Lipid-Based Nanocarrier Systems: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Mohammad Sameer Khan
,
Sradhanjali Mohapatra
,
Vaibhav Gupta
,
Ahsan Ali
,
Punnoth Poonkuzhi Naseef
,
Mohamed Saheer Kurunian
,
Abdulkhaliq Ali F. Alshadidi
,
Md Shamsher Alam
,
Mohd. Aamir Mirza
,
Zeenat Iqbal

Nanotechnology-based tools have played a major role in this. The implementation of this multifaceted nanotechnology concept encourages the advancement of innovative strategies and materials for improving patient compliance.

  • biological barriers
  • drug delivery
  • lipid-based nanocarriers
  • solid lipid nanoparticles (SLN)

1. Liposome

Liposomes are small, spherical vesicles that contain natural or synthetic non-toxic phospholipids as their key ingredients. They have an aqueous core surrounded by a hydrophobic lipid bilayer membrane in such a way that the hydrophilic solutes dissolved in the core cannot readily pass through the bilayer. Both hydrophilic and hydrophobic molecules can be loaded in liposomal vesicles and hence can be used for drug delivery. The liposomes can be classified as unilamellar vesicles (having one bilayer membrane), oligo lamellar vesicles (having 2–5 bilayer membranes) and multilamellar vesicles (having 5 or more bilayer membranes). Unilamellar vesicles are further subdivided into three categories that include small unilamellar vesicles, large unilamellar vesicles and giant lamellar vesicles. Among these, unilamellar vesicles are mostly used in drug delivery because of their small size (e.g., nanosized range), uniform drug capsulation and they release kinetics together with long circulation times [1]. The distribution of these molecules to the site of action occurs by the fusion of lipid bilayers with the cell membrane, thus delivering the liposomal contents [1]. Liposomes can be fabricated by the thin-film method, detergent removal method, pro-liposome method, solvent injections method, reverse phase evaporation method and emulsification method, etc. [2]. Occasionally, post-formation processing is employed to further reduce the size of the vesicles to achieve specific objectives. Sonication, high-pressure homogenization and extrusion are the most widely used methods that are used for post-formation downsizing of the vesicles in this liposome formulation approach [3]. Currently, novel technologies such as lyophilization, supercritical fluid-assisted technology, microfluidic, membrane contactor methods, etc. are employed to avoid the critical issues related to traditional methods [3]. The advantages of liposomes include their biocompatibility, biodegradability, drug delivery specifically to sensitive tissues, their flexibility to couple with site-specific ligands for achieving active targeting and their improved stability owing to encapsulation, etc. However, their low solubility, short half-life, high production cost, poor stability, etc. are a few of the disadvantages associated with them [4].
The majority of the conventional liposomes are restricted to the first layer of the epidermis and are unable to reach systemic circulation. Hence, they are restricted to use in local dermal drug delivery and demand new classes of nano lipid vesicles for enhancing flexibility and skin permeation. However, in the case of the brain, the interstitium is dense and highly charged, thus restricting the movement of many classes of nanocarriers within the CNS. This issue can be circumvented by liposomes with surface modifications that mask the particle charge, thus allowing for more uniform brain penetration. Secondly, the modification of nanocarriers with targeting moiety can enhance retention in a diseased site. Therefore, the disrupted BBB can be targeted with liposomes that are specifically formulated for penetration and retention at the diseased location [5].
Liposomal formulations can be further categorized into (1) rigid vesicles (liposomes and niosomes) and (2) elastic or ultra-deformable vesicles (transferosomes and ethosomes). Their composition, structure and preparation methods are more or less similar; however, their differences relate to their deformability and mechanism of penetration through the skin [6].

2. Niosomes

These are non-ionic surfactant vesicles composed of single-chain surfactant molecules in combination with cholesterol. These surfactants form an enclosed bilayer in a water medium. The presence of surfactant alters the permeation through biological barriers and makes it more penetrable with enhanced systemic absorption. These systems are capable of carrying both lipophilic and hydrophilic drugs and comparatively more stable than traditional liposomes [7]. They offer better drug concentrations at the site of action administered by several routes such as parenteral, oral and topical. Drugs with a low therapeutic index and low water solubility can be utilized for sustained action through these delivery systems, but simultaneously they have problems like clustering, fusion and leaking. Sonication, micro fluidization, thin-film hydration, reverse phase evaporation, ether injection, trans-membrane pH gradient drug uptake (remote loading) and multiple membrane extrusion are various methods used for preparing these vesicles [8][9][10].
Niosomes can penetrate into the skin by adsorption onto the cell surface with little or no internalization of either aqueous or lipid components. It may take place either as a result of attracting physical forces or as a result of binding by specific receptors to ligands on the vesicle membrane, thus transferring the drug directly from vesicles to the skin. Further, niosomes may fuse with the cell membrane, resulting in the complete mixing of the niosomal contents with the cytoplasm. Lastly, niosomes may undergo endocytosis, with lysozymes present in the cytoplasm degrading the membranous structure of the niosome, thereby releasing the entrapped material into the medium vehicle, which can be achieved by forming a niosomal gel [11]. Niosomes have also the capability to overcome the BBB and access drug delivery to the brain by surface modification. They improve the therapeutic performance of the drug by surface modification and limiting the effects to target cells, thus decreasing the clearance of the drug [12].

3. Ethosome

These are non-invasive, phospholipid-containing nano lipid carriers that are more efficient at delivering drug molecules into the skin in terms of both the quantity and depth as compared to the other vesicles. They are mainly composed of lipids, ethanol and water. The percentage of ethanol in this vesicular system has been reported to be in the range of 10–50% [13][14]. It has been investigated that with an increase in ethanol concentration in this range, the vesicular size decreases [15][16]. These vesicle systems differ from liposomes as they include high concentrations of ethanol [17]. The mechanism of penetration of the ethosomes involves two concurrent mechanisms, which include the effect of ethanol and ethosomal vesicles on the stratum corneum lipid bilayer that will enhance the delivery of molecules through the skin [18].
These can be prepared by four principal methods including the cold method; hot method; classic method; and mechanical dispersion method [18][19]. These are relatively safe, biocompatible and friendly carriers used to deliver large molecules through the skin with an enhanced permeation and good therapeutic index. They have a large market share in the pharmaceutical, veterinary and cosmetic fields. On the other hand, they are limited only to potent molecules that require high blood levels; they are not a means to achieve rapid bolus-type drug input, rather they are usually designed to offer slow, sustained drug delivery; drugs having an adequate solubility in both lipid and aqueous environments are capable of reaching dermal microcirculation and gain access to the systemic circulation [18][20].
The enhanced delivery of drugs through ethosomes may be ascribed to an interaction between ethosomes and skin lipids. The presence of ethanol interacts with the polar heads of the lipid molecules, resulting in a reduction in the transition temperature of the lipids present in the stratum corneum, thus improving their fluidity and reducing the density of the lipid layers [20][21][22]. This is followed by the fusion of ethosomes to the skin lipids which results in their penetration and permeation by the opening of new pathways. This is mainly due to the malleability and fusion of ethosomes on the skin lipids which results in the permeation of the drug into the deep layers of the skin. The presence of ethanol makes the vesicles soft and flexible, which allows them to penetrate more easily into the deeper layers of the skin and results in systemic absorption [23].

4. Transethosome

Transethosomes are a combination of transferosomes and ethosomes. Transferosomes are composed of phospholipids and an edge activator (single-chain surfactant) that weakens the lipid bilayers and increases their deformability by reducing the interfacial tension. These have a deformable quality as well as a skin permeation capability and can be taken up by systemic as well as topical routes. Ethanol is a central character of transethosomal systems, giving a unique identity to them as a vesicular system. It is believed that the first part of the mechanism is due to the “ethanol effect”, whereby the intercalation of the ethanol into intercellular lipids increases lipid fluidity and decreases the density of the lipid bilayer. The lipid layer of the stratum corneum is fluidized by the impact of ethanol and its high concentration in transethosomes promotes the malleability and flexibility of these systems, enhancing their penetration through tiny openings formed in the stratum corneum due to fluidization. The presence of the alcohol amount in the vesicular system also controls its diameter, as it provides a net negative charge to the vesicle surface by reducing its size [24]. Transethosomes can be prepared by various methods such as ethanol injection, the thin-layer hydration method, cold, direct and reverse-phase evaporation methods [25]. Transethosomes are stable, non-invasive vesicles having a high patient compliance as they can be administered in semisolid dosage forms such as gels, creams, lotions, etc. On the other hand, they cause occasional skin irritation and other allergic reactions as ethanol is used in their formulation.

5. Solid Lipid Nanoparticles (SLNs)

SLNs are one of the novel carriers in the pharmaceutical industry for the delivery of multiple drugs [26][27]. SLNs are generally spherical in shape, whose size ranges from 100 nm to 1000 nm. The central portion of the SLNs is made up of lipid (solid-state) which is well stabilized by the emulsifiers encapsulating the lipidic molecules in a stable lipid matrix [28]. SLNs can be prepared with different techniques such as high shear homogenization and ultrasound, solvent emulsification, solvent evaporation and microemulsion [29]. The advantages of SLNs include improved skin penetration, prolonged release of the drug from formulation that takes place owing to erosion of the lipid matrix or by degradation due to the enzymatic action, enhanced bioavailability, minimal drug absorption in blood vessels and high storage stability. The limitations can be listed as: the wastage of drugs while in fabrication, small loading capacity specifically for hydrophilic or polar molecules, the chance of drug expulsion from the lipid matrix as a result of polymorphic conversion while in storage, the inability to show robust release patterns and poor knowledge about clinical safety [30].

6. Nanostructured Lipid Carriers (NLCs)

NLCs emerged as the second generation nano lipid carriers to surmount the limitations of first generation nanocarriers. NLCs are nanocarrier systems derived from oil-in-water-type nanoemulsions. They are composed of lipids (physiological and biocompatible lipids), water and emulsifying agents/surfactants/co-surfactants. These are formulated by mixing solid lipids with small amounts of liquid lipids, which results in the rearrangement of the matrix structure. The components used in formulating the NLCs include oils (cetiol V, coconut oil), solid lipids (beeswax, palmitic acid, etc.), counter-ions (sodium hexadecyl phosphate, monodecyl phosphate) and emulsifying agents (egg lecithin, polyvinyl alcohol, etc.) [31]. NLCs and SLNs can be distinguished depending on this composition, i.e., if they have only solid lipids, they are called SLNs and when they have both solid and liquid lipids they are called as NLCs. Furthermore, due to the presence of a mixture of both lipids, a more amorphous structure is found which results in an improved loading capacity for lipophilic drugs as compared to SLNs. These can be easily prepared by three major techniques, which are the solvent-emulsification diffusion technique; double emulsion technique; and membrane contactor technique [31].
The advantages of NLCs can be listed as: a decreased polymorphic transition, little crystalline index, enhanced encapsulation efficiency, drug loading, physical stability, chemical stability and bioavailability, with the controlled release of the encapsulated components. Moreover, they can be altered with various targeting ligands such as peptides, antibodies or even small targeting moieties. Comparatively, the disadvantages include the irritation and sensitizing action of the surfactants; cytotoxic effects related to the nature of the lipid matrix and concentration; and the efficiency in the case of proteins, peptide drugs and gene delivery systems that need to be exploited [32]. Both SLNs and NLCs are considered suitable delivery systems for both skin and CNS distribution because of their aforementioned properties [33]. It is worth noting that NLCs have superior formulation properties (relatively more potent in controlling drug release and stability) over SLNs [30][34].
Both SLNs or NLCs having a particle size of less than 200 nm show good adhesiveness over the skin by forming a monolayer. This hydrophobic monolayer film exhibits occlusive action on the skin and hinders the loss of moisture owing to evaporation. This results in a reduction in the corneocyte packing and the opening of inter-corneocyte gaps, hence facilitating drug penetration into the deeper layers of the skin. The loss of water content from the SLN induces crystal modification of the SLN matrix and this can induce drug expulsion and penetration [35]. Moreover, the mechanism behind the enhanced drug bioavailability through the BBB could be explained by the surface modification of the SLN with Pluronic F-68. This results in a steric hindrance, which would further reduce the adsorption of opsonin onto SLN in the plasma therefore decreasing the RES uptake and delaying the plasma retention time. Further, a high load of SLN results in a higher concentration gradient at the brain capillary, resulting in enhanced transport across the brain endothelium following endocytosis and drug release [36].

7. Lipid Nanoemulsion (LNEs)

This has an oil-like lipid matrix and is usually prepared by incorporating drugs in the internal oil phase or at the interface of oil–water [37]. Thus, drugs with poor aqueous solubility can be loaded into the interior oil phase of a nanoemulsion, thereby reducing the hydrolytic reaction. These consist of submicron-sized lipid droplets, stabilized by surfactants that prevent accumulation and coalescence in an aqueous solution. LNEs can be prepared mainly by two broad techniques including high-energy methods (involving ultrasonication and high-pressure homogenization) and low-energy methods (involving phase inversion temperature and emulsion inversion point) [38]. LNEs were previously used for intravenously administered nutrients without having a drug carrier function, consisting mostly of plant-based lipid droplets with an average size of less than 500 nm [39]. These also serve as carriers for anaesthetic drugs, cancer therapeutics and vitamins and find applications in the pharma, cosmetics and food industries [40]. Homogenized milk and plant-based milk products can partly be considered as LNEs with additional protein ingredients.
These are also good vehicles for drug administration through the skin. LNEs are used to augment physicochemical properties that are desirable for transdermal drug delivery systems. They can enhance adhesiveness and hydration when they are applied over the skin. Nanosized fragments are able to form a thin film on the skin surface, thus enhancing the pore obstruction and hence reducing the water evaporation from the skin by maintaining skin hydration. LNEs are used for improving drug absorption through the skin, providing protection from degradation through the oral route, reducing irritation and offering a sustained release action [41][42]. These are also a promising system for delivering drugs directly into the brain (CNS targeting) through the intranasal route. Small (nano) droplets with a high surface area make them suitable for nose-to-brain delivery by avoiding the BBB. The possible mechanism for the transportation of drugs can be explained as transcytosis/endocytosis of the droplets by the brain endothelial cells through the nose. However, the presence of surfactant(s) in the formulation could have a fluidizing action on endothelial cell membranes, leading to improved drug permeability [43].
On the other hand, these have many factors that limit their uses, such as the use of ultrasounds or high-pressure homogenizers, the use of high concentrations of emulsifier, expensive production, the lack of knowledge about the mechanisms that affect and cause problems during their production (Ostwald ripening, i.e., the oil diffusion in the aqueous phase), etc. [44].

8. Microemulsion

Microemulsions are transparent, thermodynamically stable, colloidal drug carrier systems consisting of isotropic mixtures of oil, water and surfactant, often in combination with a cosurfactant. Usually, they have a droplet size of less than 100 nm and hence cannot be seen by the naked eye. Although microemulsions and nanoemulsions are completely different systems from the thermodynamic point of view, the size of the microemulsion may create confusion with a nanoemulsion. Microemulsions have a simple fabrication method, good stability, increased solubilization and bioavailability with a reduced cost which makes them suitable for practical applications [45]. They have the capability to incorporate both hydrophilic and lipophilic drugs which makes them advantageous over other delivery systems. They offer good solubilizing properties and improved drug permeation through biological membranes. Currently, these dispersions are used to deliver the drug through the skin and nasal membrane to reach blood and brains respectively [46][47][48]. Further, the smaller size of microemulsions can make their sterilization easy with a simple filtration method. Three distinct microemulsion systems that can be used in the pharmaceutical industry for drugs are oil in water, water in oil and bi-continuous microemulsions.
Microemulsions act as potential drug delivery systems through biological membranes. The efficacy of a microemulsion can be related to the improved solubilization as compared to conventional dosage forms. Further, the specific composition of microemulsions and the presence of surfactants and co-surfactants (may act as co-solvents for poor water-soluble drugs) can interact with the stratum corneum (as permeation enhancers) and enable the penetration of active ingredients through the skin [49][50][51]. Additionally, in the case of O/W microemulsions, oil droplets incorporating drugs can act as a reservoir, thus maintaining a high concentration gradient between the biological membrane and the applied formulation. The water causes increased hydration of the stratum corneum, thus improving the permeability [52].

This entry is adapted from the peer-reviewed paper 10.3390/membranes13030343

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