The Nutraceutical Market & Novel Advanced Delivery Systems

Image courtesy of Gencor.

In 2021, the global nutraceuticals market size was valued at USD 454.55 billion with an expected compound annual growth rate of 9.0% from 2021 to 20301 (Grandview Research). More retailers will invariably enter the market as demand for nutraceuticals grows and, to remain competitive, they must provide high-quality products that are effective for the stated purpose.

Nutraceuticals MarketHowever, the efficacy of nutraceuticals is a function of absorption and bioavailability after ingestion. Absorption refers to the process of a molecule’s movement from ingestion to its entry into systemic circulation. Bioavailability refers to the amount of the molecule that was absorbed and reached systemic circulation relative to what was ingested.

As consumers and brands begin to recognise the importance of bioavailability, a working knowledge of the mechanisms and interactions that affect nutraceutical bioavailability is imperative for determining the best approach for development of novel and innovative advanced delivery systems.

Novel Advanced Delivery Systems

Nutraceutical ingredients such as quercetin, curcumin, resveratrol, and vitamin D3 all have demonstrable beneficial effects on health but, due to their lipophilicity, they are poorly soluble in the aqueous environment of the gastrointestinal tract. Therefore, an effective delivery system is required to enhance their absorption and subsequent efficacy.

There is no-one-size-fits-all solution, and the right delivery system must be carefully selected based on various factors including the active ingredient, the final dosage format (i.e., tablet, capsule, powder, liquid spray, effervescent, etc), and the end user.

Here come liposomes

Liposomes are tiny, spherical, engineered, nanostructures that are mainly made up of a lipid bi-layer membrane around an aqueous core. They are mainly made up of biological materials, so they are seen by the body as inert. Both hydrophilic and lipophilic active ingredients can be incorporated into the liposome to achieve targeted delivery of your desired active to the cells that need it.

Liposomes rely on electrostatic charge, between the lipid molecules, to keep the membrane in place. They also rely on the subsequent electric potential at the interface of the lipid bi-layer and the liquid carrier (in our case, water).

As liposomes are generally below the visible wavelength of light (380 to 700 nm2) it is not possible to see them using a standard light microscope. So, how do you confirm that you have actually made liposomes and not a “soup” of ingredients?

Other than particle size and distribution, two important tools around the characterisation and presence of liposomes are zeta potential and transmission electron microscopy imaging.

Zeta potential

Zeta potential is the electric potential at the interface of the lipid bi-layer and the water surrounding it.

Colloidal dispersions (eg, liposomes in water) with a medium to high zeta potential (negative or positive charge greater than 20 eV) are electrically stable while those with a low zeta potential (anything below 20 eV) are unstable and tend to coagulate or flocculate (clump).

Also, zeta potential is one of the available tools to characterise a double layer, such as that in a liposome. The below chart shows the difference between a particular formulation made by two different manufacturers using different methods of manufacture.

Zeta Potential

Pharmako Biotechnologies Competitor Liposomal D3 
Competitor Liposomal D3
PlexoZome® D3 – high zeta – low zeta potential means 
Potential means more less stability and high coagulation. stability and no coagulation. 

TEM (Transmission Electron Microscopy) imaging

TEM is an imaging technique that uses an electron beam to image a nanoparticle sample. It provides much higher resolution than is possible with light-based imaging techniques.

TEM is an important method for the characterisation of the presence, size and shape of liposomes. It can directly visualise single particles (at the low end nano scale) and even go into detail of their inner structure, eg lipid bi-layer. There are two distinct methods for TEM visualisation. One is cryo-electron microscopy (cryo-TEM) and the other is negative staining TEM.

Liposomes need to be preserved for the electron microscope to best visualize them close to their native structure. As such, cryo-TEM is best suited for this application. Cryo-TEM uses thin films of suspensions that are plunge frozen to create vitrified ice films that can be imaged directly in the electron microscope under liquid nitrogen temperature. This requires very expensive equipment, detailed methods, and experienced operators, hence it is not commercially readily available.

The other method is negative staining TEM (usually with uranyl acetate). As liposomes do not have enough contrast they need to be stained in order to distinguish their features. Negative staining TEM is faster and simpler than cryo-TEM. It also requires less advanced equipment, methods and is more readily available.

Negative Staining TEM
Picture 1. Negative staining TEM of competitor D3 with 2% uranyl acetate. Liposomes are not clearly visible and, whatever structures are there, appear to be clumping, due to their very low zeta potential.
Negative Staining TEM
Picture 2. Negative staining TEM of Pharmako Biotechnologies PlexoZome® D3 with 2% uranyl acetate. Liposomes are clearly visible and are freely distributed in the liquid medium.
Cryo TEM
Picture 3. Cryo-TEM of Pharmako Biotechnologies PlexoZome® D3. Liposomal multilamellar membrane is clearly seen.

Education opportunity

Formulation opportunities and new ingredients were discussed in depth at the Naturally Informed virtual event Stress and Mental Wellness: Mastering the Market on September 20-22, 2022. A session presented by Gencor titled Mental Wellness for the Seven Living Generations covered the emerging research. Register here to view on demand.

*Content provided by Gencor.

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George is Pharmako Biotechnologies’ Technical Director and Co-founder. He is the inventor of a number of the technologies used in Pharmako’s products and has 30 years of experience with the industry. George received his degree in chemistry from the Australian National University and started his working career with the Therapeutic Goods Administration (TGA). The following nine years saw George into his last position within the TGA at an Executive Level 1, heading special projects in the Complementary Medicines Branch. He then moved to industry and went on to become the General Manager of a therapeutic goods regulatory consulting firm. He managed a portfolio of over 100 clients with over a thousand products. The next position was with a medicine manufacturing brand company, as the General Manager, with the main tasks being to modernise the manufacturing arm, introduce new product development, regulatory and expand business development. George now coordinates all technical aspects of Pharmako with a keen interest in new delivery technologies, clinicals and advanced manufacturing methods.