Using cyclodextrins encapsulation to increase the bioavailability of a hydrophobic active ingredient

Capsulæ is a leading company in the field of microencapsulation. It develops solutions for industrial customers to optimize active and inactive ingredients’ performance and facilitate their use. The company had a project that required finding an effective alternative solution to meet its client’s biodegradability requirements. It turned to the experts from CAPACITÉS to develop a new formula involving its method of encapsulation by cyclodextrins. The preliminary results are promising.

Increasing the bioavailability of a hydrophobic active ingredient

In the fields of food and feed, microencapsulation can improve an active ingredient’s stability. “Nevertheless, using conventional encapsulation materials does not always let us obtain all the beneficial effects from some active ingredients. This is due to weak bioavailability and is often linked to hydrophobicity,” explains Gisèle Ongmayeb, PhD, the R&I manager at Capsulæ.

Capsulæ wanted to explore other materials with structures that can protect hydrophobic active ingredients and simultaneously facilitate their bioavailability. Cyclodextrins were identified among these materials. They originate naturally and meet current regulatory demands concerning material biodegradability.

In this context, the company asked CAPACITÉS’ experts to encapsulate vitamin E as a model molecule. The intermediary results are very encouraging; the cyclodextrins selected allowed vitamin E to be encapsulated and improved its solubility in an aqueous phase. The results delivered in August 2021 confirm this trend, and a second phase of the project will begin with the aim of optimizing the process to reduce costs. Capsulæ’s goal is to offer its clients an innovative encapsulation technique at a competitive price.

An efficient collaboration in Research & Innovation for industry

“Private companies must join forces with researchers in academic laboratories, such as the experts at CAPACITÉS, to overcome certain scientific obstacles and use the latest methods of characterization. So, you must collaborate to innovate,” recommends Gisèle Ongmayeb.

In the context of this collaboration, “CAPACITÉS has knowledge and a high level of scientific expertise in a particular groundbreaking skill. Capsulæ has extensive experience and a unique global vision of the encapsulation market. For CAPACITÉS, this is the opportunity to make full use of its expertise with cyclodextrins for new industrial applications,” adds Gisèle Ongmayeb.

Do you need help solving bioavailability issues for an active compound? CAPACITÉS is your partner for finding ingenious solutions. Contact us.

Cosmetics: how to determine the biodegradability of complex matrices?

Due to the lack of standardised tests, the cosmetics industry is unable to evaluate the biodegradability of a mixture of substances with any degree of precision. Expectations of a simple and reliable method are high: manufacturers wishing to optimise the environmental impact assessment of their products, and European institutions looking to reassure and protect their citizens. In order to confront this methodological void head on, experts from CAPACIÉS and the GEPEA Laboratory, backed by Tronico and L’Oréal, teamed up to develop a new method for assessing the biodegradability of complex matrices. The issue lies in its standardisation, so as to meet the manufacturers’ economic requirements in terms of speed and reliability. New measuring equipment that is designed to automate testing is already being evaluated. ECHA, the European Chemicals Agency, is keeping a close eye on the progress of this innovative approach.

We asked two of CAPACITÉS experts to explain this concept in more depth: Prof. Gérald Thouand, a researcher at the GEPEA Laboratory, and Mickaël Crégut, an R&D engineer specialising in biodegradability and ecotoxicity.

An automated bioreactor to facilitate biodegradability assessment

In a nutshell

Key words


Discussions are under way in Europe about providing a framework for the assessment of the biodegradability of mixtures. Could you tell us a bit more about this issue?

G. Thouand: The European legislation, REACH, has been regulating pure substances since 2008. Eventually, mixtures will also be subject to legislation. We are all perfectly aware of the fact that it isn’t pure substances which are found in nature, but mixtures. A molecule can be perfectly biodegradable in a laboratory, yet not be biodegraded during wastewater treatment plant processing because it’s surrounded by hundreds of other molecules. This is what I call the “cocktail effect”, as no one has a standardised way to evaluate it.

For the time being, ECHA, the European Chemicals Agency, recommends isolating molecules in order to measure the biodegradability of each one separately. This is neither chemically nor technically feasible. Biodegradability and ecotoxicity specialists are simply unable to separate hundreds of substances from a mixture in a timely and cost-effective manner.

Manufactures are waiting for laboratories to offer them an alternative approach, so that they can finally be a driving force behind ECHA. The latter seeks to find a compromise between manufacturers’ capabilities with respect to evaluating their products, and a degree of certainty that the assessment methods employed are sufficiently reliable to protect society.

Do you have an answer for the manufacturers?

G. Thouand: Yes, Capacités and the GEPEA Laboratory, backed by L’Oréal and Tronico, have been developing a new approach for assessing the biodegradability and ecotoxicity of complex matrices since 2015.

We know that undegraded elements may remain after a biodegradation event and that these residues can be composed of hundreds of substances. We measure numerous parameters, including the toxicity of the final mixture, so as to assess whether it is more or less toxic than the initial mixture. Providing that there is no increase in toxicity, the mixture is characterised as biodegradable. This is what we refer to as “weight of evidence”.

In order to arrive at this conclusion, the complex matrix to be assessed and a certain quantity of environmental microorganisms are placed in a reactor. The substance is biodegraded if the microorganisms feed on it in order to grow: they consume oxygen to oxidise the substance and release CO2 to integrate it into their metabolism.

M. Crégut: In order to evaluate the biodegradability of a substance, there are thus four factors to be observed: oxygen decreases, carbon dioxide is produced, biomass is created and the substance disappears. These parameters are relatively easy to study separately, but very difficult to measure together. We managed to combine them into a single assessment system.

Repeating this procedure for four of five substances is already a painstaking task. Doing it for hundreds of substances would require an infinite amount of time… In order to address this issue, we developed a machine that carries out biodegradability and ecotoxicity testing automatically. Operators only have a single procedure to perform in the beginning, then they can leave it to carry on with the task for around 28 days.

Your testing method has been integrated into a new automatic assessment machine for establishing the biodegradability of mixtures. Can you tell us a bit more about its industrial roll-out?

M. Crégut: This is an important innovation, made possible by Tronico that backed the GEPEA Laboratory and Capacités from the very beginning, as well as L’Oréal that followed us. We received the first prototype in December 2020. At the moment, it’s in the laboratory evaluation phase. It will soon be sent to Eurofins in Nancy, where testing will be carried out under the aegis of L’Oréal that is financing the operation. Such field experiments are essential prior to the market launch in 2022.

G. Thouand: The main challenge was to combine all the parameters for assessing the biodegradability of a complex matrix into one machine, and in a way that was automatic and fast… We succeeded by combining numerous technologies that had already been mastered. We miniaturised each operation in order to create a compact machine that occupies only 1 m2. It takes only one person to operate it.

ECHA is looking for a compromise between their need for safety and the manufacturers’ need for a method that can be applied at a reasonable cost and within a reasonable time. Could your method be that compromise?

M. Crégut: Yes, that’s a possibility. In any case, ours will most likely be one of the methods recommended by ECHA for biodegradability testing. Together with L’Oréal, we published an article in the journal Green chemistry that was presented at SETAC Europe, the global biodegradability and ecotoxicity congress, in 2019. We feel that our approach is starting to become the general consensus.

It is a valid means of assessment that is economically viable, while addressing the key ecological issues. Our citizens need transparency, that’s normal. Manufacturers also need to understand precisely what this entails.

To find out more about our expertise in biodegradability and ecotoxicity, please visit our dedicated page or contact us directly.

Our projects

Characterizing ecotoxicity in complex substances

The client concerned is a leading player in the specialty ingredients sector for health and beauty. In 2019, it reaffirmed its confidence in Capacités and the GEPEA laboratory by requesting that their teams assess a new polymer’s ecotoxicity.


Significantly increasing the solubility of active ingredients via cyclodextrins encapsulation

Cyclodextrins are a cyclic oligosaccharide derived from amylose. These molecules, featuring a hydrophobic cavity and a hydrophilic surface, serves to resolve two issues which are frequently encountered in the development of medicinal products and active ingredients in general: the solubility and stabilisation of the molecules in question. There are obvious benefits to be gained from using cyclodextrins, providing that this is backed by specialised skills in glycoscience in order to optimise its affinity with the relevant compound.

We asked two of Capacités experts to explain this concept in more depth: Dr Sébastien Gouin, CNRS from the CEISAM Laboratory, and Dr Dimitri Alvarez-Dorta, an R&D engineer specialised in organic chemistry.

In a nutshell

Key words

enzyme engineeringmolecular biologyGlycochemistry Enzymology

What main factor should be considered in order to optimise the efficacy of an active ingredient? What do cyclodextrins have to offer in terms of a solution?

S. Gouin: The solubility of an active ingredient is crucial with respect to developing a formulation. Many drug candidates are too hydrophobic to be used as is for in vivo studies. Their inclusion into a cyclodextrin resolves this issue by significantly increasing their water solubility. The active ingredient is thus dispersed in the bodily fluids and is able to reach its intended target.

We developed sugar-based compounds that selectively detach certain E. coli bacterial strains that are responsible for the inflammation of the intestinal wall in Crohn’s disease patients. A company called Enterome is currently developing a drug candidate (Phase IIa clinical trials) based on this concept. Our collaboration revealed that several of our key compounds were very active, yet too water insoluble to be used pure. Owing to cavity-matched cyclodextrin encapsulation, we managed to increase their water solubility significantly by up to several dozen grams per litre.

To what extent do cyclodextrins improve the preservation of active ingredients?

D. Alvarez Dorta: The molecules might be perfectly water soluble, yet degrade over time, which undermines the effectiveness of the active ingredient. Encapsulation preserves these delicate molecules by protecting them from oxidation, light and heat.

This is how we were able to stabilise the active ingredient of a myorelaxant medication used in anaesthesia: we encapsulated the molecule in commercial cyclodextrin. Degradation tests showed a very significant level of stabilisation of the muscle relaxant, both in solution and in a lyophilised preparation for reconstitution. As a result, this medication can now be stored at room temperature for two months without losing efficacy.

Cyclodextrin encapsulation clearly presents an effective method for significantly increasing the effect of unstable and low-solubility active ingredients. How do you go about encapsulating these molecules?

S. Gouin: Through various analytical techniques, we select the cyclodextrin that is best suited to the compound requiring encapsulation: the ligand. We measure the affinity of the cyclodextrin for the ligand, and then blend them with an organic solvent to create the inclusion complex. Once encapsulated, we determine the obtained gain in solubility. Lastly, we prepare the inclusion complex in the form of an easy-to-use powder.

What specific expertise does cyclodextrin encapsulation require?

D. Alvarez Dorta: The difficulty lies in optimising the cyclodextrin’s affinity for the ligand. The properties of the cyclodextrin are chemically modified in order to correctly encapsulate the ligand.

One laboratory wanted to use cyclodextrin as an antidote for an active ingredient. The commercially available cyclodextrin didn’t have enough affinity for the active ingredient, so we carried out a selective functionalisation of the cyclodextrin until we had managed to increase the cyclodextrin’s affinity for the compound by a factor of 1000.

Are you able to encapsulate all molecules in cyclodextrin?

S. Gouin: We play around with the size of the inclusion cavities of the various cyclodextrins (alpha, beta and gamma) in order to encapsulate molecules of different sizes. The encapsulation can either be complete, for small molecules, or partial, for larger ones. In most cases, only the most hydrophobic part is encapsulated, which is enough to significantly increase water solubility.

To find out more about cyclodextrin synthesis and its applications, we invite you to either explore our know-how in glycochemistry or to contact us directly.

Our projects

Capacités develops an enzyme for…

Sourcing, modeling and high-throughput screening of DNA synthesis enzymes


Enzymes at the Heart of…

A company that manufactures pharmaceutical grade hyaluronic acid contacted Capacités’ enzyme engineering experts: the company aims at developing a new deacetylation process which keeps overall polymer structure while increasing its interactions with stem cells.


Industrial ecology: large-scale cultivation of microalgae in French Guiana

In February 2021, the refining company SARA launched an ambitious industrial ecology project, managed by ADEME (French Agency for Environment and Energy Management).  This pioneering industrial ecology undertaking will serve to implement the construction of an immense demonstrator facility in French Guiana — the largest of its kind to be built on French territory to date. It aims to create novel, sustainable systems based on the valorisation of industrial CO2 through the large-scale production of microalgae. This highly innovative venture draws upon several research projects in order to roll out the cultivation of microalgae for third-generation biofuels, as well as biomaterials and dietary supplements. As its research partners, SARA selected the GEPEA Laboratory via its world-renowned AlgoSolis platform, and CAPACITÉS, the private engineering and research valorisation subsidiary of the University of Nantes. As a subcontractor, the Saint-Nazaire company, AlgoSource, will also play its part.

Forging a microalgae-based bioeconomy in French Guiana

In its role as coordinator of this project, called the PIAN project, SARA, a refining company based in Martinique, Guadeloupe and French Guiana, has been developing initiatives concerning new energies, environmental protection and bio-based economies for many years. The PIAN project is geared towards fostering the microalgae sector in Overseas France, starting with French Guiana, where the climatic conditions are particularly favourable to microalgal culture. Its ultimate goal is the large-scale roll-out of simple cultivation systems that take full advantage of these conditions in order to establish and sustain a new bioeconomy, thereby promoting job creation while reducing environmental impact and valorising CO2 emissions from industrial sites.         

This long-standing partnership with the GEPEA Laboratory, for which CAPACITÉS and AlgoSource act as subcontractors, dates back to 2017. Our initial collaboration involved evaluating the viability of integrating microalgal culture into industrial ecology and circular economy. CAPACITÉS’s engineers took samples of around 10 strains of algae from their natural environment in French Guiana and screened them for their growth rate and capability to accumulate lipids at the AlgoSolis facility in Saint-Nazaire. Their research served to isolate, among others, several high-potential endemic strains, with three strains showing particular promise for biofuel production.

Scaling up a cultivation process devised in 2017

The PIAN project has served to consolidate these efforts by confirming their viability with respect to integrating microalgal production into French Guiana. Having been selected during a call for proposals issued by “Programme d’Investissement d’Avenir” (PIA assigns innovation funding financed by the French government), entitled “Bioéconomie et Protection de l’Environnement” (Bioeconomy and Environmental Protection), which is managed by ADEME, the PIAN project will be developed over a period of three years. Its total cost is €5.64 million, of which €4.9 million qualifies for ADEME funding, and whereof €0.74 million was awarded to the GEPEA for its partnership role.

These funds are to finance the installation of a demonstrator facility at one of the SARA industrial sites in order to define, approve and optimise integrated procedures for two strains that have yet to been grown over large areas. The selected strains are spirulina, which will be cultivated for new applications in nutrition, cosmetics and biomaterials, as well as a local oleaginous microalgae, previously identified by the GEPEA Laboratory, for the production of 3G biofuels. New generation processes, called wet processes, which were developed on the GEPEA’s AlgoSolis platform, will be tested here.

Thanks to PIA’s funding, SARA will thus be able to launch a new phase in its industrial development by constructing a demonstrator facility that will provide the necessary data for further implementation on future sites. It has demonstrated its continued trust in the GEPEA, which in turn has chosen to join forces with CAPACITÉS and AlgoSource, once again, in order to bring this project to fruition.

This far-reaching project represents the culmination of several years of research and collaboration with CAPACITÉS regarding the use of microalgae in industrial ecology, large-scale solar cultivation and third-generation biofuels.

Université de Nantes and Capacités receive an Emmy® Award

The National Academy of Television Arts and Sciences (NATAS) recently presented Université de Nantes with the Technology & Engineering Emmy® Award. This prestigious award was granted to the Nantes researchers in recognition of their development of “open” tools that optimise the perceptual quality of video compression. Capacités’s teams played an important role in this major contribution to the field of audio-visual sciences.

“We are very pleased and, above all, very proud. This Emmy recognises the open innovation approach that resulted from an exemplary collaboration between industrial stakeholders and academic institutions”, explained Patrick Le Callet, a professor at Polytech Nantes, a researcher at the Laboratoire des sciences du numérique de Nantes (LS2N, Nantes Digital Science Laboratory) and a lead scientist at CAPACITÉS. “The subtle, intelligent and agile interaction of all those involved, notably Université de Nantes Foundation and CAPACITÉS, was the deciding factor with respect to the success of this endeavour.”

The Laboratoire des sciences du numérique de Nantes (LS2N) enjoys global recognition for its expertise in the field of visual perception for multimedia applications. Its researchers have spent several years working on the automatic evaluation of image and video quality, as well as on improving this quality.

Since 2017, assisted by CAPACITÉS and two American universities, they have been developing a particular encoding system (called the “dynamic optimizer”) for a renowned VOD giant, namely Netflix. Their main objective was to preserve video quality, even when streaming over low bandwidth on a smartphone, which was considered a major contribution to the field of new technologies.

Find out more about the video encoding algorithms that were developed for Netflix under Our Achievements.

The European Space Agency has entrusted QinetiQ and CAPACITÉS to harvest spirulina in zero-gravity conditions

As part of the MELiSSA project (Micro-Ecological Life Support Alternative), the European Space Agency (ESA) has selected QinetiQ, partnered with CAPACITÉS, to demonstrate the efficacy of a process for cultivating and harvesting spirulina in zero-gravity conditions. This microalgae has the ability to recycle space-station waste by feeding on carbon and nitrogen, to produce food with high nutritional potential. 

The goal: create an autonomous space station

Launched in 1989, the MELiSSA project aspires to transform a spaceship into a closed ecosystem by recycling carbon dioxide and organic waste and transforming it into food, oxygen and water. For instance, supplying the International Space Station (ISS) with oxygen, water and food is indeed very costly and time-consuming. Long-haul space missions to the moon or Mars would require 30 tons of supplies; hence the need to develop a bioregenerative system.

The challenge: cultivate and harvest spirulina in zero-gravity conditions

Spirulina is extremely beneficial microalgae from a nutritional standpoint. Is recycles the water in which it grows and produces oxygen. Moreover, it grows up to 100 times faster than a terrestrial plant. It is the ideal candidate for a space mission.

The challenge is to succeed in cultivating and harvesting it in space, and therefore in zero gravity. With this aim, our microalgae bioprocesses engineers will soon attempt to validate an axenic process to continuously cultivate and harvest spirulina in a controlled photobioreactor developed by the laboratory GEPEA: HECTOR. QinetiQ and CAPACITÉS will study several types of filtration technology, with the goal of achieving microalgae filtration in the absence of gravity.

The project began in December 2020 and should last a little over one year.

The CPV recognised by the State as “Manufacturing Integrator in Gene Therapy”

The Nantes “Centre de Production de Vecteurs”, known as the “CPV” (Vector Production Centre), which is part of the gene therapy laboratory, was named winner of the State’s Grand Défi (Big Challenge) in the “Biopharmaceuticals” category.

Integrators are required to participate in cutting-edge consortia in order to improve yields and curb the production costs of emergent biological molecules.

What does the certification “Manufacturing Integrator” mean?

The State launched the Grand Défi for Biopharmaceuticals in the spring of 2019 with a view to “improving yields and managing production costs.” Following a call for expressions of interest that was initiated in June 2020 by the Secretary-General of Investment, six technology platforms were selected to become manufacturing integrators for the Grand Défi, including the Nantes CPV for its gene therapy products issuing from viral vector bioprocessing.

The goal of the Grand Défi for bioproduction is to encourage the manufacture of innovative advanced therapy medicinal products, while improving their yields and curbing their production costs in order to meet the challenges of the pharmaceutical industry and thus facilitate patient access to these promising new treatments.

The CPV platform: producing and characterising viral vectors

Founded in 1997, the Centre de Production de Vecteurs — the Vector Production Centre of the Gene Therapy Laboratory in Nantes, UMR1089 — develops viral vector production and characterisation processes for gene transfer based on adenoviruses and AAVs (adeno-associated viruses). These are intended for applications ranging from basic research up to translational levels.

The CPV, a Capacités partner

Teams from the CPV and Capacités are currently collaborating on viral vector production and characterisation projects. Together, they are developing customised analytical tests to improve the characterisation of future gene therapy medicinal products. To find out more about our joint projects, please see below.

If you have any questions concerning a partnership with the Nantes CPV, a manufacturing integrator of the Grand Défi in biopharmaceuticals, please contact Oumeya Adjali and Emilie Audran.


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