Recent Advances In Nanostructured Lipid Carriers For Oral, Parenteral, And Topical Drug Delivery

Fig. 1: Types of lipid based Nano carriers

Lipid-based Nano carriers are Nano sized drug delivery systems composed of physiological lipids that are biocompatible and biodegradable. They are designed to encapsulate, protect, and transport drugs, particularly poorly water-soluble compounds. Due to their lipid nature, these carriers enhance drug solubility, improve stability, and increase bioavailability.

Lipid-based Nano carriers can efficiently control drug release and improve therapeutic efficacy while reducing drug-related toxicity. Their small particle size and high surface area enable better interaction with biological membranes, leading to improved absorption and targeted delivery².

Because of these advantages, Lipid-based Nano medicines such as liposomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and lipid micelles have shown promising potential in drug delivery applications. These lipid-based Nano carriers provide effective approaches for achieving improved drug accumulation at the desired site of action. They also help enhance the pharmacokinetic properties of drugs, including issues related to poor oral absorption and short biological half-life. In addition, lipid-based Nano medicines improve drug safety by reducing the formation of toxic degradation products and enabling localized drug delivery, thereby minimizing systemic side effects³. Different types of lipid based nano carriers  are depicted in Fig No.1 and Table No. 1

Table No 1: Types of Lipid Nano carriers

Nanostructured lipid carrier

Nanostructured lipid carriers (NLCs) are advanced drug delivery systems recognized for their safety and biocompatibility. Drugs are dissolved or integrated into a mixture of solid and liquid lipids in NLCs (Fig No.2), which typically have a size range of 10 to 500nm. In comparison to polymeric and metallic nanoparticles, NLCs are advantageous due to their non-toxic nature and higher drug loading capacity. These carriers enhance drug solubility, permeability, and targeting efficiency. Moreover, surface modification of NLCs can prolong systemic circulation and enable site-specific drug delivery. NLCs have been widely explored for the delivery of drugs used in the treatment of cancer, infectious diseases, neurological disorders, diabetes, and hypertension¹².

NLCs are formulated using biodegradable and biocompatible solid and liquid lipids along with suitable emulsifiers. Lipids form the core of the system and play a crucial role in improving drug loading efficiency, providing sustained drug release, and enhancing formulation stability. The incorporation of liquid lipids into the solid lipid matrix disrupts its crystalline arrangement, leading to a less ordered and more imperfect structure. This structural modification minimizes drug expulsion and improves drug entrapment efficiency. Additionally, NLCs are capable of encapsulating both hydrophilic and lipophilic drugs¹³.

Structure and properties of nanostructured lipid carriers

Figure No 2: Structure of Nanostructured lipid carriers (NLC)¹⁴.

Nanostructured lipid carriers (NLCs) are Nano sized particles with a typical size range of 10–500 nm and a spherical morphology. They are composed of a mixture of solid and liquid lipids, which creates imperfections in the lipid matrix and allows higher drug loading compared to solid lipid nanoparticles (SLNs). Despite the presence of liquid lipids, the NLC matrix remains solid at room and body temperatures due to controlled lipid composition.

The solid lipid matrix efficiently entraps drug molecules, improves stability, and prevents particle aggregation when compared to conventional emulsions. Mixed-type NLCs may contain long-chain liquid lipids in very low proportions and short-chain solid and liquid lipids in ratios such as 70:30. The characteristics of NLCs depend on the location of the drug (API) within the lipid matrix, and lipid concentrations of up to 95% can be used in NLC formulations¹⁵. Different types of NLCs are depicted in Fig No.3

Types of NLC’s

1. NLC Type I
2. NLC Type II
3. NLC Type III

Figure No 3: Types of Nanostructured lipid carrier¹⁶.

NLC Type I:

NLC Type I, also known as the imperfect type, is the incorporation of liquid lipids into the solid lipid matrix disrupts the regular crystalline arrangement. Such structural imperfections generate additional void spaces within the lipid matrix, enabling greater accommodation of drug molecules and resulting in enhanced entrapment efficiency. In this approach, the proportion of liquid lipid is kept lower than that of the solid lipid. The solid lipid and oil components are melted, blended, and emulsified in an aqueous phase to form an oil-in-water Nano emulsion, which subsequently solidifies into lipid nanoparticles upon cooling to ambient temperature¹⁷.

NLC Type II:

NLC Type II, also known as the amorphous type, is formed by blending liquid lipids with solid lipids that maintain their α-polymorphic form after solidification and during storage. This results in the development of an amorphous lipid core. Compared to Type I NLCs, this system is more advantageous because the drug remains uniformly trapped within the amorphous matrix, and crystallization is prevented. In contrast, solid lipids that undergo transformation to the β-polymorphic form produce a highly ordered crystalline matrix¹⁸.

NLC Type III

NLC Type III, also known as the multiple types, is composed of oil, lipid, and water. This concept results in the formation of various NLC structures due to the higher solubility of lipophilic drugs in liquid lipids compared to solid lipids, especially when a high proportion of liquid lipid is used. Within the lipid matrix, small quantities of oil molecules are uniformly dispersed. However, when the amount of oil exceeds its solubility limit, phase separation occurs, leading to the formation of numerous Nano-sized oil compartments surrounded by a solid lipid matrix. The major advantages of Type II NLCs include high drug entrapment efficiency, controlled drug release, and reduced drug leakage¹⁹.

COMPOSITION OF NLCS

Nanostructured lipid carriers (NLCs) are composed of lipids, surfactants, and water, forming dispersion in an aqueous medium. Their particle size, drug loading efficiency, release behaviour, and stability are influenced by factors such as lipid concentration, lipid matrix composition, and the method of preparation. NLCs typically contain a mixture of long- and short-chain solid and liquid lipids, with total lipid content ranging from 5–40%. Surfactants are used to stabilize the formulation in the aqueous phase, usually at concentrations between 0.5–5% w/w.

The main components of NLC includes as follows,

1. Lipids
2. Surfactants
3. Other excipients

Lipids: Lipids play a vital role in nanostructured lipid carriers (NLCs) by influencing drug loading capacity, release duration, and overall formulation stability. The core of NLCs is composed of a combination of solid and liquid lipids. Ideally, these lipids should be physiologically compatible, biodegradable, non-toxic, and classified as generally recognized as safe (GRAS)²⁰.

Solid lipids: These lipids constitute the solid matrix of nanostructured lipid carriers. Commonly used solid lipids include glyceryl monostearate, stearic acid, cetyl alcohol, and hydrogenated lipids. The solid lipid matrix imparts structural integrity to the carrier and protects the encapsulated drug from degradation.

Liquid lipids: These lipids act as secondary components and are incorporated to create a liquid phase within the solid lipid matrix. Liquid lipids such as oleic acid, caprylic/capric triglycerides, and medium-chain triglycerides (MCT) enhance matrix fluidity and increase drug loading capacity. The presence of the liquid lipid phase improves matrix flexibility and promotes better drug solubility²¹.

Table 2: Lipids used in earlier studies and functions

Surfactants: The type and concentration of surfactants play a crucial role in determining the performance and stability of nanostructured lipid carriers and other nanolipid systems. Due to their amphiphilic nature, surfactants reduce interfacial tension between the lipid and aqueous phases and preferentially localize at the interface. Non-ionic emulsifiers, particularly Poloxamer 188, provide additional steric stabilization, thereby preventing particle aggregation in colloidal dispersions²².

Table No.3: Surfactants used in earlier studies and examples

Co-surfactant: Differential scanning calorimetry and static light scattering techniques are commonly employed to evaluate the influence of co-surfactants on the crystallization behaviour and physical stability of nanostructured lipid carriers. Studies have shown that the most effective co-surfactants are amphiphilic in nature, possessing both hydrophobic and hydrophilic domains. An optimal co-surfactant should contain a sufficiently large hydrophobic moiety along with high aqueous solubility, which ensures an adequate availability of molecules to efficiently stabilize the lipid–water interface²³.

Active pharmaceutical ingredient: The active pharmaceutical ingredient (API) is the primary therapeutic component incorporated into nanostructured lipid carriers (NLCs). NLCs can be designed to encapsulate both hydrophobic and hydrophilic drugs by appropriately modifying the lipid matrix. Hydrophobic drugs, which are generally lipophilic in nature, are particularly well suited for incorporation into NLCs, as these systems enhance drug encapsulation efficiency and enable controlled drug release. Examples of such drugs include chemotherapeutic agents, antifungal drugs, and anti-inflammatory agents such as ibuprofen and diclofenac.

Although NLCs are primarily developed for lipophilic drugs, hydrophilic drugs can also be successfully encapsulated by modifying the lipid matrix with suitable surfactants that improve drug solubility. Using this approach, hydrophilic drugs such as antibiotics and corticosteroids can be effectively incorporated into NLC formulations²¹.

Emulsifiers: Emulsifiers are essential for stabilizing lipid dispersions in nanostructured lipid carriers (NLCs). Hydrophilic emulsifiers such as Pluronic F68, polysorbates, polyvinyl alcohol, and sodium deoxycholate are commonly used, while lipophilic or amphiphilic emulsifiers like Span 80 and lecithin are employed when required. The use of combined emulsifiers has been shown to more effectively prevent particle aggregation.

Polyethylene glycol (PEG) may be added to NLCs to reduce uptake by the reticuloendothelial system and prolong drug circulation time. Preservation is also critical for NLC stability; however, some preservatives can adversely affect lipid dispersions. Hydrolite® 5 has been reported as a suitable preservative for coenzyme Q10–loaded NLCs without compromising stability²⁴.

ADVANTAGES OF NLC

1. High Drug Loading Capacity
   NLCs exhibit higher drug loading due to the presence of liquid lipids, which create an imperfect lipid matrix and prevent drug expulsion during storage.
2. Improved Stability
   The solid or semi-solid lipid matrix of NLCs provides better physical and chemical stability compared to emulsions and liposomes.
3. Controlled and Sustained Drug Release
   NLCs allow controlled and prolonged drug release, reducing dosing frequency and improving patient compliance.
4. Enhanced Bioavailability
   NLCs improve the bioavailability of poorly soluble drugs by increasing surface area, enhancing membrane interaction, and promoting lymphatic uptake.
5. Multiple Routes of Administration
   NLCs can be administered via oral, topical, ocular, pulmonary, and parenteral routes due to their biocompatible lipid composition.
6. Biocompatibility and Low Toxicity
   NLCs are prepared using biodegradable and GRAS-approved lipids, resulting in minimal toxicity    and suitability for long-term use.
7. Targeted Drug Delivery Potential
   Surface modification of NLCs enables site-specific targeting, improving therapeutic efficacy and reducing systemic side effects.
8. Scalable and Cost-Effective Production
   NLCs can be easily scaled up using established manufacturing methods and economical lipid materials²¹.

DISADVANTAGES OF NLC

• Although improved compared to SLNs, nanostructured lipid carriers may still show limited drug loading for certain drugs with poor lipid solubility.
• NLC dispersions can undergo gelation during storage under unfavourable conditions, affecting their physical stability.
• Long-term storage may induce lipid polymorphic transitions, which can potentially result in partial drug expulsion from the lipid matrix²⁵.
• The biocompatibility of NLCs may be influenced by the type of lipid matrix employed and the concentration of the formulation, which can lead to cytotoxic effects at higher doses.
• Certain surfactants used for NLC stabilization may cause skin or tissue irritation and sensitization, particularly at elevated concentrations or with repeated exposure.

METHOD OF PREPARATION

Fig. 4: Methods of Preparation of (NLCs)²⁶.

1. High pressure homogenization technique

High-pressure homogenization (HPH) is one of the most widely used techniques for the preparation of nanostructured lipid carriers. In this method, the lipid phase containing a mixture of solid and liquid lipids along with the drug is dispersed into an aqueous surfactant phase and subjected to high pressure. The intense mechanical forces generated during homogenization, such as shear stress, cavitation, and turbulence, lead to the breakdown of lipid droplets into Nano sized particles, resulting in stable NLC dispersions. Advances in nanotechnology and a better understanding of fluid dynamics have significantly improved high-pressure homogenizer design, enhancing processing efficiency, reproducibility, and scalability. This technique enables precise control over particle size, size distribution, and physical stability of NLCs. Therefore, high-pressure homogenization plays a crucial role in particle engineering and is extensively applied in the formulation of nanostructured lipid carriers for pharmaceutical drug delivery²⁷.

Fig. 5: High pressure homogenization technique²⁸.

2. Hot homogenization technique

In the hot homogenization technique, the lipid phase containing the drug is heated above its melting point and mixed with an aqueous surfactant solution maintained at the same temperature. High-shear mixing is used to form a hot oil-in-water pre-emulsion, which is then processed by high-pressure homogenization at 500–1,500 bar for several cycles to obtain a Nano emulsion. During homogenization, temperature rise may occur, and excessive pressure or cycles can increase particle size. Upon cooling to room temperature, lipid recrystallization takes place, leading to the formation of nanostructured lipid carriers²⁹.

3. Cold homogenization technique

In the cold homogenization technique, the drug is first incorporated into the molten lipid phase, similar to hot homogenization. The lipid melt is then rapidly cooled using liquid nitrogen or dry ice, resulting in solidification of the lipid mass. This solidified lipid is subsequently ground to obtain micro particles, which are dispersed in a cold aqueous surfactant solution to form a pre-suspension. High-pressure homogenization is then performed at or near room temperature, leading to size reduction and formation of nanostructured lipid carriers. This technique was developed to overcome the limitations associated with hot homogenization, particularly drug degradation and redistribution at elevated temperatures³⁰.

Fig. 6: Hot homogenization and cold homogenization technique.

4. Micro emulsion technique

In this method, the lipid phase is melted and the drug is incorporated into the molten lipid. An aqueous phase containing surfactant and co-surfactant is heated to the same temperature as the lipid melt and then added under gentle stirring. When appropriate ratios of lipid, surfactant, co-surfactant, and water are used, a clear and thermodynamically stable micro emulsion is formed, which serves as the precursor for nanoparticle formation. The hot micro emulsion is subsequently dispersed into a cold aqueous medium under mild mechanical stirring, typically at a dilution ratio of 1:25–1:50. This rapid cooling induces recrystallization of the lipid droplets, resulting in the formation of nanostructured lipid carriers.

Commonly used surfactants and co-surfactants include lecithin and bile salts, often combined with short-chain alcohols such as butanol; however, the use of such alcohols is limited due to regulatory concerns. For large-scale production, the micro emulsion is prepared in a temperature-controlled vessel and then transferred into a cold aqueous phase to facilitate nanoparticle precipitation³¹.

5. Solvent evaporation

In this technique, the drug and lipids are dissolved in a water-immiscible organic solvent and emulsified in an aqueous phase using ultrasonication or high-shear homogenization. The organic solvent is removed under reduced pressure (40–60 mbar), resulting in the formation of nanostructured lipid carriers. This method is suitable for heat-sensitive drugs; however, residual solvent traces and the need for additional filtration may limit large-scale application and reduce product yield³².

Fig. 7: Solvent evaporation technique.

6. Solvent injection technique

The solvent injection method is an effective technique for preparing nanostructured lipid carriers. In this approach, lipids are dissolved in a water-miscible organic solvent, such as acetone, ethanol, methanol, or isopropyl alcohol. The lipid solution is rapidly injected into an aqueous surfactant solution under continuous stirring, causing the spontaneous formation of lipid nanoparticles. The resulting dispersion is then filtered to remove any excess lipids. Nanoparticle formation occurs due to the fast diffusion of the organic solvent into the aqueous phase, with particle size primarily determined by the solvent diffusion rate. This method is simple, versatile, efficient, and does not require sophisticated equipment, while using pharmaceutically acceptable solvents³³.

7. Phase inversion technique

In this method, nanostructured lipid carriers are prepared by repeated phase inversion processes, during which emulsion interfacial properties are optimized. The resulting NLCs consist of a liquid lipid core surrounded by a cohesive interfacial layer and are stably dispersed in an aqueous medium. Particle size and morphology are characterized using photon correlation spectroscopy, AFM, and TEM, while thermal behaviour is evaluated by DSC. The formulation parameters allow precise control of particle size in the range of 25–100 nm with a narrow, monodisperse distribution and good stability upon dilution³⁴.

Fig. 8: Phase inversion technique³⁵.

8. Ultrasonic homogenization technique

In this method, lipophilic drugs are uniformly dispersed or dissolved in a molten blend of solid and liquid lipids. The lipid melt is then added to a heated aqueous phase containing surfactant and mixed under continuous stirring to form a pre-emulsion. The processing temperature is typically maintained at 5–10 °C above the melting point of the solid lipid to ensure complete melting. The pre-emulsion is subsequently subjected to ultrasonic homogenization, resulting in the formation of a fine microemulsion. Upon cooling and solidification of the lipid phase, nanostructured lipid carriers are formed³⁶.

Fig. 9: Ultrasonic Homogenization technique.