Lipid Nanoparticulate Drug Delivery Systems: Approaches toward Improvement in Therapeutic Efficacy of Bioactive Molecules

Abstract

Hybrid lipid polymers significantly changed the postulation of low or less bioavailability of conventional drug delivery systems. Several drug delivery systems already exist for the encapsulation and subsequent release of lipophilic drugs with enhanced therapeutic efficacy and are well described in the scientific literature. Among these, lipid polymer-based nanoparticles have specifically come up for dermal, transdermal, mucosal, intramuscular, and ocular drug administration routes in the last 20 years. Moreover, lipid nanoparticles showed potential for active targeting of anticancer therapy, delivery of DNA or RNA materials, and use as a diagnostic imaging agent. Therefore, the multifarious nanostructured lipid carriers can reduce the undesired effects with maximum utilization of active moiety. In this, chapter a brief discussion is presented on the source of synthetic and natural lipid polymers with the use of surfactants. Moreover, a summary on formulation and pharmaceutical characterization of nanostructured lipid carriers considering solid lipid nanoparticles and vesicular drug delivery systems has been taken into consideration. In addition, a light on bioactive fortified with lipid nanoparticles was reviewed for maximizing its therapeutic efficacy. Furthermore, this chapter’s focus to bring out the latest applications via recent scientific publications from the Scopus database on nanostructure carriers that showed promising application for the treatments of potentially life-threatening diseases has been summarized.

1. Introduction

Nanomedicine is still considered an emerging and effective formulations technique due to the fusion of nanotechnology and medicine, which is one of the most promising ways to develop effective targeted therapies. Several active pharmaceuticals fail to demonstrate the therapeutic efficacy when delivered in conventional dosage forms, which is directly or indirectly linked to their biopharmaceutical classification and hydrophobic nature. Moreover, such poor water-soluble active moiety represents several challenges: low or reduced oral bioavailability, topical permeability, therapeutic efficacy, etc. Nanoparticulate drug delivery systems comprise a wide variety of dosage forms including nanospheres, micelles, solid lipid nanoparticles, nanoliposomes, dendrimers, magnetic nanoparticles, and nanocapsules (Figure 1). Lipid nanostructure carriers such as solid lipid nanoparticles (SLNs), vesicular drug delivery system (VDDs), and or nanostructure lipid carriers (NLCs) significantly gained attention among the scientific community due to several advantages including low cost of scale-up with prolonged stability [1]. There are several carriers employed in the delivery of available drugs as an alternative to conventional drug delivery systems such as drug-lipid conjugate, lipid nanocapsules, layersomes, and lipid-polymer nanohybrids. Solid lipid nanoparticles were developed to overcome the limitations of other colloidal carriers, such as emulsions, suspensions, and polymeric nanoparticles due to the effective release mechanism and targeted delivery with physical stability [2]. Nano lipid carriers are modified versions of SLNs that improve the stability and drug loading efficacy. In addition, the potential applications of LNs in drug delivery fabrication, research, topical cosmetics, and clinical medicine indicates its efficacy. These carrier systems are mainly composed of physiologically compatible and biodegradable lipid materials, surfactants, and co-surfactants that are generally recognized as safe (GRAS) by food and drug admirations [3].

Figure 1.

Various carrier-based polymeric drug delivery systems including polymeric nanoparticle (a), polymeric micelles (b), metallic nanoparticles (c), dendrimer (d), quantum dot (e), liposome (f), solid lipid nanoparticles (g), nanostructure lipid nanoparticle (h), carbon nanotube (i), antibody-drug conjugate (j), exosome (k). Polymeric nanoparticles are particles within the size range from 1 to 1000 nm and can be loaded with active drugs entrapped within or adsorbed on the surface. Polymeric micelles are nanoscopic core or shell structures formed by amphiphilic block copolymers. Metallic nanoparticles are submicron-scale entities fabricated by reduction using synthetic or green materials. Dendrimers are a class of synthetic polymers with a structure of repeatedly branching chains, typically forming spherical macromolecules. A quantum dot is a nanoscale particle of semiconducting materials that can be embedded in cells or organisms for various experimental purposes, such as labeling proteins. A liposome is a spherical vesicle having at least one lipid bilayer that can carry drugs to deliver at the targeted site within the body. Solid lipid nanoparticles or lipid nanostructure carriers are nanoparticles composed of lipids. Carbon nanotubes are tubes made of carbon with diameters typically measured in nanometers. An antibody-drug conjugate is a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Whereas, exosomes are a class of cell-derived extracellular vesicles of endosomal origin, and are typically 30–150 nm in diameter.

Vesicles-based drug delivery was the first among the different LNs targeted carrier formulations discovered in 1965 and is still widely accepted in the fabrication of novel pharmaceutical formulations [4]. The word liposome is derived from the Greek words “lipid” which means fat and “soma” which means body. Liposomes are spherical vesicles with a hydrophobic internal sac-like structure enclosed with a lipid bilayer membrane. Moreover, several advantages associated with VDDs include low toxicity, flexibility, cyto-compatibility, biodegradable, protection of active moiety from enzymatic degradation, and non-immunogenicity [5, 6, 7]. However, most of the uses in formulations indicate limitations due to specific disadvantages such as low encapsulation efficacy, poor stability, limited shelf-life, and intermembrane transfer [8].

Solid lipid nanoparticles were introduced in the late 90,s as a potential substitute against the carrier-based VDD, emulsion, and polymeric nanoparticles. These carrier-based nanoparticulate offers advantages of spherical size (40–1000 nm), shape, and morphology, composed of single or multiple combined lipids with surfactants, where the dispersed phase is solid lipid fats and surfactant, which act as an emulsifier [9]. The selection and composition of lipid and surfactant affect the physicochemical properties and quality such as drug loading and particle size. The proper combination of lipids and surfactants used in the fabrication of solid lipid nanoparticles demonstrate excellent drug stability and prolonged release compared with VDDs and other polymeric carriers due to the evasion of organic solvent in their fabrication. However, associated disadvantages such as the formation of the crystalline structure of lipids due to inherent low incorporation rates and unpredictable gelation tendency [10, 11].

Nanocapsules have been one of the most widely studied nanosystems for the delivery of functional compounds. Moreover, nanocapsules are also known as nanoparticulate in food science constituted as external polymeric membrane and inner part composed of polymeric matrix containing bioactive compounds. Furthermore, nano-encapsulation involves the incorporation, absorption, or scattering of combinations of bioactive solid, liquid, or gas into small vesicles with nanometer-scale diameters. However, lipid nanocapsules are defined as nanovesicular delivery systems with a core-shell structure consisting of polymeric membrane or coating and target active moiety formulation added within the cavity. Moreover, lipid nanocapsules are considered as a sandwich of liposome and nanoemulsion. In addition, nanocapsules have functional properties that are maintained by encapsulation in simple solutions, colloids, emulsions, and biopolymers in food. Lipid nanocapsules are submicron particles with a broader surface area and size below the endothelium fenestration (>100 nm) that present advantages compared to multi-lamellar liposomes, especially with prolonged stability up to 18 months. Thus the lower size of lipid nanocapsules increases the transparency of solution when utilized in clear liquids such as beverages and sauces. Additionally, these lipid carriers can encapsulate efficiently lipophilic drugs, which is a much-needed feature for pharmaceutical colloidal formulations. This chapter presents an overview of the various LNs materials as a potential carrier for the delivery of poorly water-soluble drugs with enhanced therapeutic efficacy. Furthermore, a brief on various fabrication and characterization techniques involved with VDDs and SLNs with their prospect and market challenges concerning the stability. Figures 2 and 3 indicates the yearly trends of publication for retrieved data from the Scopus database system on keywords “nanocarriers*”.

Figure 2.

Total number of publications on LNs from 1936 to 2021 exported from the SCOPUS database on 2 March 2022.

Figure 3.

Total number of publications on lipid nanocarriers subject-wise from 1936 to 2021 exported from the SCOPUS database on 2 March 2022 (for interpretation of the results to color in this figure legend, the reader referred to the web version of this chapter or color print).

2. Lipids and surfactants

Lipids fulfill various functions in life as membrane constituents, for energy storage, or signaling molecules. Lipids are structurally and functionally diverse organic compounds including fats, oil, and hormones that do not interact appreciably and are insoluble in polar solvents [12]. Lipids are hydrophobic and some of them are amphipathic, which represent a part as hydrophilic and another as hydrophobic. These amphipathic lipids demonstrate a unique behavior in water that spontaneously form ordered molecular aggregates with their hydrophilic ends on the outside, in contact with the water, and their hydrophobic part on the inside, shielded from the water. Though biological lipids are similar in chemical linking to polymeric materials used for the delivery of active moiety, however they are not large macromolecules. Lipids are classified in several ways and among them, the major groups classified are fatty acids, fatty acid derivatives, cholesterol, and their derivatives, with lipoproteins. The fatty acids are available in abundant in complexed with fats and phospholipids (Figure 4). Fatty acids are also known as carboxylic acids composed of a hydrocarbon chain linked with one terminal of the carboxylic group. However, the fragment of a carboxylic acid lacks a hydroxyl group, known as the acyl group. Moreover, fatty acids in the aqueous phase of physiological condition lose a hydrogen ion (H⁺) to generate an anionic charged carboxylate group (COO⁻) and due to a common biosynthetic pathway within the organism, which involves the linking of the two-carbon unit together produces an even number of carbon atoms within fatty acids [13]. These fatty acid lipids are further classified as saturated, unsaturated, monosaturated (MUFA), and polyunsaturated fatty acids (PUFA). The saturated fatty acids specify the bonding of the maximum possible numbers of hydrogen atoms to each carbon in the molecules. Whereas, unsaturated fatty acids indicate one or more double-bonded carbon–carbon molecules. The number of double bonds attributes to mon or polyunsaturated molecules with one double bond and two or more double bonds, respectively. Common saturated and unsaturated fatty acids are lauric acids, myristic acids, palmitic acids, stearic acid, behenic acid, lignoceric acid and palmitoleic acid, oleic acid, gadoleic acid, erucic acid, and nervonic acid, respectively [14]. Furthermore, frequently polyunsaturated fatty acids used are linoleic acid, linolenic acid, and arachidonic acids. Fatty acids are alternatively also obtained from the hydrolysis of hard animal fats, coconut, palm kernel, soybean oils, and from the fractional distillation of crude tall oil. Other fatty acids are derived from petroleum. Physically, most of these fatty acids are liquid at room temperature. The difference in properties is to a large extent related to the presence of saturation and unsaturation within the molecules. Commonly, solid fats are indicated by the dominance of saturated fatty acids and liquid oils are indications of a high level of unsaturated fatty acids [15]. Cholesterol in the free and combined state is the most widely occurring sterol in animal tissue. It is an essential compound in the body’s production of steroids hormones and bile. It is also an important component for normal skin function. Cholesterol is an important functional excipient used in several pharmaceutical formulations including solid lipid nanoparticles, parenteral mRNA–based drug delivery, vesicular drug delivery, etc. As a part of lipid coating that protects the active drug moiety, and could modulate drug release, enhance the ability of the drug formulation to penetrate cell membranes, and provide a stabilization effect. Recently plant-derived cholesterol including Phytochol^®, SyntheChol^®, etc., gained significant attention among the researcher due to multifunctional application with lower adverse effects. Lipoproteins are substances made of proteins and fat that carry cholesterol through the bloodstream. Moreover, lipoproteins are complex particles that have a central hydrophobic core of non-polar lipids, primarily cholesterol, ester, and triglycerides [16]. This hydrophobic core is surrounded by a hydrophobic membrane consisting of phospholipids, free cholesterol, and apolipoprotein. Additionally, lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid molecules in water, as in blood plasma or other extracellular fluid. The lipoproteins are broadly classified into several classes, however cholesterol is broadly classified into two categories based on lipoproteins such as high-density lipoprotein (HDL) and low-density lipoprotein (LDL) (Table 1). High-density lipoproteins are generally assumed as “good” and low density as “bad” cholesterol [18].

Figure 4.

Fatty acids and their derivatives.

Lipoprotein	Density (g/ml)	Size (nm)	Lipoprotein	Density (g/ml)	Size (nm)
Chylomicrons	<0.930	75–1200	LDL	1.019–1.063	18–25
Chylomicron remnants	0.930–1.006	30–80	HDL	1.063–1.210	5–12
VLDL	0.930–1.006	30–80	Lp (a)	1.055–1.085	~30
IDL	1.006–1.019	25–35

Table 1.

Classification of lipoproteins [17].

Surfactants have been diligently associated with humans as early as 2800 BC and continue to be a necessity in day-to-day life with great usage in solubility and entrapment efficacy of drugs used within nanocarriers. The earliest record on the usage of surfactant was recorded as sopay traces in clay cylinders at the Babylonian archeological site in Mesopotamia in 2800 BC [19, 20]. The word “Surfactant” is an abbreviation for “surface-active agent”, classified as an amphiphilic compound due to the presence of both hydrophilic and hydrophobic groups. Considering hydrophilic group surfactants are broadly classified into four categories such as cationic, anionic, zwitterionic, and non-ionic surfactants. Cationic surfactants contain alkylamine or quaternary ammonium salts that can be absorbed on the negatively charged interface, with the antistatic and disinfectant application. Anionic surfactants contain carboxylic acids salts, sulfonates, sulfate salts, sulfate esters, or phosphate within hydrophobic groups, that offers detergency, foaming, and penetrability use. Zwitterion surfactants contain carboxy betaine, imidazolium betaine, amino ethyl glycine salt, or amine oxide within the hydrophobic structure. They are often used as auxiliary materials to enhance the effectiveness of other surfactants. Non-ionic surfactants have non-dissociable chemical structures in their hydrophilic groups, which are generally used in cosmetics, food emulsifiers, and skin cleaners due to low irritation and toxicity. A wide range of spontaneous, self-assembling surfactants structures in the size range spanning from a few nanometers to tens of micrometers has been reported. Moreover, the role of surfactants in the fabrication of nanocarriers has been proven in various aspects including drug loading, colloidal suspension stability, and most important formulation stability on long-term storage. The percentage instances for different surfactants found in the compositions of the investigational bioactive incorporated dosage form are presented in Figure 5.

Figure 5.

Percentage of instances for different surfactants found in the composition of the investigational bioactive incorporated dosage form [21].

3. Formulation and characterization techniques involved in lipids-based vesicles and nanoparticles

A general method used in the fabrication of VDDs involves the dissolution of the single or mixture of lipids with surfactants, followed by drying the lipid film, and then dispersion of film in an aqueous medium to obtain a multilamellar vesicular system at required hydration temperature. The hydrating temperature used in the formulation of the VDDs should be always above the phase transition temperature of the lipid used. Later developed multilamellar vesicular systems are further processed to obtained small, stable vesicles [22]. The method of preparation of vesicular systems is broadly classified into three basic modes of dispersions such as physical dispersion involving handshaking and non-hand shaking technique (i), solvent dispersion including ethanol injection, ether injection, double emulsion, reverse phase evaporation, and stable plurilamellar vesicle method (ii), and detergent solubilization (iii). Transferosomes and ethosomes were introduced as VDDs for localized and targeted administration of low or less permeable drugs through the skin, which requires the addition of permeation enhancer, however progression in the research reported that the incorporation of surfactant as edge activator within vesicles can significantly improve the penetration and drug loading capacity. The pharmaceutical characterization involves the determination of size, shape, and size distribution, surface charge, entrapment efficacy, dispersibility, syringeability, lamellarity through freeze-fracture microscopy, phase behaviors, in vitro – in vivo drug release, quantitative determination of phospholipid, and cholesterol quantification. Moreover, vesicles fortified in target or localized drug delivery systems are also evaluated for their efficacy including stability, esthetic property, etc. [23]. Table 2 represents the various types of VDDs with their therapeutic applications.

Vesicular drug carriers	Description	Applications
Enzymosomes	Vesicle provide a bio-environment in which covalently enzymes are immobilized or coupled	Targeting tumor cells
Virosomes	Vesicle spiked with virus glycoprotein	Immunological adjuvants
Ufasomes	Long-chain fatty acid incorporated vesicles using a mechanical method	—
Cryptosomes	Vesicle with surface phospholipid coat	Ligand mediated drug delivery
Emulsomes	Microscopic lipid arranged within a polar core	Parenteral administration of hydrophobic drugs
Discomes	Solubilized niosomes within non-ionic surfactant	Ligand mediated drug delivery
Aquasomes	Multi-layered self-assembly composition containing ceramic carbon nano-crystalline particulate	Molecular targeting
Ethosomes	A soft malleable vesicle	Drug delivery to deep skin
Genosomes	Artificial macromolecular complex functionalized gene	Gene transfer
Phytomes	Photolyase encapsulated within liposomes	Photodynamic therapy
Erythrosomes	Chemically crossed linked human erythrocytes	Marco-molecular drug targeting
Hemosomes	Liposome fortified with hemoglobin	Oxygen carrying property
Proteosomes	High molecular weight multi-subunit enzyme complex	Catalytic activity
Vesosome	Embedded bilayer compartment	Multi-compartmental vesicles
Archaeosomes	Archaea glycerolipids composed of vesicles	Serum protectant
Sphingosomes	Consist of an aqueous space sac inside the lipid bilayer to entrap the drug	Improved stability compared to liposomes
Menthosomes	An ultra-deformable vesicles carrier system	Excellent permeability of drug within carrier through the skin
Bilosomes	Bile salt-containing niosomes	Enhance the permeation of the drug by fluidizing the lipoidal bilayer of the vascular system and the stratum corneum.
Invasomes	lipid-based deformable vesicular carriers, enabling the drug to penetrate deeper into the skin or the systemic circulation by non-invasive delivery	Improved dermal delivery due to deformable nature
Niosomes	Made of non-ionic surfactant with neutrally charged compound, compared to the bilayer lipid vesicles	Deliver drug within the dermal layer by perturbation od lipidic membrane
Cubosomes	A cubic-phase lipid-drug delivery system composed of the curved continuous lipid bilayer, which is extending in 3-dimensions and isolating two consistent systems of water channels	Potential delivery of protein, peptides, amino acids, and nucleic acid
Transfersome	An ultra-flexible liposomes composed of bilayer as a backbone and an edge activator	Highly elastic and stress-responsive than the conventional vesicular system
Transethosomes	An advanced VDDs that differs from liposome and niosomes to their fluidic membrane and ethanol concentration with elasticity	Penetrate easily keratinized mammalian skin layer

Table 2.

Market available and various emerging advanced VDDs for therapeutic applications [23, 24].

Solid lipid nanoparticles are generally formulated using high shear homogenization, ultrasonication, microemulsion followed by supercritical liquid innovation, splash drying, dissolvable emulsification/vanishing, dissolvable infusion, and dissolvable emulsification-dissemination techniques [25]. Solid lipid nanoparticles are extensively characterized for size, shape, polydispersity index, zeta potential, entrapment efficacy, crystallization tendency, polymorphic behavior, the viscosity of the solid-state formulation, and in vitro-in vivo drug release. Solid lipid nanoparticles are administered via various routes including oral, parenteral, transdermal, pulmonary, rectal, etc. for achieving enhanced therapeutic efficacy of low or less permeable drugs via dermal administration or low water-soluble drugs with improved bioavailability [26]. Recent updates on lipid nanocarriers-based drug delivery systems (solid lipid nanoparticles and vesicle entrapped drug delivery systems) are presented in Table 3.

Lipid/surfactant	Applications	Characterization			References
		Zeta potential (mV)	Size (nm)	PDI
Phospholipid	Solid lipid nanoparticles fortified with Erlotinib indicated a 2.12 fold increase in oral bioavailability with a reduction in pharmacokinetic variabilities, compared with the conventional dosage form	−33	177	—	[27]
Glyceryl mono stearate and Olieac acid	Solid lipid nanoparticles loaded vitamin E within cream indicated good stability at cold temperature with improved and controlled permeability indicated by diffusion study	~ − 24	~210	~ 0.24	[28]
Compritol 888	Rapamycin loaded solid lipid nanoparticles showed promising results for the treatment of lymphagioleiomyomatosis following pulmonary pathway with an appropriate size and necessary charge for controlled aerosol performance	−11.2	237	0.4	[29]
Phospholipid	A two-fold improvement in solubility was demonstrated for BCS class II drug in an entrapped solid lipid nanoparticulate form prepared via lyophilization process.	—	< 1000	—	[30]
Compritol 888 and phospholipid 90 G	Thiopental sodium loaded solid lipid nanoparticles showed cardiac protective effect with altered apoptosis marker, pro-inflammatory cytokines, inflammatory parameters, and reduced p38-MAPK level.	—	~ 68	~0.149	[31]
Glycerin monostearate and soybean lecithin	Paeonol lipid nanoparticulate via high-temperature emulsification-low temperature curing combined with ultrasound indicated improved oral bioavailability compared to alone Paeonol in simulated biological fluid.	~ −10	~ 150	~ 0.22	[32]
Stearic acid	The freeze-dried binary solid lipid nanoparticle of poor oral bioavailable cefixime showed 88% of encapsulation efficacy improvement in bioavailability	- 30.7	206.6	0.271	[33]
Gelucire	Statistically optimized thymoquinone lipid nanoparticles indicated 62.5% of encapsulation efficiency with potential dermal delivery carrier in the treatment of psoriasis	—	84.2	0.26	[34]
Polysorbat 80	Sustained-release carnitine entrapped solid lipid nanoparticles indicated improved bioavailability via oral route of administration	−0.549	68–458.7	—	[35]
Oleic acid	Hydrophobic scaffolds fortified with oleic acid entrapped mRNA lipid nanoparticles showed promising material for curing inflammatory disease	1.5	93	0.08	[36]
Glyceryl monostearate	Nano lipid formulation remarkably improved the bio-efficacy of poorly water-soluble thymoquinone and demonstrated a promising perspective for oral delivery compared with conventional suspension.	- 12.32	188.66	0.319	[37]
Dioleo-yl-sn-glycero-phosphatidylcholine	Lipid nanoparticles containing short interfering RNA (siRNA) developed via alcohol dilution-lyophilization with cryoprotectants in a combination of sucrose and polyethylene glycol indicated significant particle stabilization compared to that of conventional ultrafiltration techniques	−1.89	155.0	0.118	[38]
Polyethylene glycol	Glutamic acid derivatives functionalized with non-ionic lipid nanoparticles were exposed as diagnostic tools for diabetic retinopathy.	—	120	0.259	[39]
Phosphatidylcholine	Curcumin loaded lipid vesicular system with surfactant demonstrated entrapment efficacy of 89.6% with Higuchi release kinetic and fickian diffusion	−11	339.3	—	[40]
1-stearoyl-rac-glycerol and L-α-phosphatidylcholine	Artemisone encapsulated nano-vesicular nisomes and solid lipid nanoparticles were evaluated against human melanoma A-375 cells and human keratinocytes cells, the results showed that the formulations have promise for use in cancer chemotherapy	−38 and − 12	211 and 295	—	[41]
Lecithin	Intranasal drug delivery of rizatriptan lipid nanoparticles indicated a significant increase in drug concentration in the brain compared with administered intravenously and could be a promising approach in the treatment of migraine	~ − 20	~ 250	~ 0.35	[42]
Stearic acid	Lopinavir fortified with stearic acid complexed γ-cyclodextrin indicated that inclusion complex can be used in the fabrication of solid lipid nanoparticles	−19.7	212	—	[43]
Coconut and jojoba oil	Lipid nanoparticles prepared using coconut oil indicated high encapsulation efficacy compared with jojoba oil with a regulated release profile	~ − 28	270	—	[44]
Cholesteryl oleate, glyceryl trioleate, cholesterol	Cationic solid lipid nanoparticles, reconstituted from low-density lipoprotein for the delivery of siRNA prepared following solvent-emulsification techniques demonstrated significant uptake by cells.	+ 41.76	117	—	[45]
Sodium taurodeoxycholate, oleic acid, stearic acid	Nanostructured lipid carriers loaded with lopinavir were developed for enhanced drug permeation with significant efficacy for transdermal administration	~ 37.5	179	~ 0.182	[46]
Gelucir and Precirol	Grape seed extract lipid nanoparticles followed melt homogenization an demonstrated increase in antioxidant response in the cells	+ 25.6	139–283	0.44–0.59	[47]
Glyceryl monostearate	Intranasal Repaglinide loaded solid lipid nanoparticles in-situ gel demonstrated maximum therapeutic outcome with dose reduction frequency for diabetes mellitus treatment	—	96.34	—	[48]
Glyceryl monostearate	Flavonoids incorporated solid lipid nanoparticles and nanolipid carrier indicated improved oral bioavailability with sustained therapeutic effect	~ 30	131–189	0.152–0.198	[49]
Lecithin	A temperature-dependent release of doxorubicin from cationic microgels fortified with vesicles indicated retardation at 25°C, compared with temperature between 39 and 41°C	—	—	—	[50]
L-α-phosphatidylcholine	Ethosomal gel fortified with quercetin demonstrated enhanced permeability with effective management of dermatitis on animals study	−26.33 – 39.3	324.1–359	0.241–0.554	[51]
Dioleoylphosphatidylcholine, PEG 2000, cholesteryl hemisuccinate, and cholesteryl	Folate-coated and pH-sensitive liposome drug delivery containing irinotecan showed improved antitumor activity drug alone.	−4.1 – −11.1	159.2–165.2	0.09–0.12	[52]
Hydrogenated phosphatidylcholine, dipalmitoyl-sn-glycero-phosphorylglycerol sodium salt	Isoniazid-hydrogenated phosphatidylcholine induced the formation of ultra-stable quadrupole complexes, characterized by a high temperature showed the effect of isoniazid on the lipid organization that can be possibly employed as anti-TB nano-carries.	−35 – −53	52–57	0.07–0.11	[53]
1,2-dioleoyl-3-dimethylammonium-propane	pH-responsive nanocarrier based on dispersed self-assemblies of 1,2-dioleoyl-3-dimethylammonium-propane with human cathelicidin LL-37 in excess water was characterized and found that the fundamental structure contribute significantly to release of peptide	−4 – +10	269–286	0.16–0.21	[54]
Cholesterol, PEG-2000	Epirubicin is a lysyl oxidase that inhibits the crosslinking of elastin and collagen fibers that were complexed with lipid demonstrated superior inhibition of triple-negative breast cancer with prolonged survival, minimal cytotoxicity, and enhanced biocompatibility compared to free epirubicin.	−21.3 – −30.7	156–231	0.027–0.164	[55]
Kolliphor 188, stearyl amine, oleic acid, tween 80, kolliphor HS 15	pH-responsive multilamellar vesicle loaded vancomycin indicated effective targeting with enhanced antibacterial efficacy	- 5.55	62.5	0.15	[56]
Phosphatidylcholine	Chrysin transfersomes vesicle fortified within chitosan composite showed improvement in the therapeutic performance against doxorubicin-induced cognitive impairment	−26.5 – +46.3	121.5–617.2	0.154–0.66	[57]
Phosphatidylcholine, cholesterol	An attempt for the nose to brain delivery of olanzapine liposome using Design-Expert demonstrated regulated release for 24 h with acceptable physicochemical characterization	−11.46 – −27.53	268.25–325.32	—	[58]
Cholesterol, Dipalmitoyl phosphatidylcholine	Vesicle entrapped amikacin liposome fabricated in aerosol-based drug delivery systems demonstrated efficacious delivery of amikacin after nebulization using lamira nebulizer through inhalation every time with no or low variation	—	269–296	—	[59]
Phospholipon, polysorbate 80	Elastic liposome loaded with desmopressin acetate demonstrated a high permeation flux for therapeutic efficacy on transdermal drug delivery with hemo and biocompatibility	23.6–77.4	111.7–335.6	0.11–0.47	[60]
Amphiphilic block copolymer containing PEG	Synchrotron small-angle x-ray scattering techniques-based synthesis of amphiphilic block copolymer stabilize monoolein nanoparticles containing a range of non-lamellar lyotropic liquid crystal mesophases, demonstrated response towards H2O2, pH, and temperature.	—	140–300	0.38	[61]
Sorbitan monostearate – 60, Tween 80, Brij 97	Carvedilol-loaded nano-spanlastics prepared by ethanol injection techniques demonstrated good deformability index and stability with enhancement in permeability flux after 24 h of release study. Moreover, in vivo study indicated superiority in the protection of heart tissue over Carvid^®.	—	196.5–512.1	0.21–0.43	[62]
1,2-Dioleoyl-sn-glycero-3-phosphocholine	An integrated quartz crystal microbalance dissipation and localized surface plasmon resonance single sensor were developed to monitor the adsorption and rupture of the liposomes. The results indicated that the device could provide a powerful tool to gain deeper insights into biomolecular interactions, expanding with numerous applications such as monitoring of conformational changes in proteins, oligonucleotides, viruses, bacteria, vesicles, and cells.	—	—	—	[63]
Polyoxyethylenesorbiton monooleate, sodium cholate	Ethosomes and transethosomes loaded cholecalciferol demonstrated rapid intracellular accumulation to support the scientific background for exploring the transdermal and in vivo investigation of administration in different experimental and pathological conditions.	—	111.2–276.7	0.085–0.163	[64]
Glycerol	Minoxidil-lo glycerosomesaded demonstrated stable zeta potential, controlled size, and regulated in vitro release with excellent stability on storage. Moreover, the presence of high content of glycerol indicated multifaceted application including humectant, emollient, and penetration enhancer.	—	—	—	[65]
Phosphatidylcholine, cholesterol, oleic acid, stearic acid	Amphotericin B-miltefosine nanovesicle prepared using ethanol injection technique showed good compatibility, extended drug release, convenient vesicle size, and high drug entrapment for effective in vivo antileishmanial investigations.	−27.3 ± 2.8	169.7–202.6	0.19 ± 0.04	[66]
Dimyristoyl-sn-glycerol3-phosphocholine, dipalmitoyl-sn-glycero-3-phosphocholine	Label-free surface-sensitive quartz crystal microbalance with dissipation monitoring method used to understand the time-dependent phase transition from nano viscosity measurements, the transfer rates, between two vesicle populations consisting of lipids with the same head group and differing alkyl chain length can be estimated.	—	110.0–130.0	0.05–0.12	[67]
Phospholipon^®	Topical application across the stratum corneum of unsaturated fatty acid vesicles loaded ammonium gntlycyrrhizinate demonstrated high efficacy compared to its free form.	−42 – −50	146–284	0.17–0.22	[68]
L-α-phosphatidylcholine	The fusion of amphiphilic polypeptides with n-decyl side chains leads to the engulfing of liposomes and multilayered vesicles. Such multilayered vesicle comes with the advantage of reducing the permeability of the cargo in the aqueous core	—	100	—	[69]
Phospholipon 90H	Terbinafine HCl loaded ethosome for enhanced topical application in the management of fungal diseases	−23 – −48	90–199	0.33–0.47	[70]
Hydrogenated soybean lecithin	Black soybean seed coat extract encapsulated nano-dispersion showed improved stability, radical-scavenging capacity with high cellular compatibility	−3.50 – −30.12	27.6–121.1	0.194–0.386	[71]
1,2-Dioleoyl-sn-glycero-3-phosphocholine, cholesterol	Ferulic acid loaded vesicle showed effective membrane surface interaction due to electrostatically zwitterionic polar heads of the lipid, which also depends on the concentration of lipids	−0.4 – 1	117–124	0.06–0.09	[72]
Dipalmitoyl-phosphatidylcholine; Hyaluronic acid	Thermosensitive liposomal formulation functionalized with hyaluronic acid encapsulated cisplatin demonstrated a controlled release profile with a possible diffusion rate before reaching 42°C.	20–38	100–130	—	[73]
PEGylated soy lecithin	PEGylated soy lecithin liposome of oxaliplatin showed enhanced activity against human breast cancer cells with reduced cytotoxicity against mouse fibroblast cells.	−39 – −50	180–200	0.2–0.3	[74]
L-α-phosphatidylcholine	In situ gel fortified with ketoconazole, trans ethosomes showed no irritation to the cornea with deep penetration to the posterior eye segment without cytotoxicity	12.8–36.8	220.6–1063.3	—	[75]
Pramipexole dihydrochloride, 1,2-Dioleoyl-sn-glycero-3-phosphocholine, 1-Arachidoyl-2Hydroxy-sn-Glycero-3-Phosphocholine, 1–2-didecanoyl-sn-Glycero-3-phosphocholine, cholesterol, sodium cholate, sodium hexadecyl sulfate, cetylpyridinium chloride	Liposomal formulation gel of pramipexole incorporated with edge activators and charge inducer improved the drug permeation, and the extent of penetration depending on phospholipid compared with conventional liposomal gel.	+3.83 – −52.2	117.0–289.7	—	[76]

Table 3.

Recent updates on LNs based drug delivery system considering solid lipid nanoparticles and vesicular drug delivery system.

4. Future prospects and challenges with vesicular and solid lipid nanoparticulate drug delivery system

Nanostructured lipid carriers contain an unsaturated solid lipid core that enables the encapsulation of highly lipophilic drugs, protecting them from degradation, and enhancing their stability. Literature indicates that during the past decades, the number of studies elaborating NLCs-based formulations has been drastically increased. Lipid nanostructure carriers such as SLNs, VDDs, and or NLCs have been extensively used and further investigated as carrier systems for drug delivery. Moreover, these nanostructure carrier has demonstrated excellent improvement in the therapeutic efficacy with an increase in targeting specific tissue or organ for low permeable and water-insoluble drugs. The rise in NLCs technology is essentially due to defeated barriers within the technological process of lipid fortified nanoparticles formulation and increased knowledge of the underlying mechanisms of transport of NLCs via varied routes of administration. Although NLCs have shown several advantages, compared with conventional dosage form and promising application in the delivery of various categories of synthetic and bioactive, that presents challenges in their application. The challenges associated with NLCs are as follow: complex manufacturing process, stability during storage, clinical translational barriers, cell-specific delivery, misconceptions, challenges specific to the receptor, ligand, and carriers, etc. [77].

5. Conclusions

Nano lipid structure carriers, composition and formulations techniques have a profound influence on their physicochemical properties and efficacy as drug delivery systems. The lipid carriers have evolved over the years and they have shown promise for treating various clinical diseases and complications including psoriasis, dermatitis, rosacea, vitiligo, acne, fungal infections, several systemic infections, etc. Taking into account the increase in the number of patented NLCs-based formulations and the increase in the availability of data so far, it can be expected that the number of clinical trials pertaining NLCs will substantially increase in near future. Moreover, now NLCs appear to be one step closer to its translation into the market to the clinic.