Historical Background
Since the 1960s, nanotechnology has garnered significant attention among pharmaceutical scientists due to its potential in drug delivery.[
3] One of the earliest examples of this was the introduction of liposomes in 1965, which rapidly became a popular method of drug delivery.[
4] Subsequently, in 1978, an article was published demonstrating the use of nanoparticles as drug carriers.[
5] In essence, nanotechnology refers to the ability to produce and manipulate materials or objects at the nanoscale level. These drug delivery systems, with particle sizes in the nanometer range, are commonly referred to as nano-drug delivery systems. The development of such systems has become a routine technology for studying the activity of drugs both in vivo and in vitro. They prove particularly useful when faced with challenges such as large molecular weight, poor stability, difficult absorption, or the need for targeted or controlled release of drugs. As such, nano-drug delivery systems serve as one of the most promising solutions to these challenges as shown in
Figure 1.
Despite their vast potential benefit, a large number of nutraceuticals are hydrophobic (poorly water-soluble), resulting in poor bioavailability when taken in their “pure” form. This challenge is not limited to the nutraceutical industry, as it is estimated that 90 % of preclinical small-molecule drug candidates are poorly water-soluble too.[
6] While an accurate definition of bioavailability defers slightly between different sources and fields, it generally refers to the extent to which an administered drug, nutrient, or substance is absorbed and used by its intended target in the body. It is thus essential to maximize the bioavailability of any pharmaceutical or nutraceutical of interest to ensure maximum benefit and efficacy. Increasing the administered dose in order to increase the amount of absorbed drug to a therapeutic concentration seems like a simple solution. Furthermore, this approach is not recommended as it involves numerous complications in terms of the feasibility of administering such a large dose, potential side effects such as toxicity and immunogenicity, and the monetary and environmental cost of wasted material.
Numerous approaches have been taken to improve the bioavailability of insoluble drugs and nutrients.[
6,
7] These approaches generally fall under three strategies:
- i)
Modifications of the chemical or physical properties of the drug;
- ii)
Mixing with co-ingredients or co-solvents;
- iii)
Development of drug carrier systems that improve the interactions between the drug and surrounding biological molecules, tissues and cells.
The latest drug delivery biotechnologies employ various strategies to improve drug solubility, circulation time, penetration, absorption, targeted activity, and off-target accumulation.[
8] These biotechnologies aim to enhance patient tolerability and acceptance, ultimately leading to better treatment outcomes. Transdermal delivery (TDD) systems have become an increasingly popular drug delivery option due to their non-invasive nature and ability to bypass the gastrointestinal tract. These systems utilize biodegradable microneedle patches that are composed of materials such as polylactic acid and hyaluronic acid.[
9] These microneedles have been designed to be minimally invasive and painless, penetrating only the outermost layer of the skin to increase drug permeability. After use, the microneedle patches dissolve and leave no sharp waste, making them a safe and eco-friendly drug delivery option.
Nano-drugs have emerged as a promising avenue in the treatment of chronic human diseases and in targeted delivery of medicines. Despite the potential benefits, there is limited knowledge regarding their commercial availability and associated challenges. In this review, we present a synthesis of challenges and perspectives in commercially available nano-drugs and nano-delivery systems. Our aim is to bridge the gap between academic studies and industrial availabilities. We have categorized commercially available nano-drugs based on their modifications, name, parent company, and applications. Our review provides a concrete framework for academia and industry to enhance their understanding of commercially available nano-drugs and their potential applications. By consolidating and presenting the latest research on the topic, we hope to contribute to the literature gap and facilitate further advancements in this field.
Drug Modification
Drug modification is a process that entails chemical and physical alterations to improve the interaction between drugs and their microenvironment. One of the primary objectives of drug modification is to enhance the water solubility of drugs.[
10] By modifying the chemical structure of drugs and/or their physical properties, drug modification aims to make them more compatible with the microenvironment. The ultimate goal is to optimize the efficacy and safety of drugs, thereby improving patient outcomes. The solubility and absorption of a drug can be significantly improved by chemically altering the existing functional groups of the drug. For example, ritonavir (Norvir by Abbvie, Inc), a critical protease inhibitor for HIV, is modified by a thiazole moieties to improve its water solubility and metabolic stability.[
11] Another approach is the synthesis of prodrugs, most commonly alkyl ester prodrugs such as the angiotensin-converting-enzyme inhibitors benazepril (Lotensin by Novartis Pharmaceuticals, Inc) and enalapril (Vasotec by Merck).[
12] The ester prodrugs have been used in pharmaceutical formulations for a long time, whichgive them improved solubility and penetration of the new structure that is a non-active precursor. This prodrug undergoes
in vivo chemical or enzymatic cleavage of the ester group upon there uptake and generate the active drug. Although chemical modifications can serve as a versatile tool, it can be extremely challenging and resource exhausting to achieve for some specific APIs. Chemical modifications might include challenging synthetic routes, where the product (if obtained) must undergo extensive pre-clinical and clinical characterization and testing to ensure the desired therapeutic and chemical properties are obtained. This means that any new product will be subjected to extensive regulatory considerations.
Modifications to the physical properties of the drug may circumvent the above-mentioned synthetic and regulatory challenges of chemical modifications. “Physical” modifications primarily target the crystal form of the drug. When a drug possesses a stable crystal form, it can be an extremely challenging task to break those strong intermolecular interactions in order to solubilize it. Disordered, amorphous packing, on the other hand, renders the drug more water soluble.[
13] One case example is Ceftin by GSK, an amorphous form of the antibiotic cefuroxime which is completely insoluble in water in its original form.[
14] Because the solubility of amorphous forms relies on the reduces molecular-packing stability of the latter, they can be very challenging to form and stabilize. Therefore, they are often protected by multiple patents which prevent early generic entry.
Co-Ingredients and Co-Solvents
Another strategy to improve the bioavailability of insoluble drugs and nutraceuticals is by addition of a co-ingredient or co-solvent that improves its solubility and penetration. One of the main co-ingredient strategies is the addition of pH modifiers, which can alter the pH of the drug’s local environment into one in which the drug is in an ionic and more soluble form.[
15] A classic example is the antibiotic Ciprofloxacin (Cipro IV), which is poorly soluble in water alone, but is formulated with hydrochloric acid and lactic acid for improved solubility.[
16] This approach, however, relies on the ionizability (acidity) of the drug, and the compatibility between its optimal solubility pH range and physiological pH.
The bioavailability of nutraceuticals can be further improved by the addition of excipients (co-ingredients) that act as penetration enhancers. In fact, many penetration enhancers can be found in natural sources, and are often plant extracts, alkaloids and flavonoids such as piperine and quercitin, with well studied mechanisms of actions.[
17] BioPerine
® is a patented standardized piperine extract by Sabinsa Corporation that has been shown to increase the bioavailability of certain nutraceuticals. Other natural ingredients, such as (Piper nigrum L.), long pepper (Piper longum L.) and ginger (Zingiber officinalis L.) have also been shown to increase the bioavailability of drugs, though their mechanism of action is not well know.[
18] Non-herbal penetration enhancers include fatty acids, alcohols and cholates, which often decrease the barrier effect of cells by disrupting the lipid arrangements between them.[
19] Zemvelo by Mineralife Nutraceuticals relies on the addition of fulvic acid in its formulations to promote the absorption and bioavailability of delivered nutrients and minerals.
Formulation of drugs with co-solvents is also a commonly used practice. It involves increasing drug solubility and penetration by addition of co-solvents such as alcohol, polymers, and biomolecules that solubilize non-polar drugs, but require the addition of surfactants to prevent precipitation upon dilution in biological fluid. Chemotherapy drugs paclitaxel and docetaxel have been commonly formulated using the co-solvent approach, their most common formulations being Taxol (by Bristol-Myers Squibb) and Taxotere (Sanofi-Aventis), respectively.[
20] Both these formulations however lead to hypersensitivity reactions from the surfactants used. As a result, newer co-solvent formulations use polyethylene glycol (PEG) as co-solvent and Tween 80 as surfactant, which have reported better patient tolerance and less adverse effects compared to the solvents and surfactants used in older formulations.[
21] However, the co-solvency method still presents some disadvantages, such as uncontrolled precipitation of the drug upon its interaction with biological fluid, and potential decrease in the stability and effectiveness of the drug.[
6]
Drug Carrier Systems
Development of drug carrier systems is the most recurrent strategy to improve the bioavailability of insoluble drugs (
Figure 1). Carrier systems serve as an interface that facilitates the interactions between the pharmaceuticals and their microenvironment, mainly by increasing solubility, penetration, circulation time, and offering potential targeting benefits. Glow LifeTech, for example, relies on the formation of micelles through their plant based MyCell
TM Technology to increase the water solubility of fat-soluble nutraceuticals (
Figure 1a). Most drug carrier technologies fall under one of two categories: lipid-based or polymer-based drug delivery systems.
Lipid-based drug delivery technologies involve the use of emulsions, micelles, liposomes and pro-liposomes, or solid-lipid nanoparticles (SLN) to enhance the solubility of the APIs and to deliver their to target site. Products such as CUREpods
TM and CUREdrops
TM from CURE Pharmaceuticals rely on a range of lipid-based drug delivery technologies.[
22,
23]
Micro- and nano- emulsions have seen increased use in drug delivery technologies. In fact, these suvramolecular structures are composed of a thermodynamically stable mixture of oil/lipid, water, surfactants and co-surfactants, and the APIs itself, all together forming a stable heterogenous system compared to conventional emulsions (
Figure 1b). SōRSE Technology, Industrial Sonomechanics, and VESIsorb
® for example rely on the formation of stable nanoemulsions for the improved delivery of nutraceuticals like hemp extracts and cannabidiols.[
24] Perhaps the most attractive type of micro-emulsions is self-micro-emulsifying drug delivery systems (SMEDDS). Self-emulsifying formulations involve an isotropic mixture of oil/lipid, surfactants and APIs (without water) which spontaneously emulsifies upon ingestion and interaction with gastro-intestinal fluid resulting in droplets smaller that 250 nm in size. μGOO by EmbarkNano is marketed as a nanoemulsion “precursor” to be used to generate their other products such as μSHOT nanoemulsions and μCREAM “nano topical”. Lipid based micro-emulsions, such as Vitalipid by Kabi, O2W by Micellae Delivery Systems, and SureNano
TM have been frequently used for the enhanced delivery of nutraceuticals.[
25,
26,
27] As higher surface area of nanoparticles results in their faster absorption, micro-emulsions often require the addition of a large concentration of surfactants in order to reduce their size and increase their surface area-to-volume ratio. This presents the major drawback of self-micro-emulsifying delivery technologies, and emulsion technologies overall, as large concentrations of surfactants may result in a decrease of the drug encapsulation ability of the micro-emulsions due to increase hydrophilicity of the matrix, which may lead to the precipitation of the drug upon dilution in physiological fluid.[
28] Additionally, the utilization of large concentrations of surfactants has been shown to lead to patient hypersensitivity and low tolerance.[
29]
Liposomes represent a type of lipid-based drug delivery technology that circumvents the need for surfactants. These spherical nanoparticles are composed of phospholipid bilayers and have been employed as a promising candidate in the field of drug delivery. They contain an aqueous center that is entrapped by a hydrophobic lipid bilayer shell (
Figure 1c). Liposomes can thus be great carriers of both hydrophobic and hydrophilic compounds. Hi-Tech Pharmaceuticals, for example, uses their Cyclosomes
TM technology to entrap hydrophobic compounds inside cyclodextrins and deliver them using a liposome carrier. Quicksilver liposomal Delivery Systems
® by Quicksilver Scientific also relies on high-phosphatidylcholine phospholipid mixes to produce stable small delivery vehicles, whereas Indena S.p.A. relies on natural lecithin phospholipids in there Phytosome
® drug delivery system.[
30] Liposomes are often formulated with the addition of PEG for additional water solubility and non-immunogenicity, as PEG helps reduce their detection and clearance. Liposomes can further be functionalized by targeting moieties to provide site-specific activity. Perhaps the most relevant examples of the use of liposomes as carrier systems are the mRNA based COVID-19 vaccines such as the ones developed by Moderna and Pfizer/BioNTech.[
31] Moreover, the first FDA-approved nanoparticle therapeutic was PEGylated liposomal doxorubicin (Doxil by Sequus Pharmaceutical, Inc.).[
32] One major drawback of liposomes is their reduced shelf-life and long-term stability, and potential leakage of the entrapped drug over time. A solution to that was the introduction of pro-liposomes, a dry mixture of powder lipid, drug, and other ingredients that form multilamellar vesicles (liposomes containing liposomes) upon their hydration right before drug administration or upon reaction with physiological fluid
in vivo.
Figure 1.
Drug carrier systems of poorly water-soluble drugs for (a) lipid or surfactant-based micelles, (b) mico- and nanoemulsions, (c) phospholipid-based liposomes, (d) PEGylated polymeric nanoparticles, (e) polymer-based solid dispersions, and (f) cyclodextrin-based inclusion complexes.
Figure 1.
Drug carrier systems of poorly water-soluble drugs for (a) lipid or surfactant-based micelles, (b) mico- and nanoemulsions, (c) phospholipid-based liposomes, (d) PEGylated polymeric nanoparticles, (e) polymer-based solid dispersions, and (f) cyclodextrin-based inclusion complexes.
Polymer-based drug delivery technologies offer the same advantages as lipid-based technologies (enhanced bioavailability of drugs, site-targeting), with the added benefits of ease of functionalization and higher stability. Polymer-based technologies typically involve liquid formulations of polymeric micelles/nanoparticles, or solid formulations of solid dispersions and co-crystals.
Polymeric micelles are nanoparticles that encapsulate hydrophobic drugs and nutraceuticals as a result of hydrophobic-hydrophilic interactions. To ensure both a hydrophobic environment for the drug as well as solubility in aqueous solutions, the nanoparticles are formed of bi-block of tri-block copolymers, polymers that contain both hydrophobic and hydrophilic blocks (
Figure 1d). The polymeric micelles have low critical micellar concentrations, meaning they maintain their stability and form even at low polymer concentrations. They also provide improved solubilization, stability, and patient tolerability compared to micelles formed with hydrophilic surfactants. Genexol-PM by Samyang, a polymeric nanoparticle containing paclitaxel, reported better safety and less side effects compared to its earlier formulations relying of co-solvency with ethanol and cremophore EL.[
33] The hydrophobic block of the polymer is often made of PEG, which increases the circulation time of the nanoparticles by making less likely to be cleared by the reticuloendothelial system. However, it has been reported recently that pre-existing anti-PEG antibodies can lead to the quick clearance of PEG-containing nanoparticles, with an increased risk of immunogenicity and adverse events.[
34,
35]
Solid formulations relying on the formations of solid dispersions and co-crystals have been successful at increasing the bioavailability of drugs as well as generating commercial success to the manufacturer.[
6] Solid dispersions are often formed from a polymer “solvent” such as PEG, polyvinyl pyrrolidone (PVP), or HPMC (a cellulose derivative) with interspersed drug withing the polymer, either in as amorphous form or as a molecular dispersion within the polymer matrix (
Figure 1e). Solid dispersions increase the solubility of drugs by preventing the packing of the drug into a stable crystalline form and/or due to an increase in hydrotrophy behavior by forming a molecular adduct.[
36] Multiple formulations involving solid dispersions have shown considerable increase in drug solubility, such as Sporanox by Janssen Pharmaceuticals,[
37] a solid dispersion of the antifungal itraconazole in HPMC, or Nimotop by Bayer ltd.,[
38] a solid dispersion of the calcium channel blocker nimodipine in PEG. Despite their benefits, solid dispersion is the most commonly formed by hot melt extrusion, a very energy-exhaustive technique. Other formation techniques include spray-layer, which requires the presence of an additional substrate onto which the polymer and drug are deposited.[
39,
40]
One derivative of the solid dispersion method that has seen increased application is the formation of “inclusion complexes”. Inclusion complexes rely on a similar mechanism to molecular solid dispersions in that they form “host-guest” complexes where drugs are held inside matrix cavities by intermolecular interactions such as van der Waals interactions and hydrogen bonding. Inclusion complexes have been formed from natural biomolecules such as fenugreek fibers and starch,[
41,
42] synthetic cyclic oligomers like calixarenes,[
43] and poly- and oligosaccharides like arabinogalactan, glycyrrhizin, and cyclodextrins.[
44] FENUMAT
TM by Akay Natural Ingredients Private Limited is based on the complexation of active ingredients in fenugreek fiber matrix to enhance the bioavailability of phytonutrients. Natural and synthetic cyclodextrins (CD) are by far the most commonly used “host” molecules in inclusion complexes for drug delivery applications. CDs have a truncated cone structure, with a hollow hydrophobic interior and a hydrophilic exterior, which provides a good environment to trap hydrophobic drugs and solubilize them in aqueous media (
Figure 1f). The first FDA approved cyclodextrin-containing drug product was Sopranox oral and IV solution by Janssen Pharmaceuticals, which contained itraconazole entrapped in a synthetic CD.[
45] Tesseract Medical Research uses their proprietary CyLoc
TM and DexKey
TM technologies to entrap and then release active ingredients from cyclodextrin cages. These CD inclusion complexes are typically formed by freeze-drying, spray-drying, kneading or co-precipitation.[
45,
46,
47,
48]
This mini-review was not meant to discuss the all theorical and commercially available portfolio of delivery systems, however, it is reported the following definition of dendrimers and nano-gels, since the pivotal impact that these structures are showing in the pharmaceutical space.
Alternative and Non-Canonical Delivery Technology
A novel formulation in delivery systems is broke out by Folium Labs. This delivery system consists of proprietary solid-state reactive mixing (SSRM) technology that relies on encapsulating active ingredients and nutrients with hyaluronic acid (HA) matrices.[
52]
HA is a naturally-occurring polysaccharide and a primary constituent of extracellular matrices. Given its biocompatibility, biodegradability, and natural presence within the human body, HA is a superb matrix for forming inclusion complexes. Additionally, its remarkable mucoadhesive properties make it an excellent carrier for buccal and sublingual drug delivery.[
19] HA and its derivatives have been widely used as carriers of multiple classes of drugs and active molecules (nucleic acids, peptides and proteins, chemotherapeutics, imaging agents, and photosensitizers) in multiple drug delivery technologies (nanoparticles, micelles, hydrogels, emulsions, films).[
53,
54,
55]
HA has specific receptors expressed on cell surfaces that mediate its absorption into cells (endocytosis). These receptors are present in high concentrations in joint tissue (articular cartilage) and fluid (synovial fluid). They are overexpressed by tumors,[
53,
54] making HA an ideal carrier to deliver anti-inflammatories and chemotherapeutics with little to no synthetic alteration required for targeted delivery. Moreover, the functional groups (carboxyl and hydroxyl groups) present on HA enable its easy functionalization with bonds that are signal-responsive and break upon encountering specific chemical or physical cues such as pH, light, or molecules that are over expressed in tumor environments, enabling not only targeted tumor delivery, but also triggered release of the drug/nutraceutical of interest.[
55] SSRM technology involves a solvent-free, low-energy, green, one-step complexation process. The drugs, nutrients, and matrix used are all commercially available, making SSRM a very low-cost technology. The active ingredients are held within the HA matrix by hydrogen-bonding and van der Waals interactions and do not rely on any specific interactions between the drug and HA, making SSRM an easily scalable and translatable technology to use with a wide range of hydrophobic drugs and nutraceuticals. Moreover, the fact that SSRM is not a nanotechnology, nor does it rely on chemical modifications to the drug or natural HA makes it easier and faster to meet regulatory compliance and bring the products to market.
Proof-of-concept animal studies on a number of nutraceuticals formulated using SSRM have shown a significantly increased bioavailability by up to 10 times depending on the ingredient studies.[
56,
57]
The first use of HAs in nanotechnology for delivery systems date back in the early 2010s. The introduction of HAs follows the need for the stealth effect of nanoparticles that have been introduced in the previous years via conjugations of high hydrophilic proteins with several kinds of combination: HPMA/PEG/PLA/PLGA.[
58]