics.[6, 29] The strongest evidence for "brain exposure" in the presented material includes, among others, an 11.93-fold increase in brain AUC for oral curcumin NLC, detection of SLN outside the brain vasculature for andrographolide after IV, and measurable concentrations of GA/GB/Bb in the brain after oral EGb 761®, demonstrating that selected botanical or natural lipophilic compounds can achieve measurable CNS exposure when distribution barrier and PK are addressed in formulation design and/or compound selection.[13, 17, 18]
Technologically, the arguments for LFHC as a practical dosage form stem from the fact that SEDDS are mixtures that can be administered in soft or hard gelatin capsules, and examples of SNEGs in hard capsules show a 2–3-fold increase in release and a 2-fold increase in permeability in intestinal models, supporting the hypothesis that encapsulated self-nanoemulsifying systems can improve the oral absorption step for lipophilic molecules.[10, 11]
At the same time, "catecholamine homeostasis" should be formulated cautiously, as catecholamines typically do not cross the mature BBB, and therefore the real mechanisms of action of botanicals and their formulations in the CNS will be indirect (e.g., modulation of neurotransmission or neurotrophy, as in data on Bacopa or BDNF after targeted resveratrol liposomes), rather than based on direct delivery of dopamine or norepinephrine to the brain.[15, 51, 54] Future work, to merit the designation of a "pharmaceutical" BBB penetration technology in the nootropics field, should combine:
- rigorous PK methods (including differentiation of free form and metabolites),
- direct CNS exposure measurements, and
- the design of lipid systems with precipitation/dispersion control and potential ligandation, which directly follows from observations about the limitations of free curcumin determination, the dependence of absorption on dispersion, and the benefits of functionalization in BBB models.[14, 28, 42]
