Nanostructured Lipid Carriers (NLCs): A Comprehensive Review of Design, Applications, and Future Directions

Abstract

Nanostructured lipid carriers (NLCs) have emerged as a novel generation of lipid-based drug delivery systems designed to overcome the limitations of solid lipid nanoparticles (SLNs). Comprising a blend of solid and liquid lipids, NLCs enhance drug loading, stability, and bioavailability while enabling controlled drug release. This review provides a critical overview of NLC design, types, preparation methods, advantages over traditional systems, current pharmaceutical applications, and future prospects. Emphasis is placed on formulation challenges, scalability, and regulatory considerations, highlighting the ongoing need for innovation in nanomedicine.

Keywords

Nanostructured Lipid Carriers, Lipid-Based Drug Delivery, Solid Lipid Nanoparticles, Controlled Release, Nanomedicine

Introduction

Drug delivery systems have seen a major change as a result of nanotechnology's breakthroughs, which have provided creative answers to persistent pharmaceutical problems like unstable active pharmaceutical ingredients (APIs), low bioavailability, poor solubility, and uncontrolled drug release. Lipid-based nanoparticles have drawn a lot of interest among the many nanoparticulate systems because of their potential for targeted delivery and controlled release, biocompatibility, and capacity to encapsulate both hydrophilic and lipophilic medications.

Nanostructured Lipid Carriers (NLCs) constitute the second generation of lipid nanoparticles, intended to solve the constraints associated with Solid Lipid Nanoparticles (SLNs), which include low drug loading capacity and drug expulsion during storage due to lipid crystallization. NLCs are made up of a matrix of liquid and solid lipids that is usually stabilized by surfactants. Because of its distinct composition, the lipid matrix develops structural flaws that increase drug encapsulation effectiveness and stop drug ejection during storage (Müller et al., 2002; Naseri et al., 2015).
By adding flexibility to the lipid matrix, the employment of both liquid and solid lipids inhibits the development of the highly ordered crystalline structure that is characteristic of SLNs. More drug molecules can fit into an amorphous matrix as a result of this disturbance in crystallinity. Furthermore, NLCs are very adaptable for a variety of administration routes, including oral, parenteral, dermal, ocular, and pulmonary. This is because their physicochemical characteristics, such as particle size, surface charge, and lipid composition, can be modified to affect drug release profiles and biodistribution (Jenning et al., 2000; Wissing et al., 2004).

NLCs are being investigated for the delivery of biomolecules like peptides, proteins, and nucleic acids (e.g., siRNA and mRNA) in addition to traditional small-molecule drugs. This underscores their growing significance in cutting-edge treatments like gene delivery and personalized medicine (Garcia-Fuentes & Alonso, 2012). In cosmeceuticals, their potential has been expanded to include enhancing skin penetration and extending the retention of active substances in the stratum corneum. NLCs have formulation and production issues such stability, scalability, and repeatability despite these benefits. Clinical translation is also hampered by the lack of established regulatory standards for nanomedicines. NLCs are still at the vanguard of next-generation drug delivery systems, nevertheless, as research continues to focus on removing these obstacles.

2. Advantages of Nanostructured Lipid Carriers (NLCs)

Nanostructured Lipid Carriers (NLCs) offer a wide array of advantages that address many of the limitations faced by traditional drug delivery systems. These advantages span multiple domains, including physicochemical stability, bioavailability, drug loading capacity, controlled release, and biocompatibility, among others. Below is a detailed discussion of the major benefits associated with NLCs.

2.1 Improved Drug Loading Capacity

One of the most significant improvements of NLCs over Solid Lipid Nanoparticles (SLNs) is their enhanced drug loading capacity. The inclusion of liquid lipids (oils) disrupts the crystalline structure of the solid lipid matrix, creating an amorphous region within the nanoparticles that accommodates more drug molecules. This structural imperfection prevents premature drug expulsion during storage and improves encapsulation efficiency (Müller et al., 2002; Pardeike et al., 2009).

2.2 Enhanced Stability

NLCs exhibit greater physical and chemical stability compared to other colloidal drug carriers such as emulsions and liposomes. Their solid or semi-solid lipid matrix minimizes the risk of phase separation and degradation of encapsulated compounds. Furthermore, their resistance to oxidation and hydrolysis ensures longer shelf life and sustained performance (Doktorovová et al., 2014; Mehnert & Mäder, 2001).

2.3 Controlled and Sustained Drug Release

Due to their solid lipid content and structured matrix, NLCs can provide controlled and sustained release of drugs. This helps maintain therapeutic levels of the drug over extended periods, reducing dosing frequency and improving patient compliance. The degree of release modulation can be fine-tuned by altering the lipid composition, surfactants, or particle size (Jenning et al., 2000; Souto & Müller, 2010).

2.4 Enhanced Bioavailability

NLCs significantly enhance the bioavailability of poorly soluble drugs, particularly through oral and topical routes. Their small particle size increases surface area and facilitates better interaction with biological membranes. Moreover, their lipidic nature promotes lymphatic uptake, bypassing the hepatic first-pass effect for orally administered drugs (Sharma et al., 2009; Beloqui et al., 2016).

2.5 Versatile Drug Delivery Routes

NLCs are adaptable to multiple routes of administration: oral, dermal, ocular, pulmonary, and parenteral. Their biocompatible and non-irritant lipid components make them suitable for sensitive tissues such as the eyes and lungs. For dermal applications, NLCs enhance drug penetration and provide an occlusive effect, increasing skin hydration (Wissing et al., 2004; Pardeike et al., 2009).

2.6 Biocompatibility and Low Toxicity

Since NLCs are composed of physiological and biodegradable lipids, they offer high biocompatibility and minimal systemic toxicity. The excipients used in NLC formulations are generally recognized as safe (GRAS) by regulatory authorities, making them ideal for long-term use in chronic therapies (Naseri et al., 2015; Müller et al., 2002).

2.7 Potential for Targeted and Personalized Therapy

NLCs offer promising potential in targeted drug delivery and personalized medicine. Surface modification of NLCs with ligands such as antibodies, aptamers, or peptides can enable active targeting to specific tissues or disease sites, such as tumors or inflamed tissues. This not only increases therapeutic efficacy but also reduces off-target effects (Garcia-Fuentes & Alonso, 2012; Patel et al., 2022).

2.8 Scalability and Industrial Feasibility

Compared to many nanocarrier systems, NLCs are relatively easy to scale up using established techniques such as high-pressure homogenization or ultrasonication. Their composition, based on inexpensive and biocompatible lipids, also makes them cost-effective for industrial production (Pardeike et al., 2009; Souto & Müller, 2010).

3. Disadvantages of Nanostructured Lipid Carriers (NLCs)

Despite the numerous advantages of Nanostructured Lipid Carriers (NLCs), they are not without limitations. These drawbacks should be carefully considered when developing NLC-based drug delivery systems, as they can influence the choice of formulation, manufacturing process, and final therapeutic application. The key disadvantages associated with NLCs include limited scalability, complex formulation design, potential for instability under certain conditions, and possible toxicity concerns related to some of their components.

3.1 Limited Scalability and Manufacturing Challenges

One significant disadvantage of NLCs is the limited scalability of their production. Although lab-scale synthesis methods such as high-pressure homogenization, ultrasonication, and microemulsion techniques are well-established, scaling up these methods for industrial production can be challenging. Achieving consistent size distribution, drug encapsulation efficiency, and product stability on a larger scale often requires additional optimization of parameters such as surfactant concentration, processing speed, and temperature control (Müller et al., 2002; Pardeike et al., 2009).

Moreover, the cost of raw materials, such as lipids and surfactants, can also increase the production cost, which may be prohibitive for large-scale commercial applications (Naseri et al., 2015).

3.2 Stability Issues Under Specific Conditions

Although NLCs are known for their enhanced physical and chemical stability compared to other nanoparticulate drug carriers, they can still encounter stability issues under certain environmental conditions. For example, exposure to high temperatures, humidity, or light can cause lipid crystallization or phase separation, leading to drug expulsion and a reduction in the overall encapsulation efficiency (Doktorovová et al., 2014; Mehnert & Mäder, 2001).

Additionally, the presence of free drug in the NLC formulation, which is often due to incomplete drug encapsulation, can lead to an undesirable burst release of the drug, resulting in reduced control over the release kinetics (Beloqui et al., 2016).

3.3 Complex Formulation Design

The formulation of NLCs is often more complex compared to other colloidal carriers such as liposomes or solid lipid nanoparticles (SLNs). The lipid matrix of NLCs requires a combination of solid and liquid lipids, and the selection of suitable excipients and surfactants must be done with great care to ensure compatibility and stability (Müller et al., 2002; Pardeike et al., 2009). The lipid matrix must also be designed to ensure the controlled release of the drug, which may require fine-tuning of the lipid composition (e.g., solid lipid type, liquid lipid choice, or surfactant concentration).

In addition, achieving an optimal balance between high drug encapsulation and low toxicity is a challenging task. Toxicity can arise from either the lipid components or the surfactants used to stabilize the NLCs. Thus, the formulation process becomes highly sensitive to the choice of materials, which can complicate product development (Beloqui et al., 2016).

3.4 Limited Clinical Data and Regulatory Concerns

While NLCs have shown promise in preclinical and animal studies, their clinical application remains limited. Regulatory approval for NLC formulations is often complicated due to concerns regarding long-term toxicity, stability under physiological conditions, and immune system interactions. Since NLCs are a relatively novel delivery system, there is a lack of comprehensive clinical data to establish their safety profiles (Sharma et al., 2009; Patel et al., 2022).

Additionally, the regulatory pathways for nanotechnology-based drug delivery systems are still evolving. As a result, gaining market approval for NLC-based formulations can be more time-consuming and costly compared to conventional drug delivery technologies (Patel et al., 2022).

3.5 Toxicity Concerns of Surfactants and Lipid Components

Another potential disadvantage of NLCs involves the toxicity of surfactants and certain lipid components. Surfactants, such as polysorbates, are commonly used to stabilize NLCs, but their toxicity can be a limiting factor for clinical applications. Surfactant-induced cytotoxicity can lead to undesirable side effects such as inflammation or cell membrane disruption (Souto & Müller, 2010). Moreover, certain lipids used in NLC formulations may pose risks if administered in large amounts, especially if the lipid degradation products are toxic (Mehnert & Mäder, 2001).

3.6 Limited Control Over Drug Release in Some Applications

While NLCs are known for providing controlled drug release, achieving precise modulation of release rates remains a challenge. Depending on the composition of the lipid matrix and the properties of the drug itself, some NLC formulations may exhibit non-linear or erratic release profiles that do not meet the desired therapeutic objectives (Sharma et al., 2009). This is particularly problematic for drugs requiring very specific release rates or those that have narrow therapeutic windows.

4. Classification of NLCs

NLCs are composed of a mixture of solid and liquid lipids stabilized by surfactants. The inclusion of liquid lipids disrupts the perfect crystalline structure of solid lipids, resulting in an amorphous matrix that can accommodate higher amounts of drugs (Jenning et al., 2000).

Types of NLCs

• Type I (Imperfect matrix): Formed by mixing structurally different lipids, resulting in lattice imperfections that enhance drug accommodation.
• Type II (Multiple type): Includes tiny oil nano-compartments within the solid lipid matrix, enabling dual drug loading.
• Type III (Amorphous): Uses special lipids that do not crystallize, providing long-term stability and uniform drug distribution (Naseri et al., 2015).

4.1 Type I NLCs (Imperfect matrix)

Type I NLCs are composed of a solid lipid matrix in which a fraction of the solid lipids is replaced by liquid lipids. This liquid lipid core improves the overall fluidity and flexibility of the lipid matrix, which results in improved drug loading capacity and better drug release profiles. The solid lipid phase typically consists of fatty acids, wax esters, or triglycerides, while the liquid lipid phase usually contains oils like medium-chain triglycerides (MCT) or caprylic/capric triglycerides (Müller et al., 2002).

Key Characteristics:

• Higher drug loading capacity due to the presence of the liquid lipid phase.
• Improved stability and controlled release of lipophilic drugs.
• More flexible matrix, which can accommodate a wider range of drugs with varying solubility profiles.

Type I NLCs are often preferred in applications requiring longer circulation times and sustained drug release, such as parenteral or topical drug delivery (Wissing et al., 2004).

Applications:

• Cancer therapy, where lipophilic chemotherapeutic agents need to be delivered in a controlled manner.
• Topical drug delivery for the treatment of skin disorders such as eczema or psoriasis.

4.2 Type II NLCs (Multiple type)

Type II NLCs are characterized by a solid lipid core, but with disorder or imperfections in the crystalline structure. These imperfections arise from the incorporation of liquid lipids into the solid lipid matrix, leading to a disordered structure. This disordered lipid matrix provides more space for drug molecules to be incorporated, which results in an enhanced drug encapsulation efficiency compared to solid lipid nanoparticles (SLNs) (Müller et al., 2002).

Key Characteristics:

• Enhanced drug loading capacity compared to SLNs.
• Disordered lipid matrix increases drug solubility and drug release rate.
• The disordered matrix results in greater stability and less crystallization than conventional SLNs, thus improving the overall storage stability of the drug-loaded system.

Type II NLCs are particularly useful for the delivery of poorly water-soluble drugs that require a stable carrier for effective delivery (Patel et al., 2022). The disordered lipid matrix also prevents the expulsion of the drug during storage, which can sometimes occur with SLNs.

Applications:

• Gene therapy, where nucleic acids are encapsulated in a solid lipid matrix for enhanced stability.
• Delivery of hydrophobic drugs with poor solubility in water, such as anti-cancer agents and anti-inflammatory drugs.

4.3 Type III NLCs (Amorphous)

Hybrid NLCs represent an advanced class of NLCs that combine lipid components with other materials, such as polymers, surfactants, or biodegradable polymers. This hybrid structure allows for the optimization of both the lipid matrix and polymeric component, enabling more tailored drug release profiles and increased stability. Hybrid NLCs are being explored for targeted drug delivery and combination therapies, particularly in cancer treatments and gene delivery (Beloqui et al., 2016).

Key Characteristics:

• Increased stability of the lipid matrix due to the incorporation of polymeric or other stabilizing agents.
• Ability to modulate drug release profiles more precisely due to the unique combination of lipid and polymer components.
• Targeting capabilities can be integrated by adding specific ligands or antibodies to the nanoparticle surface.

Hybrid NLCs can be formulated with a higher degree of customization, making them suitable for precision medicine approaches where the drug release profile must be tightly controlled or where the particle needs to target specific tissues or cells.

Applications:

• Cancer therapy where hybrid NLCs can carry both chemotherapeutic agents and gene therapies for synergistic effects.
• Nucleic acid delivery for gene silencing or CRISPR-based gene editing.

5. Components Required for Manufacturing Nanostructured Lipid Carriers (NLCs) Topical Cream

Topical creams based on Nanostructured Lipid Carriers (NLCs) are formulated using a variety of ingredients that enhance the product's stability, effectiveness of medication encapsulation, and skin penetration. The essential ingredients needed to make an NLC-based topical cream are listed in detail below, along with an explanation of each one's roles and functions during the formulation process.

5.1. Lipids

Lipids are the fundamental building blocks of nanostructured lipid carriers, or NLCs. The active pharmaceutical ingredient (API) is encapsulated by these lipids, which also determine the drug's release profile.

• Solid Lipids: These are the main lipid constituents that make up the NLC's solid matrix. Glyceryl monostearate, stearic acid, cetyl alcohol, and hydrogenated lipids are examples of common solid lipids. The carrier's structural stability is provided by the solid lipid matrix, which also shields the medicine inside from deterioration (Müller et al., 2002).
• Liquid Lipids: These are the secondary lipid ingredients that are incorporated into the formulation to generate a liquid core inside the solid lipid matrix. Improved fluidity and drug loading capacity are provided by liquid lipids like oleic acid, caprylic/capric triglycerides, and medium-chain triglycerides (MCT) (Beloqui et al., 2016). The liquid phase gives the lipid matrix flexibility and aids in improving the drug's solubility.

5.2. Surfactants (Emulsifiers)

In order to prepare and stabilize NLCs, surfactants are required. By promoting the dispersion of lipids and creating stable emulsions along the way, they aid in the creation of nanocarriers. In order to promote the production of smaller particle sizes, surfactants are necessary to lower the surface tension between the lipid and water phases.

• A nonionic surfactant is one that Poloxamers, cetyltrimethylammonium bromide (CTAB), and polysorbates (like Tween 80) are often utilized surfactants for NLCs. These surfactants are well known for stabilizing lipid nanoparticles in topical formulations and for being somewhat compatible with the skin (Naseri et al., 2015).
• Anionic Surfactants: To stabilize the NLCs in an aqueous phase, anionic surfactants, such as sodium dodecyl sulfate (SDS), can be used with nonionic surfactants.

5.3. Active Pharmaceutical Ingredients (APIs)

The main therapeutic substance contained in the NLCs is the active pharmaceutical ingredient (API). Both hydrophobic and hydrophilic APIs are possible, and the lipid matrix of NLCs is made to hold these different kinds of medications.

Drugs that are hydrophobic are usually lipophilic substances that need NLCs for effective encapsulation and regulated release. Chemotherapeutic medications, antifungal medications, and anti-inflammatory medications (such as ibuprofen and diclofenac) are a few examples.

Hydrophilic pharmaceuticals: NLCs can encapsulate hydrophilic pharmaceuticals by altering the lipid matrix with surfactants that increase solubility, even though they are typically made for lipophilic medications. Antibiotics and corticosteroids can also be added to NLC formulations.

5.4. Aqueous Phase (Water Phase)

Usually utilized in the formulation process to create an emulsion, water acts as the dispersing medium for the NLCs. To prevent any contaminants that could compromise the stability of the NLCs, the water phase must be deionized or distilled. To maintain the pH and improve the solubility of the active components, buffer solutions may occasionally be added.

5.5. Co-Surfactants

Co-surfactants are added to the formulation to further stabilize the emulsions and improve the solubility and skin penetration of the NLCs. Co-surfactants reduce the interfacial tension between the lipid and aqueous phases, helping to maintain the nanostructure of the NLCs.

• Ethanol is often used as a co-surfactant in topical formulations because it can enhance skin permeation by disrupting the stratum corneum lipid barrier, facilitating better drug absorption (Müller et al., 2002).

5.6. Preservatives (if desired)

Preservatives are frequently added to the recipe to keep the topical cream stable and stop microbiological infection. Phenoxyethanol, methylparaben, and ethylparaben are examples of common preservatives.

6. Methods of Preparation

Several techniques have been developed for NLC production, including:

• High-pressure homogenization (HPH): The most commonly used method, applicable in both hot and cold conditions.
• Ultrasonication or high-shear mixing: Produces smaller particle sizes but may lead to metal contamination.
• Microemulsion techniques: Offers better control over particle size but less suitable for large-scale production.

- Solvent evaporation and emulsification: Allows precise control over the drug encapsulation process (Wissing et al., 2004).

6.1 High-pressure homogenization (HPH) :

A popular method for creating lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and other nanoformulations is high-pressure homogenization (HPH). It is essential for producing nanoparticles with improved drug delivery capabilities and a consistent size distribution. In order to break down large particles into smaller, nanometer-sized particles, this approach applies high pressure to push the formulation through a narrow gap where it quickly shears and cavitates.

Principle for High-Pressure Homogenization: The HPH approach works on the basis of the idea that dispersion of nanoparticles is forced through a limited space between two surfaces by high pressure (up to 2000 bar or more). The enormous lipid droplets or emulsions are broken up into much smaller ones by mechanical forces like shear and cavitation.

• Shear Stress: The particles are broken down by the shear stress that is applied when the dispersion is pushed through a small opening at a fast speed.
• Cavitation: The liquid flows quickly enough to form microbubbles or cavities due to the high velocity. When these bubbles burst, strong localized forces are created that cause the particles to disintegrate.
• Turbulence: The lipid particles are further broken down by the turbulence created by the high-pressure flow.

Advantages of High-Pressure Homogenization:-

• Scalability: Because of its scalability, this method can be used for both large-scale industrial production of nanoparticle formulations and laboratory study. Because of its ease of adaptation for big batches, it is economical for commercial production.
• Control over Particle Size Distribution: To achieve constant drug release and therapeutic efficacy, HPH offers a high degree of control over the size distribution of nanoparticles (Beloqui et al., 2016).
• Minimal Use of Organic Solvents: HPH is environmentally safe and appropriate for pharmaceutical applications because it can function in aqueous-based systems, which eliminates the requirement for hazardous organic solvents in the formulation.

Disvantages of High-Pressure Homogenization:-

• Restricted to Specific Viscosity Ranges: HPH works well with low-to-moderate viscosity dispersions. Systems that are extremely viscous might not flow through the homogenization chamber well, necessitating process changes or the use of alternative methods (Naseri et al., 2015).
• High Energy Consumption: The homogenization process requires high pressures and fast flows, which leads to a considerable energy consumption. This might raise the operational expenses of large-scale production (Mehnert & Mäder, 2001).
• Wear and Tear of Equipment: Over time, maintenance and part replacement may be necessary due to the extreme forces employed in the process.

6.2 Ultrasonication or high-shear mixing :

High-shear mixing and ultrasonication are crucial processes for creating and refining nanoparticle formulations, such as lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and other colloidal systems. By using mechanical forces to break up bigger particles into smaller, more uniform ones, both methods aim to improve homogeneity within dispersions and reduce particle size.

High-frequency sound waves, usually between 20 kHz and 10 MHz, are used in ultrasonication to create powerful mechanical waves inside the dispersion that reduce particle size. This technique is frequently used to create lipid nanoparticles or nanosuspensions in medicinal and cosmetic formulations.

Principle for Ultrasonication: The creation of acoustic cavitation is the foundational idea of ultrasonication. Areas of compression and rarefaction alternate when ultrasonic vibrations travel through a liquid. This causes small bubbles (cavitation) to form and burst. The particles in the formulation may fragment into smaller pieces as a result of the strong local heat and shear stresses produced by the collapse of these bubbles.

Advantages of Ultrasonication

• Effective Size Reduction: Large lipid droplets or particles can be effectively broken down into the nanoscale range (10-500 nm) by ultrasonication.
• Rapid Process: Ultrasonication can produce results more quickly than other techniques and is appropriate for both laboratory and industrial operations.
• Scalability: Ultrasonication can be used for both small-batch and large-scale production since it can be scaled up utilizing huge ultrasonic baths or sonicators.
• Environmentally Friendly: This process usually eliminates the need for hazardous organic solvents, which is advantageous for the manufacturing of cosmetic and pharmaceutical goods.

Disadvantages of Ultrasonication

• Thermal Degradation: Drugs or lipids that are sensitive to temperature may degrade due to the heat produced by cavitation. In order to lessen this effect, cooling systems can be required.
• Particle Size Distribution: Ultrasonication can create smaller particles, but it might not necessarily result in narrow size dispersion. In order to achieve size homogeneity, other processing stages may be necessary.
• Equipment Cost: Especially for large-scale industrial applications, high-power ultrasonicators can be costly.
• Restricted to Specific Viscosity: Formulations with lower viscosities respond well to ultrasonication. Systems that are extremely viscous might not cavitate well, requiring the use of different techniques or modifications to the equipment.

6.3 Microemulsion technique :

The microemulsion technique is a low-energy method used to produce nanostructured lipid carriers (NLCs) and other lipid-based nanocarriers. It relies on the spontaneous formation of thermodynamically stable, isotropic mixtures of oil, water, surfactant, and co-surfactant. Unlike other techniques such as high-pressure homogenization or ultrasonication, microemulsion formation occurs without applying intense mechanical force, making it suitable for heat-sensitive drugs or lab-scale production. Microemulsions are clear, thermodynamically stable colloidal systems formed when a suitable mixture of oil phase (lipid), aqueous phase (usually water), surfactants, and co-surfactants are combined under specific conditions. These systems typically have droplet sizes between 10–100 nm. The microemulsion technique for NLCs involves the preparation of a hot microemulsion, which is then dispersed into cold water under controlled stirring to produce nanoparticles through precipitation of the lipid phase.

Steps in Microemulsion-Based NLC Preparation:

1. Formulation of Hot Microemulsion:

• A temperature 5–10°C over the solid lipid's melting point melts a lipid phase, which includes both liquid and solid lipids.
• The molten lipid is mixed with surfactants and co-surfactants.
• When water is added, a transparent microemulsion forms, signifying that the water and oil phases are evenly distributed.

2. Dispersion into Cold Water:

• With careful swirling, the heated microemulsion is quickly put into ice-cold water.
• The lipids quickly solidify and form nanostructured lipid particles when they come into touch with cold water.

3. Developing NLCs:

• The NLC, or lipid phase precipitation, creates nanostructures with both liquid and solid lipid domains.

6.4 Solvent evaporation and emulsification

An established technology for creating nanostructured lipid carriers (NLCs), the solvent evaporation and emulsification method works especially well for lipophilic medications. It creates nanoparticles with a consistent size distribution and improved drug encapsulation efficiency by fusing the ease of emulsification with the potency of solvent diffusion and evaporation.
The process involves dissolving the lipid phase—which includes both liquid and solid lipids—in an organic solvent to create an oil-in-water (O/W) emulsion. This stage is emulsified in a solution of aqueous surfactants. Lipids precipitate as nanoparticles as a result of the organic solvent's subsequent evaporation, creating a stable NLC dispersion.

Step-by-Step process

1. Lipid Phase Preparation

• Lipids, both liquid and solid, dissolve in an organic solvent, usually dichloromethane, ethanol, or chloroform.
• The lipid-organic mixture also dissolves the medicine, if it is lipophilic.

2. Emulsification

• Under high-speed stirring or ultrasonication, the organic phase is introduced to an aqueous solution that contains surfactants (such as Tween 80 or Poloxamer 188).
• A pre-emulsion (oil-in-water) is created as a result.

3. Evaporation of Solvents

• The organic solvent is allowed to slowly evaporate by stirring the emulsion at room temperature or slightly above it.
• Lipid nanoparticles generate a nanostructured lipid dispersion as the solvent evaporates.

4. Purification

• To get rid of aggregated particles or unentrapped medication, the NLCs are usually filtered or centrifuged.

7. Evaluation Parameters

Evaluating nanostructured lipid carriers (NLCs) is crucial to ensure their stability, performance, safety, and therapeutic efficacy. A thorough characterization helps in understanding the physicochemical and biological behavior of NLCs, optimizing the formulation, and predicting in vivo outcomes.

7.1. Particle Size and Polydispersity Index (PDI)

• Particle Size and Polydispersity Index (PDI) Significance: Particle size influences the formulation's stability, skin penetration, bioavailability, and drug release.
• Method: Photon Correlation Spectroscopy (PCS) or Dynamic Light Scattering (DLS).
• Interpretation of PDI:

• A homogeneous size distribution is indicated by values less than 0.3.
• Greater values indicate a wide size distribution or aggregation.

7.2. Zeta Potential (Surface Charge) Significance:

• Importance: Indicates the stability of the colloidal system.
• Method: Electrophoretic light scattering was used for measurement.
• The ideal range:-

• Good electrostatic stability is ensured by a zeta potential greater than ±30 mV.
• Steric stabilization using surfactants can be necessary for lower values.

7.3. The percentages of drug loading (DL%) and entrapment efficiency (EE%)

Entrapment Efficiency:

• Percentage of the medication added overall that is encased in NLCs.
• Method: Drug quantification by UV or HPLC after ultracentrifugation, dialysis, or filtration.

Drug Loading (DL%):

• The quantity of medication per lipid weight.
• Crucial for formulation effectiveness and dosage accuracy.

7.4. Thermal Analysis

• Differential Scanning Calorimetry (DSC):
  • Determines melting behavior, crystallinity, and drug-lipid interaction.
  • Confirms amorphous state of the drug for better release.
• Thermogravimetric Analysis (TGA):
  • Assesses thermal stability and moisture content.

7.5. X-ray diffraction (XRD):

• Assesses medication incorporation and the crystalline structure of lipids.
• Amorphization, which contributes to improved drug solubility, is shown by diminished or absent strong peaks in NLCs.

7.6. In Vitro Drug Release Studies

• Purpose: Evaluates the release profile (immediate, sustained, or controlled release).
• Methods:
  • Dialysis bag method
  • Franz diffusion cells (for topical formulations)
• Medium: Simulated biological fluids or phosphate-buffered saline (PBS).

8. Stability Studies

• Parameters: Particle size, zeta potential, EE%, and physical appearance are monitored over time.
• Conditions: Store at various temperature and humidity conditions (e.g., 4°C, 25°C/60% RH).
• Purpose: To determine the shelf-life and storage requirements.

8. Pharmaceutical Applications

8.1 Anticancer Therapy

NLCs have been widely explored for the delivery of chemotherapeutic agents like paclitaxel and doxorubicin. Their enhanced permeability and retention (EPR) effect allows for targeted tumor accumulation with reduced systemic toxicity (Zhang et al., 2008).

8.2 Dermatological and Cosmetic Applications

NLCs improve skin hydration and drug penetration, making them ideal for topical formulations containing anti-inflammatory, antifungal, and anti-aging agents (Müller et al., 2007).

8.3 Oral Drug Delivery

Poorly water-soluble drugs like curcumin and resveratrol have shown improved absorption when delivered via NLCs due to enhanced solubilization and lymphatic uptake (Doktorovová et al., 2014).

8.4 Gene and Vaccine Delivery

Recent advancements have seen NLCs used for nucleic acid delivery, including siRNA and mRNA, and as adjuvants in vaccines due to their immunogenic potential and biocompatibility (Garcia-Fuentes & Alonso, 2012).

9. Challenges and Limitations

Despite their promise, several hurdles remain in the development and commercialization of NLCs:

• Scalability: Some preparation methods are not easily adaptable to industrial scale.
• Regulatory Uncertainty: Lack of standardized guidelines for nanomedicine approval.
• Stability: Potential for lipid oxidation and drug leakage over time.
• Toxicity: Long-term safety profiles are not fully established (Naseri et al., 2015).

10. Future Prospects

Because of their enhanced stability, high drug-loading capacity, and controlled release characteristics, nanostructured lipid carriers (NLCs) have shown great promise as a unique and efficient drug delivery platform. However, a number of scientific, technological, and regulatory issues need to be resolved in order for future and continuing research to fully utilize NLCs. The combination of NLCs and targeted delivery methods, including ligand-conjugated nanoparticles that may identify and attach to particular receptors that are overexpressed on sick cells, is one promising avenue for enhancing drug accumulation at the intended location (Patel et al., 2022). This is especially helpful in precision medicine and cancer treatment, where reducing systemic adverse effects is essential.

Furthermore, another developing field is tailored nanomedicine with NLCs. NLCs could be customized to administer patient-specific medicines that match unique genetic and metabolic profiles because to developments in pharmacogenomics and molecular profiling (Beloqui et al., 2016). Particularly for chronic and complicated illnesses like cancer, neurological diseases, and autoimmune diseases, this strategy has the potential to completely alter current therapy paradigms. Furthermore, NLCs are increasingly being used for gene and RNA delivery, particularly in the wake of the success of lipid-based vaccinations and treatments. Non-viral gene therapy platforms can be made possible by optimizing NLCs to safely and effectively distribute siRNA, mRNA, or CRISPR-Cas components (Patel et al., 2022). Emerging trends in NLC research include:

• Targeted Delivery: Surface modification with ligands for active targeting.
• Combination Therapy: Co-delivery of multiple drugs or drug-gene combinations.
• Smart NLCs: Stimuli-responsive carriers for site-specific release.
• Green Production Methods: Solvent-free and environmentally friendly manufacturing processes.

CONCLUSION

Nanostructured lipid carriers have demonstrated tremendous potential as versatile drug delivery systems. Their ability to enhance drug loading, stability, and bioavailability makes them suitable for a wide range of therapeutic applications. Addressing current challenges through innovative design and thorough evaluation will pave the way for their successful translation into clinical practice.

One of the most inventive and promising lipid-based drug delivery methods created to get over the drawbacks of conventional solid lipid nanoparticles (SLNs) is nanostructured lipid carriers (NLCs). NLCs offer increased stability, controlled release profiles, higher drug loading capacity, and more design freedom by combining a blend of liquid and solid lipids. They are especially appropriate for a variety of pharmaceutical, cosmetic, and biological applications due to their capacity to encapsulate both hydrophilic and lipophilic medicines, shield labile pharmaceuticals from degradation, and offer site-specific delivery (Müller et al., 2002; Beloqui et al., 2016).

The production of NLCs with desired physicochemical properties, such as small particle size, low polydispersity index (PDI), and high entrapment efficiency, has been further simplified by technological advancements in formulation techniques, such as high-pressure homogenization, ultrasonication, solvent evaporation, and microemulsion-based methods (Mehnert & Mäder, 2001; Naseri et al., 2015). Additionally, by improving skin penetration, extending drug release, and lowering dose frequency, NLCs have demonstrated better therapeutic effects for both topical and systemic drug administration (Pardeike et al., 2009; Wissing et al., 2004). Before NLCs may be widely used in clinical settings, a number of issues need to be resolved, including scalability, physical instability during long-term storage, and possible cytotoxicity of excipients. Additionally, more research and standardization are required for the regulatory and quality control concerns unique to nanocarriers.

In conclusion, NLCs offer a flexible platform with extensive therapeutic potential, marking a substantial improvement in drug delivery facilitated by nanotechnology. Unlocking the full therapeutic potential of NLCs in targeted drug delivery and customized medicine will require ongoing research and development that focuses on overcoming present constraints and maintaining regulatory compliance.

REFERENCES

1. Jenning, V., Thünemann, A. F., & Gohla, S. H. (2000). Characterization of a novel solid lipid nanoparticle carrier system based on binary mixtures of liquid and solid lipids. International Journal of Pharmaceutics, 199(2), 167–177. https://doi.org/10.1016/S0378-5173(00)00378-6
2. Mehnert, W., & Mäder, K. (2001). Solid lipid nanoparticles: Production, characterization and applications. Advanced Drug Delivery Reviews, 47(2-3), 165–196. https://doi.org/10.1016/S0169-409X(01)00105-3
3. Müller, R. H., Radtke, M., & Wissing, S. A. (2002). Nanostructured lipid matrices for improved microencapsulation of drugs. International Journal of Pharmaceutics, 242(1-2), 121–128. https://doi.org/10.1016/S0378-5173(02)00180-1
4. Naseri, N., Valizadeh, H., & Zakeri-Milani, P. (2015). Solid lipid nanoparticles and nanostructured lipid carriers: Structure, preparation and application. Advanced Pharmaceutical Bulletin, 5(3), 305–313. https://doi.org/10.15171/apb.2015.043
5. Pardeike, J., Hommoss, A., & Müller, R. H. (2009). Lipid nanoparticles in cosmetic and pharmaceutical dermal products. International Journal of Pharmaceutics, 366(1-2), 170–184. https://doi.org/10.1016/j.ijpharm.2008.10.003
6. Patel, M., Shukla, P., Parmar, R., & Singh, D. (2022). Lipid-based nanocarriers for delivery of therapeutic RNA molecules. Drug Delivery and Translational Research, 12(2), 221–240. https://doi.org/10.1007/s13346-021-01017-3
7. Wissing, S. A., Kayser, O., & Müller, R. H. (2004). Solid lipid nanoparticles for parenteral drug delivery. Advanced Drug Delivery Reviews, 56(9), 1257–1272. https://doi.org/10.1016/j.addr.2003.12.002
8. Beloqui, A., Solinís, M. Á., Rodríguez-Gascón, A., Almeida, A. J., & Préat, V. (2016). Nanostructured lipid carriers: Promising drug delivery systems for future clinics. Nanomedicine: Nanotechnology, Biology and Medicine, 12(1), 143–161. https://doi.org/10.1016/j.nano.2015.09.004
9. Doktorovová, S., Araújo, J., Garcia, M. L., Rakovsky, E., & Souto, E. B. (2014). Formulating fluticasone propionate in novel PEG-containing nanostructured lipid carriers (NLC). International Journal of Pharmaceutics, 476(1-2), 205–213. https://doi.org/10.1016/j.ijpharm.2014.09.017
10. Mehnert, W., & Mäder, K. (2001). Solid lipid nanoparticles: Production, characterization and applications. Advanced Drug Delivery Reviews, 47(2-3), 165–196. https://doi.org/10.1016/S0169-409X(01)00105-3
11. Müller, R. H., Radtke, M., & Wissing, S. A. (2002). Nanostructured lipid matrices for improved microencapsulation of drugs. International Journal of Pharmaceutics, 242(1-2), 121–128. https://doi.org/10.1016/S0378-5173(02)00180-1
12. Naseri, N., Valizadeh, H., & Zakeri-Milani, P. (2015). Solid lipid nanoparticles and nanostructured lipid carriers: Structure, preparation and application. Advanced Pharmaceutical Bulletin, 5(3), 305–313. https://doi.org/10.15171/apb.2015.043
13. Patel, M., Shukla, P., Parmar, R., & Singh, D. (2022). Lipid-based nanocarriers for delivery of therapeutic RNA molecules. Drug Delivery and Translational Research, 12(2), 221–240. https://doi.org/10.1007/s13346-021-01017-3
14. Pardeike, J., Hommoss, A., & Müller, R. H. (2009). Lipid nanoparticles in cosmetic and pharmaceutical dermal products. International Journal of Pharmaceutics, 366(1-2), 170–184. https://doi.org/10.1016/j.ijpharm.2008.10.003
15. Sharma, A., Baldi, A., & Rawal, R. K. (2009). Nanostructured lipid carriers: A novel approach for drug delivery system. Journal of Drug Delivery and Therapeutics, 9(3-s), 58–63. https://doi.org/10.22270/jddt.v9i3-s.2748
16. Souto, E. B., & Müller, R. H. (2010). Lipid nanoparticles: Effect on bioavailability and pharmacokinetic changes. Handbook of Drug Delivery, 2, 115–126.
17. Beloqui, A., Solinís, M. Á., Rodríguez-Gascón, A., Almeida, A. J., & Préat, V. (2016). Nanostructured lipid carriers: Promising drug delivery systems for future clinics. Nanomedicine: Nanotechnology, Biology and Medicine, 12(1), 143–161. https://doi.org/10.1016/j.nano.2015.09.004
18. Müller, R. H., Radtke, M., & Wissing, S. A. (2002). Nanostructured lipid matrices for improved microencapsulation of drugs. International Journal of Pharmaceutics, 242(1-2), 121–128. https://doi.org/10.1016/S0378-5173(02)00180-1
19. Beloqui, A., Solinís, M. Á., Rodríguez-Gascón, A., Almeida, A. J., & Préat, V. (2016). Nanostructured lipid carriers: Promising drug delivery systems for future clinics. Nanomedicine: Nanotechnology, Biology and Medicine, 12(1), 143–161. https://doi.org/10.1016/j.nano.2015.09.004
20. Doktorovová, S., Araújo, J., Garcia, M. L., Rakovsky, E., & Souto, E. B. (2014). Formulating fluticasone propionate in novel PEG-containing nanostructured lipid carriers (NLC). International Journal of Pharmaceutics, 476(1–2), 205–213. https://doi.org/10.1016/j.ijpharm.2014.09.017
21. Garcia-Fuentes, M., & Alonso, M. J. (2012). Lipid nanoparticles for gene therapy. European Journal of Pharmaceutics and Biopharmaceutics, 80(1), 113–117. https://doi.org/10.1016/j.ejpb.2011.08.004
22. Jenning, V., Thünemann, A. F., & Gohla, S. H. (2000). Characterization of a novel solid lipid nanoparticle carrier system based on binary mixtures of liquid and solid lipids. International Journal of Pharmaceutics, 199(2), 167–177. https://doi.org/10.1016/S0378-5173(00)00378-6
23. Mehnert, W., & Mäder, K. (2001). Solid lipid nanoparticles: Production, characterization and applications. Advanced Drug Delivery Reviews, 47(2–3), 165–196. https://doi.org/10.1016/S0169-409X(01)00105-3
24. Müller, R. H., Radtke, M., & Wissing, S. A. (2002). Nanostructured lipid matrices for improved microencapsulation of drugs. International Journal of Pharmaceutics, 242(1–2), 121–128. https://doi.org/10.1016/S0378-5173(02)00180-1
25. Naseri, N., Valizadeh, H., & Zakeri-Milani, P. (2015). Solid lipid nanoparticles and nanostructured lipid carriers: Structure, preparation and application. Advanced Pharmaceutical Bulletin, 5(3), 305–313. https://doi.org/10.15171/apb.2015.043
26. Pardeike, J., Hommoss, A., & Müller, R. H. (2009). Lipid nanoparticles in cosmetic and pharmaceutical dermal products. International Journal of Pharmaceutics, 366(1–2), 170–184. https://doi.org/10.1016/j.ijpharm.2008.10.003
27. Patel, M., Shukla, P., Parmar, R., & Singh, D. (2022). Lipid-based nanocarriers for delivery of therapeutic RNA molecules. Drug Delivery and Translational Research, 12(2), 221–240. https://doi.org/10.1007/s13346-021-01017-3
28. Sharma, A., Baldi, A., & Rawal, R. K. (2009). Nanostructured lipid carriers: A novel approach for drug delivery system. Journal of Drug Delivery and Therapeutics, 9(3-s), 58–63. https://doi.org/10.22270/jddt.v9i3-s.2748
29. Souto, E. B., & Müller, R. H. (2010). Lipid nanoparticles: Effect on bioavailability and pharmacokinetic changes. Handbook of Drug Delivery, 2, 115–126.
30. Wissing, S. A., Kayser, O., & Müller, R. H. (2004). Solid lipid nanoparticles for parenteral drug delivery. Advanced Drug Delivery Reviews, 56(9), 1257–1272. https://doi.org/10.1016/j.addr.2003.12.002
31. Kadam, D. D., Kharche, A. S., Gaware, S. S., Jayswal, M. G., & Pawar, R. J. (2023). A Comprehensive Review on Nanostructured Lipid Carriers. International Journal of Pharmaceutical and Phytopharmacological Research, 13(1), 1–15. This review discusses various evaluation parameters such as particle size, zeta potential, entrapment efficiency, and crystallinity studies, highlighting their significance in ensuring the performance and stability of NLCs.
32. Souto, E. B., & Müller, R. H. (2010). Lipid nanoparticles: Effect on bioavailability and pharmacokinetic changes. Handbook of Drug Delivery, 2, 115–126. This chapter provides insights into the characterization of lipid nanoparticles, including NLCs, focusing on parameters like particle size, surface charge, and drug loading capacity.
33. Wissing, S. A., Kayser, O., & Müller, R. H. (2004). Solid lipid nanoparticles for parenteral drug delivery. Advanced Drug Delivery Reviews, 56(9), 1257–1272. The article elaborates on the methods used to evaluate SLNs and NLCs, emphasizing the importance of parameters like particle size distribution and zeta potential in determining the stability and efficacy of the formulations.
34. Pardeike, J., Hommoss, A., & Müller, R. H. (2009). Lipid nanoparticles (SLN, NLC) in cosmetic and pharmaceutical dermal products. International Journal of Pharmaceutics, 366(1–2), 170–184. This paper discusses the characterization techniques for NLCs used in dermal applications, focusing on parameters such as particle size, polydispersity index, and entrapment efficiency.
35. Naseri, N., Valizadeh, H., & Zakeri-Milani, P. (2015). Solid lipid nanoparticles and nanostructured lipid carriers: Structure, preparation and application. Advanced Pharmaceutical Bulletin, 5(3), 305–313. The review provides comprehensive information on the structural aspects of NLCs and the evaluation parameters critical for their development and application.
36. Mehnert, W., & Mäder, K. (2001). Solid lipid nanoparticles: Production, characterization and applications. Advanced Drug Delivery Reviews, 47(2–3), 165–196. This foundational paper outlines the production methods and characterization parameters, including particle size analysis and drug loading efficiency, essential for NLCs.
37. Jenning, V., Thünemann, A. F., & Gohla, S. H. (2000). Characterization of a novel solid lipid nanoparticle carrier system based on binary mixtures of liquid and solid lipids. International Journal of Pharmaceutics, 199(2), 167–177. The study focuses on the morphological and structural characterization of NLCs, emphasizing techniques like transmission electron microscopy and differential scanning calorimetry.
38. Garcia-Fuentes, M., & Alonso, M. J. (2012). Lipid nanoparticles for gene therapy. European Journal of Pharmaceutics and Biopharmaceutics, 80(1), 113–117. This article discusses the application of lipid nanoparticles, including NLCs, in gene therapy, highlighting the importance of characterization parameters in ensuring therapeutic efficacy.
39. Doktorovová, S., Araújo, J., Garcia, M. L., Rakovsky, E., & Souto, E. B. (2014). Formulating fluticasone propionate in novel PEG-containing nanostructured lipid carriers (NLC): Comparing performance with conventional NLC and SLN. International Journal of Pharmaceutics, 476(1–2), 205–213. The paper compares different NLC formulations, focusing on evaluation parameters such as particle size, zeta potential, and drug release profiles.
40. Beloqui, A., Solinís, M. Á., Rodríguez-Gascón, A., Almeida, A. J., & Préat, V. (2016). Nanostructured lipid carriers: Promising drug delivery systems for future clinics. Nanomedicine: Nanotechnology, Biology and Medicine, 12(1), 143–161. This review highlights the potential of NLCs in clinical applications, emphasizing the critical evaluation parameters necessary for their successful development and implementation