Liposomes, Micelles, Cubosomes and Ethosomes: What are the differences between these Lipid Carriers, and which one should you use for your supplement formulations?
You will likely have heard of liposomes and liposomal supplements as they have been exploding in the supplement sphere…and on the shelves in health stores.
Yet, what do ‘liposome’ and ‘liposomal’ mean?
Furthermore, where do the other common lipid carriers micelles, cubosomes and ethosomes come in to play?
In this blog, we will discuss what liposomes, micelles, cubosomes and ethosomes are; the relationship between each of them, weigh out the pros and cons for their respective applications and ease—or difficulty—in formulating, and their delivered bioavailability.
Liposomes, micelles, cubosomes and ethosomes are lipid particles which encapsulate nutrients, vitamins, phytonutrients, etc. through emulsification for optimized oral and/or transdermal delivery and absorption.
Lipid Nano Systems image sourced from https://www.mdpi.com/1422-0067/22/15/8319
See our ‘Lipid Carriers Summarised’ sheet here.
LIPOSOMES
Liposome literally means ‘body of fat’. They are tiny spherical containers with a liquid nutrient core and a protective phospholipid bilayer, similar in structure to human cell membranes. It is in fact liposomes’ mimicry of human cells that allows them to be so efficiently and absorbed into our bodies.
Liposomes are amphiphilic molecules, meaning that they have both hydrophilic (‘water loving’ solubility) and hydrophobic (‘water hating’ resistance) traits. They measure between 50-500 nm in diameter particle size, although could be bigger.
The external layer consists of a double lipid layer that is hydrophobic, protecting the internal nutrient from dissolving in water or being destroyed through digestion. Within the lipid bilayer is the hydrophilic tail which blends easily with water. This means that they can simultaneously protect and transport nutrients into targeted areas of the body.
This ensures that the nutrient contained within the liposome is protected from oxidation, external damage, early absorption, and consequential destruction. Many nutrients are fat soluble and thus can only be effectively absorbed into the body if consumed alongside a fat, such as a phospholipid, otherwise the supplement simply passes through the body with little or no absorption.
FAT SOLUBLE BIOAVAILABILITY: WHEN IS LIPOSOMAL ENCAPSULATION IDEAL?
Curcumin, antioxidants, vitamins A, C, D, E and K are examples of fat-soluble compounds which need to be encapsulated in a lipid (in the form of a liposome) or consumed with fat to improve bioavailability. The phospholipids also act to increase absorption of nutrients, slow down and sustain the release and distribution of nutrients so that the consumer benefits from having the nutrient in their system for longer, rather than excreting the supplement out to quickly and leading to what is anecdotally known as ‘expensive pee’!
PROTECTION FROM HOSTILE ENVIRONMENTS
Other environmentally sensitive compounds, such as Glutathione, Omega3 DHA, Sulforaphane, Probiotics, NAD+ (Nicotinamide adenine dinucleotide) and SOD (Superoxide dismutase) need protection from oxidation with air, water, temperature, nitrates, preservatives, and other chemicals. The lipid bilayer within the liposome protects the sensitive inner nutrient core from reacting with the external environment. Once oxidized, some nutrients can become ineffective at best and toxic at worst.
Glutathione is an example of a supplement that can become degraded when exposed to water.* Supplements that blend glutathione and water together likely contain degraded glutathione which can have little to no health benefit. In this instance, it is essential to use a liposomal—or cubosomal—encapsulation and delivery for compounds like glutathione.
In summary, liposomes offer nutrient stability, protection from damage and oxidation, increase a nutrient’s half-life, optimize absorption and bioavailability.
The process of encapsulating a nutrient in lipids (emulsification) to create a liposomal supplement requires specialist equipment, expertise, and patience. Therefore, true liposomal supplements are more costly than their powdered, capsuled and ethosomal counterparts. We specialize in liposmal encapsulation.
MICELLES
Micelles are similar to liposomes yet far smaller. They are amphiphilic molecules with a hydrophilic outer and a hydrophobic core and unlike liposomes, do not possess the double lipid concentric layer.
Micelles’ one single lipid layer allows them to blend with water more easily. As they have a significantly smaller surface area, they can carry fewer nutrients, yet because of their more permeable outer layer they can more readily deliver nutrients directly into the cell. In fact, our bodies break down liposomes into micelles so that we can more efficiently absorb nutrients. Micelles are ideal for nutrients which need fast absorption yet supplements that are not highly reactive to the environment.
Micelle encapsulations are ideal for fat soluble, environmentally stable supplements such as: curcumin, chlorella, vitamins A, C, D, E and K and assist in the absorption of certain minerals. Due to their small size, micelles are ideal for encapsulating fat soluble compounds like terpenes, CBD, etc.
CUBOSOMES
Cubosomes resemble a fluid cubic constellation of liposomes. They are highly stable self-assembled liquid crystalline particles made up of water and lipids which are stabilized by a continuous membrane lattice structure and a polymer based outer sheath that holds everything within the cubosome structure together. They measure between 50-500nm in diameter particle size and are sometimes larger.
Like liposomes and micelles, cubosomes are made up of amphiphilic lipids that either resist or react with water. The cubic, multi-dimensional structure gives cubosomes a very large surface area in which they can encapsulate high quantities of nutrients.
The multi layers of liposomes within the cubosome, with the interwoven lattice membrane and outer lipid layer all work in synergy to protect and stabilize the nutrients encapsulated within. This lends cubosomes their uniquely high stability under environmental, chemical, and physiological conditions. Simultaneously, cubosomes’ natural composition allows them to effortlessly deliver nutrients into human cells.
Supplements ideal for cubosomal encapsulation include the environmentally reactive Glutathione, Omega3 DHA, Sulforaphane, Probiotics, NAD+ and SOD.
Talk to us innovate.today@virun.com to find out about creating your own cubosomal formulations.
From Ethanol to Ethosomes
Ethosomes are lipid carriers consisting of phospholipids, ethanol and water. They are tiny spherical containers, very similar to liposomes with a hydrophobic core, hydrophilic tail and a lipid bilayer, yet with ethanol, water and phospholipids being their main materials.
Ethosomes can effectively transport nutrients carried in their core to targeted areas. Ethanol concentrations in ethosomes vary from 10%-20% ethanol.**
10% is the commonly used lower range for ethanol concentration in Ethosome formulations. This approach aims to achieve a balance between stability, entrapment efficiency, and vesicle size, although depending on the specific nutrient and desired properties, even lower concentrations might be feasible in some cases.
TRANSDERMAL DELIVERY
Ethosomes are more effectively used for transdermal (topical/on skin) supplements, minerals and nutrient delivery as the ethanol supports dermal penetration and transportation of therapeutic agents directly into the skin and blood stream.
Ethosomes are ideal for topical application, such as a targeted magnesium, zinc, quercetin, or a CBD cosmetic cream or spray. At VIRUN, we specialize in oral supplement applications of which liposomes, micelles and cubosomes are optimum. We do not use ethanol or ethosomes in our formulations.
So, which lipid carrier is ideal for you?
Contact us today with your supplement ideas and we will help you create the most effective (and tastiest) liposomal, micelle or cubosomal supplements.
Upgrade your formulations with us: innovate.today@virun.com
See our ‘Lipid Carriers Summarised’ sheet here.
References:
Glutathione Degradation Studies:
* “Glutathione Degradation Is a Key Determinant of Glutathione Homeostasis” (2008) by Åsa Meister and Anna Björkhem-Olesen discusses the factors that influence glutathione degradation, including the presence of water. The study found that glutathione degradation rates were significantly higher in aqueous solutions compared to dry conditions.
“Study of the Oxidative Forced Degradation of Glutathione in Its Nutraceutical Formulations Using Zone Fluidics and Green Liquid Chromatography” (2019) by Ana Rita Bicho, et al., investigates the degradation of glutathione in its nutraceutical formulations, which often involve aqueous solutions. The study showed that glutathione degradation increased significantly in the presence of water and oxidizing agents.
Study of the Oxidative Forced Degradation of Glutathione in Its Nutraceutical Formulations Using Zone Fluidics and Green Liquid Chromatography research paper
“Heme Degradation in the Presence of Glutathione” (1990) by C.A. Rossi, et al., examines the interaction between glutathione and heme, another important biological molecule. The study found that glutathione can degrade heme in aqueous solutions, with the rate of degradation depending on factors such as pH and temperature.
Ethanol Studies:
** “Development and characterization of Ethosomes for transdermal delivery of meloxicam: In vitro and in vivo evaluation” (2012) by T.R. Bhalerao, et al., investigated Ethosomes for meloxicam delivery using ethanol concentrations of 10%, 15%, and 20%. The 10% ethanol formulation showed good stability and entrapment efficiency but slightly larger vesicle size compared to higher concentrations.
“Enhancement of transdermal delivery of quercetin using Ethosomes” (2011) by N.B. Jain, et al., explored Ethosomes for quercetin with ethanol concentrations of 10%, 15%, and 20%. Again, the 10% ethanol formulation yielded stable Ethosomes with satisfactory drug loading while potentially having lower skin penetration compared to higher concentrations.
“Ethosomes loaded with carvedilol: Effect of ethanol concentration on physicochemical properties, in vitro skin permeation and in vivo antihypertensive activity” (2017) by M.T. Khan, et al., evaluated Ethosomes for carvedilol using ethanol concentrations of 10%, 20%, and 30%. The 10% ethanol formulation demonstrated sufficient stability and drug entrapment but potentially lower transdermal flux compared to higher concentrations.
“Novel Drug Delivery Systems” (2018) by S.S. Shinde and P.D. Jadhav mentions that Ethosome formulations typically employ ethanol concentrations ranging from 10% to 50%, while acknowledging lower ranges are sometimes used for specific drugs requiring higher stability or smaller vesicle size.
“Transdermal Drug Delivery: Challenges and Perspectives” (2017) by P.B. Shetta, et al., briefly discusses Ethosomes and indicates that ethanol concentrations can range from 10% to 40%, depending on the desired characteristics of the formulation.
