Intranasal Spanlastics Nanocarriers: Advancing Nose to Brain Drug Delivery

Intranasal drug delivery has gained considerable attention as a noninvasive and efficient route for targeting the central nervous system (CNS) [3,14]. This approach facilitates the direct transport of therapeutic agents to the brain via the olfactory and trigeminal neural pathways, thereby bypassing the blood–brain barrier (BBB) and minimizing systemic side effects [3,14]. Despite these advantages, conventional intranasal formulations are associated with several limitations, including rapid mucociliary clearance, enzymatic degradation, limited drug permeability, and poor retention in the nasal mucosa, which collectively compromise their therapeutic efficacy [2,4].

To overcome these challenges, advanced nanocarrier systems have been extensively studied. Among these, spanlastics have emerged as a novel class of elastic nanovesicles composed of non-ionic surfactants and edge activators [1,12]. These vesicles exhibit enhanced deformability compared to conventional vesicular systems, such as liposomes and niosomes, enabling improved penetration across biological membranes [1,6]. Their flexible bilayer structure supports efficient drug encapsulation, enhances physicochemical stability, and enables the delivery of both hydrophilic and lipophilic therapeutic agents [1,5].

Spanlastics can be fabricated using various techniques, including ethanol injection and thin-film hydration, allowing precise control over the vesicle size, entrapment efficiency, and surface characteristics [6,12]. The incorporation of edge activators imparts elasticity to the vesicles, facilitating their transport through narrow intercellular spaces within the nasal epithelium [1,5]. Moreover, their nanoscale size and high surface area contribute to enhanced drug absorption and prolonged residence time in the nasal cavity [5,7].

Furthermore, spanlastics can be functionalized with mucoadhesive polymers and targeting strategies to enhance nasal retention and improve brain-targeting efficiency [8,10]. These modifications promote stronger interactions with the nasal mucosa and enable sustained drug release. Owing to these advantages, spanlastics have gained significant attention as a promising platform for nose-to-brain drug delivery, particularly in the treatment of neurological disorders, such as neurodegenerative diseases, epilepsy, and brain tumors [3,14].

Overall, spanlastics represent a versatile and efficient drug delivery system capable of overcoming the limitations of conventional intranasal formulations, thereby offering significant potential for brain-targeted therapies.

BUILDING BLOCKS OF SPANLASTICS

Spanlastics are composed of carefully selected components that collectively form flexible and efficient nanovesicular systems. The primary structural elements include non-ionic surfactants, typically from the Span series (e.g., Span 60 or Span 80), which constitute the bilayer framework of the vesicles [1,12]. These surfactants are combined with edge activators, commonly Tween surfactants (such as Tween 20 or Tween 80), which impart elasticity and deformability by disrupting the tightly packed lipid bilayer structure [1,5,15].

An aqueous phase, usually distilled water or a suitable buffer system, is essential for vesicle formation and its stabilization [6]. In several preparation methods, organic solvents such as ethanol are employed to dissolve surfactants prior to vesicle assembly, facilitating uniform dispersion and controlled vesicle formation [6,12].

In some formulations, cholesterol is incorporated to enhance membrane stability and reduce permeability; however, its concentration is typically optimized to preserve the elastic nature of spanlastics [5,7]. Additionally, functional excipients such as charge-inducing agents or mucoadhesive polymers may be included to improve vesicle stability, enhance interaction with biological membranes, and prolong residence time at the site of administration [8,10].

Fig1: Schematic diagram of spanlastics vesicle

MECHANISM OF ENCHANCED PERMEATION BY SPANLASTICS

Spanlastics enhance drug permeation through a combination of physicochemical and biological mechanisms attributed to their elastic vesicular structure and surfactant composition [1,12]. The incorporation of edge activators disrupts the regular packing of the vesicular bilayer, increasing membrane fluidity and imparting high deformability [1,5]. This enables spanlastic vesicles to traverse intercellular spaces and narrow pores within epithelial barriers without structural rupture, thereby facilitating enhanced permeation [5,6].Additionally, non-ionic surfactants interact with the lipid components of biological membranes, leading to transient disruption of epithelial lipid organization and increased membrane permeability [5,7]. Spanlastics may also promote paracellular transport by modulating tight junction integrity, thereby enhancing drug diffusion across the epithelial layers [6,10]. Their nanoscale size allows close contact with the mucosal surface, improving adhesion and prolonging the residence time at the absorption site [5,8].Furthermore, spanlastics function as drug reservoirs, providing sustained release and maintaining a concentration gradient that drives diffusion across the biological membranes [1,12]. Collectively, these mechanisms contribute to improved drug penetration, enhanced absorption, and increased bioavailability compared with conventional delivery systems [1,6].

TYPES OF PREPARATION METHODS

Two commonly employed preparation methods have been reported for spanlastics, each significantly influencing the vesicle size, entrapment efficiency, and overall stability [6,12].

1. Ethanol Injection Method

In this method, a non-ionic surfactant and edge activator are dissolved in ethanol and subsequently injected into an aqueous phase under continuous stirring [6,12]. Upon contact with an aqueous medium, spontaneous vesicle formation occurs owing to the rapid diffusion of ethanol, leading to the formation of nanosized and relatively uniform spanlastic vesicles [6].This technique is simple, reproducible, and widely utilized for laboratory-scale preparation, as it allows for better control over the vesicle size distribution and minimizes aggregation [6,12]. Additionally, rapid solvent diffusion promotes the formation of stable vesicles with satisfactory entrapment efficiency [1,6].

2. Thin-Film Hydration Method

The thin-film hydration method, also known as the rotary evaporation technique, is widely employed for preparing spanlastics [6,12]. In this method, non-ionic surfactants and edge activators are dissolved in an organic solvent, followed by solvent evaporation under reduced pressure to form a thin lipid film on the inner wall of a round-bottom flask [6]. The resulting film is subsequently hydrated with an aqueous phase under continuous agitation, leading to the formation of multilamellar vesicles, which can be further reduced to nanosized vesicles by sonication or extrusion [6,12].

CHARACTERIZATION OF SPANLASTICS

Spanlastics are characterized using various physicochemical techniques to confirm vesicle formation, stability, and performance [1,5].

Morphological analysis using scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed spherical, smooth, nanosized vesicles with a relatively uniform distribution [5,7]. Particle size, polydispersity index (PDI), and zeta potential were determined using dynamic light scattering (DLS), indicating nanoscale dimensions, homogeneity, and colloidal stability of the formulation [1,5].

Fourier-transform infrared spectroscopy (FTIR) was employed to assess drug–excipient compatibility, confirming the absence of significant chemical interactions [1,12]. Thermal and crystallinity analyses using differential scanning calorimetry (DSC) and X-ray diffraction (XRD) demonstrated reduced crystallinity or amorphous dispersion of the drug within the vesicular system, indicating successful encapsulation [5,9].

Entrapment efficiency is evaluated to determine the drug-loading capacity of the vesicles, while in vitro release studies assess the drug release profile, often demonstrating controlled and sustained release behavior [1,6]. Stability studies further confirm that spanlastics maintain their physicochemical integrity under appropriate storage conditions, supporting their suitability for drug delivery applications [5,12]

INTRANASAL DELIVERY AND BRAIN TARGETING

Intranasal drug delivery offers several advantages as a noninvasive route for systemic and brain-targeted drug delivery [3,14]

• Provides a non-invasive administration route through the nasal cavity, improving patient compliance [3] 
• Avoids first-pass metabolism, thereby enhancing drug bioavailability [3,14] 
• Ensures rapid onset of action due to the rich vascularization of the nasal mucosa [3] 
• Enables direct brain delivery via 
  • Olfactory pathway 
  • Trigeminal nerve pathway [3,14] 
• Effectively bypasses the blood–brain barrier (BBB), allowing efficient CNS targeting [3,14] 
• Requires low dose volume and is convenient for administration [2] 
• Enhances therapeutic efficiency while reducing systemic side effects [3,14]

APPLICATIONS

• Intranasal delivery has been widely explored for various therapeutic applications, particularly in brain targeting and systemic delivery [3,14].
• Delivery of drugs for central nervous system (CNS) disorders [3] 
• Management of neurodegenerative diseases, such as: 
  • Alzheimer’s disease 
  • Parkinson’s disease 
• Treatment of epilepsy and psychiatric disorders [3,14] 
• Pain management and migraine therapy [3] 
• Delivery of peptides, proteins, and vaccines via the nasal route [14] 
• Potential application in systemic delivery of poorly bioavailable drugs [2,14]

ADVANTAGES OF SPANLASTICS VESICLES OVER CONVENTIONAL VESICULAR CARRIERS [1,5,12]