An overview of nanotechnology and nanocarriers

The still-evolving science of nanomedicine includes nanodelivery as a significant component. Nanomedicine is a multidisciplinary field incorporating elements of nanotechnology, chemistry, biochemistry, and pharmaceutical sciences [1]. The study of creating, characterizing, and using objects with at least one dimension on the “nano” scale is known as nanotechnology. In comparison to conventional medication delivery techniques, nanodistribution systems have some advantages. For example, they might be able to deliver medicines that target various body tissues with excellent specificity and treat various ailments. Since they should, in principle, prevent or significantly reduce drug interactions with non-target tissues, targeted therapy using nanodelivery systems could also reduce the side effects of many medications. As a direct result of fewer undesirable drug interactions, the amount of medication needed to treat the illness would need to be reduced, ultimately resulting in a cost reduction overall [2].

Nanocarriers are colloidal drug delivery devices with submicron particle sizes, typically around 500 nm. In the last few decades, nanocarriers have received much attention owing to their tremendous potential for drug delivery [3]. Since nanocarriers have a high surface-to-volume ratio, a medication’s basic properties and bioactivity can be altered. The use of nanocarriers in drug delivery systems has been shown to improve pharmacokinetics and biodistribution, decrease toxicities, boost solubility, and stability, provide controlled release, and deliver therapeutic molecules to targeted sites [4]. Nanocarriers’ physiochemical qualities (functional groups, PEGylation or other coatings, surface charge, inclusion of targeted molecules) as well as their sizes (large or small), shapes (spherical, rod, or cube), and surface features can also be altered. Nanocarriers are used in drug delivery to effectively cure a disease with little adverse effects, as shown in Fig. 1 [5].

Fig. 1
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Nanocarriers used in drug delivery

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Although not always, many different forms of nanoparticles (NPs) utilized as drug carriers typically comprised polymers or lipids. The lipid NPs outperform the polymeric NPs when the two are compared because polymeric NPs have several drawbacks, including cytotoxicity and the absence of effective mass production techniques. Solid lipid nanoparticles (SLNs), the first generation of lipid-based nanoparticles, were characterized in the early 1990s [6]. Due to polymorphism, drug-carrying SLNs were constrained by poor drug loading efficacy and a high probability of drug expulsion from the formulation during storage. As a next-generation SLN, nanostructured lipid carriers (NLCs) were developed in the late 1990s to overcome SLN formulation challenges [7]. Müller et al. created NLCs by combining solid lipids (SL) with liquid lipids (LL), which create an amorphous solid matrix at body and room temperatures. Since LL considerably improved the formulation’s characteristics compared to SLNs, incorporating LL into the matrix was the first and most crucial step. LL aided amorphous lattice formation with significant flaws in its solid crystalline matrix, enabling a higher drug load to be added, as opposed to SLNs, which form a solid crystalline matrix that restricts the quantity of drug loaded and causing its expulsion due to their spatial capacity [8]. According to numerous scientific studies, the NLC overcomes the SLN’s drawbacks by preventing drug expulsion during storage and enhancing stability and loading efficiency [9] [10].

Types of NLCs

NLC can be divided into three types based on the variations in lipid and oil volume fractions and the diverse manufacturing techniques: the amorphous type, the imperfect type, and the multiple oil-in-solid-fat-in-water (O/F/W) types [7]. In comparison to SLN, Fig. 2 shows the many forms of NLC.

Fig. 2
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Comparison of SLN (1) and NLC (2). The NLC categories are (a) imperfect crystal, (b) amorphous, and (c) multiple types

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Improper-type NLC includes mixing spatially dissimilar lipids, such as glycerides, which are made up of many fatty acids and introduce flaws in the crystal order. By combining a combination of different glycerides with differing saturation and carbon chain length levels, the amount of drug load can be additionally enhanced by expanding defects.

Specific SL, such as isopropyl myristate or hydroxyoctacosanyl hydroxy stearate, create an amorphous matrix lacking structure. The NLC thus exists in an amorphous state as opposed to an organized state, preventing drug ejection brought on by modification during storage [11]. Numerous liquid oil compartments of various sizes spread that throughout the solid matrix are present in multiple O/F/W-type NLCs. Drug loading is augmented because these nanosized compartments have better drug solubility. The release is also prolonged because a solid lipid matrix surrounds the compartments.

Nanostructured lipid carriers (NLCs)

Due to the drug moieties’ improved solubility in the solid lipid, the combination of liquid and solid lipids makes it simple to encapsulate a variety of hydrophobic medicines. However, hydrophilic drug loading into NLC can be tricky and best accomplished by conjugating the functional groups of a matrix of lipids and drugs. Notably, NLC retained a solid state throughout the body [11]. This happens because the mixture of LL and SL tends to lower the core substance’s melting temperature without changing its physical attributes. NLCs are more stable than other nanocarriers and have lower toxicity while allowing for regulated or prolonged medication release [12]. They can also encapsulate both hydrophilic and lipophilic drug substances. Figure 3 shows a comparison between SLN and NLC.

Fig. 3
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Schematic comparisons of rigid SLNs with low drug loads and flexible NLCs with high drug loads

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Glycerol monostearate (GMS), Precirol® ATO5, stearic acid, mono-stearin, stearyl alcohol, cetyl palmitate, Witepsol®, and Gelucire® are examples of solid lipids that are frequently utilized in NLC formulation. Examples of liquid lipids include almond oil, oleic acid (OA), olive oil, sesame oil, soyabean oil, peanut oil, phosphatidylcholine, maize oil, soy lecithin, vitamin E, caprylic triglycerides, glyceryl caprylate/caprate, isopropyl myristate, etc. Poloxamer 188(P188), Polysorbate 80, Polysorbate 20, PVA21, Cremophor® RH, polyoxyethylene esters of 12-hydroxystearic acid, Cremophor® EL, Tego Care 450, Pluronic F68, Span® 85, and numerous other surfactants are also used to prepare NLC. Some of the LL, SL, and surfactants are shown in Figs. 4, 5, and 6, respectively.

Fig. 4
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Liquid lipids used in NLC

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Fig. 5
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Solid lipids used in NLC

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Fig. 6
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Surfactants used in NLC

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Potentials of NLCs in drug delivery [13]

Figure 7 shows the potential of NLCs in drug delivery. Owing to the lipid matrix’s constitution, the concentration, and the irritative and sensitizing actions of the surfactants, there might be some cytotoxic effects. Gene delivery technologies and applications for protein- and peptide-based medications still have untapped potential. One must look for scale-up strategies, improper methods, and lipid stability. In the end, most study researchers are unable to extensively replicate the results because they are entrenched at the laboratory scale or in the research evidence throughout the preclinical or clinical stages. The application of NLC for the delivery of bio-actives like peptides, genes, proteins, ribonucleic acid (RNA), and deoxyribonucleic acid (DNA) should also be given serious consideration [13].

Fig. 7
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Potential of NLCs

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An emphasis on fabrication techniques of NLC

Numerous methods can be employed to produce NLCs. The high-pressure homogenization technique is the most frequently employed that combines high temperature and high pressure. Other is the homogenization approach using low temperatures and high pressure. Table 1 shows the processes that include solvent dispersion, high-temperature emulsion evaporation–low-temperature curing, ultrasonic emulsion evaporation, microtube methods, film-ultrasonic method, microemulsion, supercritical fluid (SCF), emulsion, membrane contactor, and microchannel [14]. Some of the preparation methods are explained below.

Table 1 Fabrication techniques of NLCs
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Melt emulsification method

SL is melted at 10 °C above its melting point, followed by adding LL. Then drug is added to the molten lipid phase. At the same temperature, the aqueous surfactant solution is also heated. The aqueous phase is drop-wise added into the lipid phase with constant stirring on a magnetic stirrer at a specific rpm. Then the mixture is sonicated and allowed to cool down at room temperature.

High-pressure homogenization (HPH)

High pressure (100–2000 bar) is used, which causes shear stress and the breakup of micro- to nanosized particles. Different cycles (10,000 rpm, 800 bar with 10–12 cycles) are carried out depending on the required particle size. Both the aqueous and lipid phases must homogenize at the same temperature to produce nanoparticles. NLC can be prepared using a hot and cold high-pressure homogenization process.

Solvent emulsification-evaporation technique

Using a high-speed homogenizer, a water-immiscible organic solvent dissolves hydrophobic drugs and lipophilic materials. Furthermore, an organic solvent is evaporated at room temperature by either gentle heating or mechanical stirring.

Solvent diffusion

Using ethanol and methanol, two water-miscible solvents, to dissolve the medication and lipid in a single solvent or a solvent mixture. At the same temperature and with mechanical stirring, the organic phase is introduced to the aqueous phase that already has stabilizers, surfactants, and other excipients. The mixture is then cooled to room temperature to allow the organic phase to evaporate.

Solvent injection

Through fine needle injection, lipids are first dissolved in a water-miscible solvent and then introduced to the aqueous phase. Avoiding highly complex mixtures like high-pressure homogenizers and probe sonicators is the main benefit of adopting this mixture [15].

Landscaping of NLCs in drug delivery

We have presented the comprehensive work done with NLCs’ drug delivery via different routes. Recently, NLCs have been used to deliver drugs to particular areas utilizing various administration methods. For instance, topical administration of NLCs is frequently used in dermatological and cosmetic treatments. Fungal infections are incredibly prevalent in the current situation [16] [17]. Over a billion people yearly receive diagnoses for severe systemic or localized fungal infections. Despite their effectiveness in treating fungal infections, antifungal medications are linked to severe side effects such as liver damage, estrogen levels, and allergic reactions [18]. In the skin, there will be effective drug targeting and increased skin absorption by the NLCs. Drug absorption in the human skin enhances by incorporating NLCs. NLCs can be prepared for major tropical diseases like gout, sunburn, rheumatoid arthritis, and inflammation-related skin diseases like atopic dermatitis and psoriasis. This gives rapid onset and intermediate action [19].

Tables 2 and 3 show the use of NLC in topical and oral drug delivery, respectively. Figures 8 and 9 show the graphical representation of Tables 2 and 3, respectively. Because of the poor water solubility and unfavorable physicochemical and pharmacokinetic characteristics of researchers’ identified chemical entities, over 40% of them used in the pharmaceutical sector have limited oral bioavailability. Therefore, producing a conventional formulation that can reduce the threats bound with lipophilic medications is challenging [40]. Researchers have tried many strategies to increase bioavailability, including synthesis of the pro drug, formation of salt, drug nanosizing, and drug encapsulation in nanocarriers such as liposomes, polymeric micelles, NPs, emulsions, etc. Drug delivery techniques incorporating lipids have provided a glimmer of hope for their positive impacts on the absorption of encapsulated pharmaceuticals throughout the past few decades [41].

Table 2 NLCs for topical drug delivery
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Table 3 NLCs for oral drug delivery
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Fig. 8
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NLCs prepared for topical drug delivery

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Fig. 9
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NLCs prepared for oral drug delivery

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Further, owing to their extended absorption in the gastrointestinal tract, oral treatment of NLCs for inflammatory bowel illnesses is the subject of substantial research. Regarding chemotherapy, anti-cancer medications like paclitaxel and doxorubicin have been encapsulated in NLCs to be administered via the pulmonary route [42]. As discussed above, it offers significant advantages compared to the other conventional formulations.

Brain

Figure 10 illustrates the complex anatomy of the brain. About 2% of body weight belongs to the brain, which also needs 25% of the total glucose and oxygen supply and 20% of the overall cardiac blood supply [61]. The defensive system’s three main layers are arachnoid, blood-cerebrospinal fluid, and blood–brain barriers (BBB). The brain is unique in that it has a highly complex network of neurons that communicate with each other via neurotransmitters and neuromodulators, as well as the presence of synaptic potential in such networks and a significant number of capillaries in the range of 100 billion. The intricate BBB effectively shields each of these components. The brain’s ability to transmit signals to other body parts relies on the BBB’s ongoing exchange of ions and other chemicals.

Fig. 10
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Anatomy of the brain

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Brain and related disorders

The prevalence of neurodegenerative illnesses, defined by a continuous diminution in neuronal networks and functions, is highest in the age, although the actual reasons are unknown [62]. Central nervous system (CNS) ailments, such as brain tumors and neurological disorders, continue to rank among the leading causes of disability and fatality around the globe. Treatments for CNS illnesses are lacking despite an alarming rise in occurrence over the past few years. Limited medication accessibility to the intended brain location is one of the factors contributing to the high failure rates in CNS drug development. A drug must cross the BBB in a sufficient concentration and interact with a target in the brain to have a pharmacological effect.

The burden of neurological illnesses has significantly expanded during the last 25 years on a global scale. The Lancet Neurology released the 2015 Global Burden of Disease (GBD) survey report, which states that neurological diseases are the second highest cause of mortality internationally and the primary cause of disability-adjusted life years (DALYs) worldwide.

Only the early phases of a disease’s progression are shown to be responsive to currently available treatments. Most treatments only have symptomatic effects, meaning they treat the disease’s symptoms and do not address its underlying causes. As a result, they are ineffective at curing the disease. The primary reasons for this are the brain’s intricate structure and, more significantly, the BBB’s protective barrier, which prevents most drugs from entering the brain [63]. Therefore, researchers are developing novel approaches, nanocarrier systems, and drug delivery systems that precisely deliver active substances to the brain by bridging the BBB or any alternate route, such as intranasal drug delivery systems [11].

Blood brain barrier (BBB)

Drug distribution to the brain is greatly aided by the BBB, which divides the blood from the brain interstitial fluid (extracellular fluid). The cause is a vast network of blood capillaries, which permit the movement of substances from the blood to the brain parenchyma with an average surface area of 100 to 200 cm2 per gram of adult human brain. Although the BBB’s selectivity is essential for preserving brain homeostasis, it presents a significant obstacle to the delivery of medicines into tumor areas. Passive diffusion via the extracellular matrix is significantly hampered by tight junctions that form between endothelial cells [64].

Active moiety/nanocarrier transportation from the nose to the brain

According to the current study, the nose-to-brain channel offers a viable method for the non-invasive delivery of therapeutic agents or nanocarriers into the brain without crossing the BBB. The olfactory pathway, trigeminal nerve pathway, and systemic pathway are three transport mechanisms involved, shown in Fig. 11.

Fig. 11
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Pathway of intranasal administration

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Nose-to-brain drug delivery

An intriguing method for delivering medicine directly to the brain via the nose is the “nose-to-brain” drug delivery device. The olfactory area is directly connected to the CNS due to the olfactory receptors in neurons and their axons, which end in the olfactory bulb. The olfactory region is the sole area of the body where the CNS interacts with the surrounding environment. The active molecules can immediately enter the brain by the trigeminal and olfactory nerve pathways from the olfactory area, which is a crucial location. When medicine or formulation is delivered, it comes into contact with mucosa and travels straight to the brain, avoiding the BBB. This results in good bioavailability, a lower dose, and fewer side effects. Although nasal medication delivery generates research interest, it has certain drawbacks, such as a small dosage range (25–200 µL), mucociliary clearance, and nasal enzymatic barriers. These discourage scientists from creating cutting-edge drug delivery technology to overcome these constraints. The underlying benefit of the nose to brain medication delivery is that this is a quick, secure, non-invasive, and practical drug delivery approach [65]. It prevents the breakdown of medications in the digestive tract, especially peptide medicines [66].

Additionally, it prevents the gut wall and hepatic first-pass metabolism of medicines, resulting in increased bioavailability. Bypassing the BBB provides CNS-targeted drug delivery, lowering systemic exposure to treatments and their accompanying systemic adverse effects. No modifications are necessary for the therapeutic agent using a nose-to-brain medication delivery platform. Rapid drug absorption and speedy commencement of an action through the highly vascularized and permeable nasal mucosa are essential advantages of nose-to-brain transfer [67]. This improves patient compliance and provides a different method of parenteral delivery, particularly for medications containing proteins and peptides or even stem cells. It has good bioavailability for medicines with low molecular weight [68].

NLCs in nose-to-brain drug delivery

NLC is a combination of SL, LL, and surfactant. It can be prepared by the methods enlisted in Table 1. Some of the principles can be considered to develop NLCs for efficient brain drug delivery further, as shown in Fig. 12. Limiting the influences of protein corona/biological molecule corona/nutrient molecule corona is crucial for nose-to-brain drug delivery, as these coronas can alter the behavior and fate of nanocarriers and affect their therapeutic efficacy. It can be done through surface modification, shealth coatings, surface charge optimization, preconditioning strategies, engineered surface ligands, corona modulation agents, biological fluid mimicking media, in vitro and in vivo screenings, etc. By employing these strategies, it is possible to minimize the influences of the protein corona, biological molecule corona, or nutrient molecule corona and enhance the effectiveness of nose-to-brain drug delivery. Table 4 and Fig. 13 display the research done in NLCs for nose-to-brain drug delivery.

Fig. 12
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Principles to develop NLC

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Table 4 NLCs in the nose to brain drug delivery
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Fig. 13
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NLCs prepared for nose-to-brain drug delivery

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Modish stratagem of NLCs in drug delivery

Further, to develop better NLCs, we can also do PEGylation or surface modification on NLCs to enhance the drug-loaded carrier’s effectiveness [92] [93]. Combination devices, or those that include both functional prosthetic implants and drug-releasing components, are versatile, developing clinical technology that has the potential to enhance the functionality of implant devices across a variety of classes. Formulation techniques are insufficient to utilize this route to deliver human drugs. To target formulation deposition in the nasal passage’s olfactory region and circumvent its architecture limitations, novel technologies are currently being developed. The Vianase™ was used to administer insulin intranasally in one of the few experiments on brain delivery via the nose in humans. Kurve Technology® created the Vianase™ electronic atomizer, comprising a nebulizer coupled to a vortex chamber. The vortex chamber, where the nebulized drug particles move, maintains this flow after the particles have left the device. Increased transit to the brain encourages deposition to the olfactory area [94]. The necessity for additional administration routes for new medications and to address various targets is driving the growth of the nasal drug delivery industry. A non-invasive drug delivery method for both localized and systemic effects is aerosolization. The formulation will likely reach the olfactory area and achieve direct brain targeting if deeper nasal penetration beyond the nasal valve can be accomplished [95]. Table 5 shows the comprehensive work done in NLCs with the combination of the medical device to deliver drugs at different target sites.

Table 5 NLCs in combination with medical device
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The medium- and long-term fate of nanoparticles is likely to depend on several factors, including tissue distribution, clearance from the body, potential toxicity, metabolism, biodegradation, and environmental factors, including their stability, associations with other environmental elements, and exposure circumstances. It is still emerging, and continuous studies are geared at better comprehending their behavior and possible threats and creating techniques to lessen negative impacts.

Patent search

The patent search was carried out using the licensed version of the PatSeer® PRO database using search strings shown in Table 6. Researchers have thoroughly worked on the synthesis and solubility of the NLCs. Here we have presented formulation-based patents, including formulations with enhanced drug solubility and loading capacity, improved encapsulation efficiency, lowered dose frequency, in vitro studies, etc., as shown in Table 7. This type of literature suggests that these formulations have achieved targeted delivery of drugs and thus lessened side effects related to drug and dose.

Table 6 Search strings for patent search
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Table 7 Patents of NLCs in nose-to-brain drug delivery
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Conclusion

With better drug incorporation and enhanced bioavailability, NLCs are chemically and physically stable systems. In recent years, improvements have been significantly accelerated by the industry’s growing interest in lipid carrier systems. Currently, the industry offers more than 30 commercial NLC formulations with ingredients for drugs and cosmetics. NLCs can increase bioavailability and reduce dosing frequency, indirectly reducing dose-related side effects. Intervening NLCs directly on the targeted site displays site specificity and many more benefits than conventional dosage forms. Thus, the use of NLCs in nose-to-brain drug delivery is invigorating. NLCs provide advantageous aerosolization properties and practical stability for pulmonary use. Additionally, they can get past local defenses and gather in the lung. NLCs can enter the brain by furnishing the surface of the formidable barrier enclosing it, and they can then pass the BBB by receptor-mediated transcytosis. Given the recent increase in patent filings, NLCs should have the same opportunity for accurate clinical translation and pharmaceutical marketing in all cases. Success in this field can be imagined if the pharmaceutical business takes academic study to design this carrier system for diverse therapeutic and cosmetic agents.