Lyotropic Liquid Crystals for Intranasal Drug Delivery: A Review of A Promising Platform For Enhanced Brain Targeting

Liquid crystals (LCs) are mesophases—intermediate states of matter that exhibit characteristics of both isotropic liquids and crystalline solids. In these phases, molecules typically align in a preferred orientation while still maintaining the ability to move freely in space. The compounds capable of forming such mesophases are known as mesogens. Liquid crystals (LCs) are primarily categorized based on the physicochemical factors that drive their phase transitions, namely thermotropic liquid crystals (TLCs) and lyotropic liquid crystals (LLCs). In TLCs, the transition to a mesophase occurs with an increase in temperature, while in LLCs, it is induced by the addition of a solvent. Lyotropic liquid crystal systems—particularly reversed bicontinuous cubic and hexagonal mesophases are drawing growing attention because of their remarkable microstructures and distinct physicochemical properties [1].

Nasal therapy has garnered significant attention as a rapid, effective, and reliable route for systemic drug delivery, especially for treatments with poor oral efficacy and limited bioavailability. It also enables drugs to bypass the blood-brain barrier via the olfactory bulb, enhancing their effectiveness on the central nervous system [3]. Various nanocarriers, including liposomes, solid lipid nanoparticles, microspheres, and nano emulsions, have been explored as potential strategies for targeting the central nervous system via the intranasal route. However, these systems often face challenges related to drug encapsulation efficiency and stability [4]. In contrast, colloidal carrier systems protect active ingredients from degradation within the nasal cavity and facilitate their distribution beyond the nasal mucosa. Among these, cubosomes have attracted attention as effective delivery vehicles for brain targeting. Composed of crystalline nanostructured liquid particles with bi-continuous lipid membranes, cubosomes can encapsulate therapeutic agents regardless of their hydrophilic, hydrophobic, or amphiphilic nature. Cubosomes are biocompatible, bio adhesive, and thermodynamically stable, making them a promising option for intranasal drug delivery due to their unique properties [5]. The human nose plays vital roles in respiration and the sense of smell. Anatomically, it consists of the external nose and the nasal cavity (internal nose). The external nose, shaped like a triangular pyramid, is centrally positioned on the face and made up of bone and cartilage. It is connected to facial muscles governed by the facial nerve, contributing to expressions. Extending approximately 12 cm from the nostrils to the nasopharynx, the nasal cavity is divided into left and right halves by the nasal septum. From both structural and functional perspectives, the nasal cavity is subdivided into three main regions: vestibular, respiratory, and olfactory [6].

1.1. Vestibular Region

This is the outermost and smallest segment of the nasal cavity, covering an area of around 0.6 cm² [7]. It contains nasal hairs that trap airborne particles and is lined with squamous epithelium. Due to its limited surface area and barrier characteristics, this region contributes minimally to drug absorption.

1.2. Respiratory Region

Representing the largest portion of the nasal cavity, this region lines the lateral walls and plays a central role in air filtration, humidification, and drug absorption. The epithelium here comprises goblet cells, ciliated and non-ciliated columnar cells, and basal cells [8]. Goblet cells secrete mucus via nasal glands, while basal cells act as progenitors capable of differentiating into other epithelial cells. The presence of cilia and microvilli substantially increases the surface area, enhancing absorption. The respiratory region is highly vascularized, making it ideal for systemic drug delivery. Additionally, this area is innervated by branches of the trigeminal nerve (V1 and V2), offering a secondary route for drugs to reach the central nervous system (CNS) [9].

1.3. Olfactory Region

Located at the roof of the nasal cavity, the olfactory region offers a direct connection to the CNS via the olfactory nerve. This pathway plays a crucial role in nose-to-brain transport, bypassing the blood-brain barrier [10,11].

Nasal Administration: A Smart Route for Drug Delivery

•  Non-invasive & patient-friendly
• High permeability of nasal mucosa
• Rich blood supply → rapid absorption
• Bypasses first-pass metabolism

Challenge:

• Mucociliary Clearance
• Self-cleaning mechanism of nasal cavity
• Rapidly eliminates drug formulations

Solution: In Situ Gelation Systems

• Thermosensitive polymers (e.g., Poloxamer 407)
• Liquid at room temp → gels at nasal temperature
• Prolongs residence time
• Enhances systemic & CNS drug absorption

Thus, by overcoming physiological barriers like mucociliary clearance, in situ gelation systems significantly enhance the efficacy of intranasal drug delivery, making them a promising strategy for targeted brain therapies [12]

2.Nanoparticle preparation: technologies and methodologies

For nanoparticle systems to be considered viable for industrial-scale applications, their preparation must be cost-effective, time-efficient, and energy-conscious. The synthesis of liquid crystalline nanoparticles, such as cubosomes and hexosomes, has evolved significantly, resulting in a diverse array of preparation techniques. This section provides a concise overview of the most commonly employed methodologies [18].

2.1. Top-Down Preparation

Figure 1: Top-down preparation of Cubosomes and Hexosomes

The top-down approach, introduced in the mid-1990s, remains a widely used method for producing cubosomes and hexosomes. It relies on high-energy mechanical processes—such as ultrasonication, high-shear mixing, or high-pressure homogenization—to break down bulk amphiphilic lipid phases into stable nanoparticles.

Typically, a formulation of amphiphilic lipids, active pharmaceutical ingredients (APIs), and a stabilizer like Pluronic® F127 is mechanically agitated. Pluronic F127 ensures steric stabilization, preventing aggregation and enhancing colloidal stability.

Although scalable, this method has drawbacks:

• High energy demands (comparable to liposome preparation)
• Risk of contamination by unwanted vesicular structures
• Sensitivity to processing variables (e.g., stabilizer concentration, temperature), which can affect reproducibility.

2.2. Bottom-Up Preparation

The bottom-up approach represents a low-energy alternative to the conventional top-down method for cubosome production. This technique involves the formulation of a solution containing amphiphilic lipids, drug cargo, and, critically, hydrotropic agents—molecules that significantly enhance the solubility of amphiphiles and inhibit premature aggregation during dispersion.

Figure 2: Bottom-up preparation of Cubosomes and Hexosomes

The bottom-up approach represents a low-energy alternative to the conventional top-down method for cubosome production. This technique involves the formulation of a solution containing amphiphilic lipids, drug cargo, and, critically, hydrotropic agents—molecules that significantly enhance the solubility of amphiphiles and inhibit premature aggregation during dispersion. Upon gentle agitation, this homogeneous solution undergoes spontaneous self-assembly into nanostructured liquid crystalline particles, forming cubosomes directly from solution rather than by breaking down bulk lipid phases, as seen in top-down methods. The inclusion of hydrotropes is central to this process, as they reduce the need for high energy input and facilitate more efficient nanoparticle formation.

This method offers several advantages:

• Reduced energy consumption, making it more feasible for continuous processing and large-scale manufacturing.
• Smaller particle sizes, which may enhance bioavailability and cellular uptake.