Liposomal Delivery of Nutraceuticals: The Truth about Safety

Liposomal Delivery of Nutraceuticals: The Truth about Safety

By Dr. Christopher Shade, PhD

A recent review of lipid encapsulation technologies applied to pharmaceutical development focuses on the enduring utility of liposomes as carriers; it states, “Their attraction lies in their composition, which makes them biocompatible and biodegradable.”[1] The authors go on to state that, “Liposomes composed of natural phospholipids are biologically inert and weakly immunogenic, and they possess low intrinsic toxicity.” Another author group reiterates this sentiment, stating: “Liposomes are non-toxic, flexible, biocompatible, completely biodegradable, and non-immunogenic for systemic and non-systemic administrations.”[2] In fact, it is precisely this biocompatibility and biodegradability that draws pharmaceutical developers to use them. Liposomes in pharmaceutical delivery are dominantly administered IV, and their main function is to contain the severe toxicity of the chemotherapeutic and antibiotic drugs they carry, within an inert, pro-biological matrix that protects the biological terrain from the drug’s effects during transport to target sites in the body—usually vascularly leaky sites like tumors [1,34]. The use of liposomes in nutraceutical delivery is quite different—they increase the bioavailability of orally delivered compounds. Importantly, the intrinsic safety of a phospholipid-based system remains critical to why they are used in this regard, instead of purely synthetic surfactant systems. These basic facts make phospholipid-based deliveries a “no-brainer”.

Phospholipid-based particle systems are also a very natural fit for the body while in circulation. Liposomes, phospholipid-based nano-emulsions, and phospholipid micelles are very similar in structure and size to chylomicrons (the endogenous transport system for triglycerides) and other lipoproteins (Figure 1); it is perfectly logical that their use is inherently biocompatible. Any potential toxicity from injectable or transmucosal-absorbed liposomes lies in the clogging of the reticuloendothelial system (RES) [4]. The RES is a system of monocytic and phagocytic cells in the spleen and lymph nodes and Kupffer cells in the liver that remove particulates from circulation. Clogging these systems can result in granulomas and hepato- and splenomegaly. However, these effects are not seen until multiple injections of 100mg/Kg per day are given [4]; in humans, this would be 7–9 grams of phospholipid delivered IV multiple times per day. This data is irrelevant to liposome use of a few hundred milligrams of orally delivered phospholipids.

Figure 1. Structures of lipoproteins and phospholipid delivery vehicles

Metabolism of Liposomes

Phospholipids: Phospholipids are an integral component of the cell. The body has ready mechanisms, elucidated decades ago, for metabolism of the phospholipid base, including incorporation of the

phospholipid, intact, into membrane structures [5]. Phospholipids can also be broken down by phospholipases (e.g. phospholipase A1, A2 C, D, and lysophospholipase), yielding metabolic substrates and intermediates such as fatty acids, glycerophosphocholine, choline, and glycerol 3-phosphate [67]. These products can be used to remodel phospholipids as needed, synthesize acetylcholine, or generate ATP.

Other membrane modifiers: Different forms of polyethylene glycol are used in liposomal formulas to stabilize membranes and decrease clearance from the system by the RES [14]. These surfactants are generally cleared rapidly and unmodified in the urine [4]. However, the potential toxicity of PEGs varies greatly, as does the cost of these ingredients.

Ingredient Grades and Safety: Quicksilver Delivery Systems (QDS) products use only high-grade Phospatidylcholines (PC) and TPGS (tocophersolan), as a PEG source. Both of these ingredient grades are very expensive (e.g. The cost of TPGS is 5–10 times higher than other commercial PEG types, and high-PC fractions of lecithin cost 10–20 times more than raw lecithin), but they come with the best safety profiles. Environmental Working Group maintains a database of ingredients in foods and cosmetics and ranks them on a 1–10 scale of potential for toxicity (with 1 being the safest and 10 being the most dangerous QDS ingredients are rated as 1’s, whereas cheaper lipid delivery ingredients are ranked less favorably (Table 1). As an example of the wide array of tolerance of different surfactants taken parenterally, PEG 35 castor oil elicited negative mitochondrial responses in dogs at IV perfusion concentrations of only 100 µg/L [8]. This is a massively lower tolerance than the potential for IV phospholipid toxicity discussed above. While these are not equivalent units of measure, and not all animals saw the sensitivity to PEG 35 castor oil, this represents a 1,000-fold increase or more intolerance for liposomes over PEG 35 castor oil. Unfortunately, all excipients are not listed on Australian labels, but looking online at labels of the U.S. counterparts of the products will show you what excipients are being used in each delivery system.

Table 1. Comparison of Surfactants used for lipid nanoparticle deliveries
Surfactant EWG Hazard Rank (1-10) Relative Cost Uses
Phosphatidylcholine (50-90%PC fractions of lecithin) 1 $$$ High grade liposomes and cosmetics
TPGS (Tocophersolan) 1 $$$ High grade liposomes and lipid nanoparticles
Raw Lecithin (15-35%PC) 3-4 $ Foods, Low grade liposomes and cosmetics
PEG 35 Castor Oil 5 $ Micelles and cosmetics
PEG40 Castor Oil 5 $ Micelles and cosmetics
Polysorbate 80 3 $ Low grade micelles and liposomes

The Proof is in the Pudding – History of Use

Within its QDS portfolio, Quicksilver Scientific has manufactured and sold more than 320,000 bottles of liposome and nanoemulsion formulas over the last 7 years, without a single severe adverse event reported and no reports of developments of chronic issues. Similar to the case of toxicity profiles in pharmaceuticals, issues of hypersensitivities and intolerance to the supplements occur on the same or lower frequency as with solid-form dosages. In fact, many practitioners report greater tolerance in their patients. This may be due to 1) the distributed nature of the liquid format versus solid forms, which can dissolve and have high localized concentrations of compounds in the GI tract that may initiate immune reactions, and 2) phospholipid vesicles shielding the encapsulated compounds from overactive dendritic cells in the GI tract. While QDS liposomes are the most premium products on the market, they are not the oldest. LivOn Labs has sold their squeeze-packet liposomal delivery of Vitamin C and Glutathione for 14 years and has sold millions of units with a similar safety record.


With any new technology, well-intentioned questions are inevitable and will need to be answered. For a product that works exceptionally well, the question: “Does it work too well,” is natural and necessary. Fortunately, the answer regarding phospholipid-based delivery technologies such as liposomes is backed by decades of research and is a resounding, “Yes, they are safe.”

Join Dr. Shade's Community

Join our community and be the first to know about Dr. Shade’s articles, podcasts and events.

  1. Immordino, Maria Laura, Franco Dosio, and Luigi Cattel. “Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential.”International journal of nanomedicine 3 (2006): 297.
  2. Akbarzadeh, Abolfazl, et al. “Liposome: classification, preparation, and applications.”Nanoscale research letters 1 (2013): 1.
  3. Green, Andrew E., and Peter G. Rose. “Pegylated liposomal doxorubicin in ovarian cancer.”international Journal of Nanomedicine 3 (2006): 229.
  4. Drummond, Daryl C., et al. “Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors.”Pharmacological reviews 4 (1999): 691-744.
  5. Knoll, Gerd, et al. “Fusion of liposomes with the plasma membrane of epithelial cells: fate of incorporated lipids as followed by freeze fracture and autoradiography of plastic sections.”The Journal of cell biology 6 (1988): 2511-2521.
  6. Dennis, Edward A. “Diversity of group types, regulation, and function of phospholipase A2.”Journal of Biological Chemistry 269 (1994): 13057-13057..
  7. Baburina, Irina, and Suzanne Jackowski. “Cellular responses to excess phospholipid.”Journal of Biological Chemistry 14 (1999): 9400-9408.
  8. Burnett, C. L., et al. “Amended safety assessment of PEGylated oils as used in cosmetics.”Expert panel report, cosmetic ingredient review, Washington (2012): 7.