Just like in other fields, innovation in cosmetics is usually associated with advances derived from scientific and technical progress. But, at the end of the day, few major technological innovations contributed to the progress made in the cosmetics industry: we can mention peptides, silicones, non-ionic surfactants, and a few others. Liposomes emerged much more recently
They are often rightly introduced as a breakthrough innovation. However, this article is not aimed to make an update on the state of science or technology applied to liposomes, but to explain how this technology appeared and developed in the cosmetics sector, and how it contributed to a sustainable innovation approach in this field of application.
In 1986, following the concept of “simultaneous innovation”, which refers to how everybody does the same thing at the same time, singular products different from what was seen until then emerged on the market, marking quite significant a disruption compared to standard practices. These products gradually became new technological standards. They were the first to result from a new vectorization technology, the technology of liposomes: “Niosomes®” were developed by the L’Oréal group for Lancôme, and “Capture®” was designed by LVMH under the Dior brand. They were outstanding in how they involved new techniques, which means they provided a technological value, but also impacted other fields with their unique associated communication: more aggressive product names, almost systematic use of scientific sponsorship and valorization… Their multifaceted impact made them true innovations. In addition, the emergence of these products was enhanced by a sociological fact, the effect of babyboom, which led to setting up a new product segmentation. All these factors resulted in this adventure becoming a major breakthrough in the history of cosmetics. And that is another reason why we decided to analyze how they were developed and gradually established in this industry.
The technology of liposomes
A liposome is a globule of fat called “vesicle”. It is composed of concentric lipid bilayers which confine aqueous compartments between them. Liposomes are obtained from a great variety of mainly amphiphilic lipids, the most widely used being phospholipids. When such compounds are in the presence of an excess of aqueous solution, they organize themselves so that they minimize interactions between water and hydrocarbon chains. This system triggers the more or less spontaneous formation of lipid sheets in the form of bilayers.
Liposome
Before liposomes appeared, there were a group of substances whose behaviour already intrigued researchers long ago. They were singular lipids, called phospholipids, and more generally amphiphilic substances, which were characterized by a surprising behaviour, because they were polymorphic and crystalline.
@Wikipedia
The interest in these phenomena can be traced back to very old, late 19th century work on the states of matter. At that time, what biologists and botanists observed with polarizing microscopes on biological systems had led them to imagine that the known states of matter – solid, liquid, gaseous – had to be completed with a new notion of “organized phases”. These unexpected findings were soon associated with the properties of specific lipids, in particular lecithins, and resulted in the notion of “lyotropic liquid crystals”. Although they are not closely related to liposomes, these notions are more or less linked with them, since the subsequent studies conducted on cell membranes highlighted similar phenomena. Cell membranes were examined as part of substantial research work, but it is only in 1937 that James Frederic
Danielli and High Davson hypothesized that a cell membrane was composed of a lipid bilayer sandwiched between two layers of proteins. The two physical chemists went on with their research to obtain more complex representations based on the same hypothesis. Pretty soon, the nature of the components in these structures was characterized: this is how complex lipids known as phospholipids, and more generally amphiphilic lipids, were discovered. And multiple studies were soon to focus on these lipid bilayers.
Research on the formation of organized lipid vesicles started in 1947. Liposomes were evidenced by Alec Bangham a bit later, in 1965. By taking interest in the phospholipids contained in red blood cell membranes, this British researcher discovered how they spontaneously got organized with water. He “humbly” suggested naming these vesicles “Banghasomes”, an idea the scientific community did not adopt. Their common points with the organization of lipid bilayers were soon noticed, so that the interest in liposomes mainly focused on their structure, and more specifically on biomimicry, i.e. the structural analogy with cell membranes. The similarity of these structures with cell membranes immediately generated considerable interest. The hypothesis made was that, by fusion with membrane lipids, they might pour their content into cells. As a result, the world of research focused on these vesicles likely to become molecule carriers, among others. Then, there was a real flood of scientific publications about their properties. According to some researchers, the Medline® database contained over 35,000 references in the 1970s, for more than 2,700 journals specialized in liposomes.
Niosomes
Meanwhile, although a little later, in the late 70s, a team of physical chemists of the L’Oréal Group headed by G. Vanlerberghe and Rose-Marie Handjani developed another concept: NIOSOMES. Using the work done on lamellar phases, for quite a while the team had focused on the development of lipid aggregates able to encapsulate substances, while presenting similarities with natural membrane systems. This research was based on the idea that lipid vesicles could be prepared based on a great variety of amphiphilic compounds. They chose synthetic non-ionic lipids to formulate organized systems, alkyl glucosides, and they called this technology “Niosomes”, because it involved “non-ionic liposomes”. The work was presented for the first time at the Sydney IFSCC[1] Congress, in 1978. Back then, lipopolyglycerol vesicles were considered a most interesting innovation for cosmetics formulation. Indeed, scientists only knew anhydrous or lipid/water formulation systems and O/W and W/O emulsions: these new structured formulas represented an opportunity to make significant progress. The very first patent describing these technologies is most probably French patent no. 2.315.991 of 30/6/1975. After several studies conducted by L’Oréal, these preparations were deemed able to have an intrinsic action on the skin. Rather spectacular effects were obtained on dry skins (Nouvelles Dermatologiques, vol 5, 1986, 259). In this case, the effect suggested involved a restructured epidermal barrier rather than the delivery of actives, but these very similar concepts created confusion. Anyway, this technology was a good candidate for topical applications. However, the idea of preparing liposomal suspensions prevailed over that of structuring a lamellar phase, but progress was definitely made in executing these programmes (cf Rose-Marie Handjani).
[1] International Federation of Societies of Cosmetic Chemists
Liposomes and cosmetics
The pharmaceutical industry was the first to seriously work on liposomes as potential drug carriers. These preparations were described as “magic bullets”. Soon, start-ups – this term did not exist back then – were set up to prepare developments. However, given the multiple technical difficulties it involved, it took a very long time and did not exactly result in the desired outcome, since characterization, reproducibility, bioavailability, efficacy and safety requirements are tricky to meet with these metastable vesicles. If it took longer for the cosmetics industry to take interest in these properties, results were obtained faster. Except for a few teams working on advanced research concepts, few publications appeared on cosmetics applications until the late 1970s. In fact, the industry was interested in two scientific effects widely discussed at the time: percutaneous absorption and the role of cell membranes in ageing. As for cutaneous absorption, very little data were available on absorption kinetics. In addition, the work done to describe the structure of the stratum corneum focused on the value of the barrier effect and on the components responsible for it – specific lipids. Given the benefit offered by liposomes in terms of bioavailability, progress was definitely possible. As for the role of the cell membrane, several studies had shown that viscosity changes could be associated with the cell ageing process. According to this theory, membrane fluidity was made possible in the presence of phospholipids with unsaturated carbon chains. The idea was that incorporating plant-based phospholipids could provide the fluidity wanted. Phospholipids were involved in both cases.
A few scientific teams started working on these hypotheses.
Composition
They were mainly composed of very simple natural substances – soya lecithin or egg yolk – or synthetic lipids, like phospholipids. Cholesterol was often used as a stabilizer. Beyond these basic ingredients, depending on their characteristics, liposomes could contain a great number of substances. You will find a summary in this document: http://journalssc.com/en/articles/65815.html. After rather hesitant beginnings for a few players, including those who eventually developed the first products, the whole cosmetics industry started working on these technologies and several manufacturers devised encapsulation technologies of this type. Several types of liposomes were developed: oligo-lamellar or multi-lamellar, big-sized or small-sized unilamellar, multiple, archaeosomes, etc.
The mechanism of action of liposomes
The mechanism of action initially proposed was based on the belief that liposomes could act as suggested by academic research, i.e. by membrane fusion, to deliver the content of liposomes into the cells. As far as the skin was concerned, the situation was much different. Long discussed – and it still is today –, a consensus was found on this issue, based on the idea that it also involved a biomimicry process, though a different one. Indeed, the upper skin layers are mainly composed of a system of lipid bilayers and corneocytes. And since the similarity of these lipid bilayers with the composition of liposomes is quite obvious, one can imagine that the fusion between the two structures is easily done. Studies on skin penetration have shown that the increase of the stratum corneum “tank” capacity is closely related to skin penetration. Therefore, the affinity of liposomes for bilayers contributes to increasing the quantity of active molecules in the stratum corneum for a better penetration and/or prolonged duration of action. This is not true of all molecules: it is often necessary to conduct separate studies for each molecule. In addition, the water that makes up liposomes can impregnate the superficial stratum corneum layers, just like basic components do: phospholipids and cholesterol. This leads to better plasticizing and improved characteristics of the stratum corneum. Lastly, when they are in higher concentrations, the active molecules contained in high quantity in liposomes offer better penetration and improved bioavailability. So, although some experts kept discussing these aspects, a consensus was found in the scientific community about the fact that liposomes could significantly impregnate the stratum corneum upper layers, so that certain substances could modulate skin absorption. Many studies later confirmed their potential to be used as active molecule carriers. Here is an example Liposome FR. In the skin, liposomes played the role of a tank to prolong the topical action of actives and increase the concentrations of the encapsulated molecules so that their routes through the skin were modified.
How to prepare liposomes
Initially, it was quite tricky to prepare these systems, because they required a delicate developing phase in laboratories, and then this phase was to be carefully reproduced for industrial-scale production.
In laboratories, scientists mixed lipid compounds with lipophilic “actives” by dissolving them in a solvent like chloroform or dichloromethane, which was evaporated under vacuum with a rotary evaporator. This operation formed a film directly integrated by the aqueous phase containing the water-soluble actives, so that a dispersed lamellar phase consisting of big liposomes was obtained. Over time, these vesicles could aggregate and flocculate. So, to curb their fusion with one another, their size had to be reduced below 200 nm with an ultrasound probe. This made the suspension turn bluish and transparent, which was typical of the Tyndall effect.However, in the late 70s, liposomes could only be manufactured by millilitres, which is why researchers started conducting the first studies on industrial preparation, in particular through Spray Drying, to obtain dehydrated lamellar phases, and High-Pressure Homogenization, to reduce the size of vesicles. In addition, they focused on the skin penetration of substances encapsulated in liposomes [Lipophilic substances: retinoids, phytosterols, vitamins… and Hydrophilic substances: peptides, vitamins, enzymes…]. All these studies, some of which were conducted by Gérard Redziniak and Alain Meybeck, of the Christian Dior laboratories, now known as LVMH Research, helped substantiate solid concepts and encouraged teams of different disciplines to go on with their work in order to pave the way for applications both in cosmetology and medicine, in particular oncology. From an industrial standpoint, since certain phases were not feasible, significant studies to develop specific manufacturing procedures were conducted (Dior patent FR 19820.002.620). The same happened for the preparation of Niosomes by L’Oréal (patent 2.315.991). And since the problem was solved, product development could get started
Products:
Brands started interest in technologies like that of liposomes in the 1980s. It should be reminded that without a market, inventions can never become innovations – laboratory curiosities, at best. So, the market that promoted their development was anti-ageing. Of course, the cosmetics industry had long paid attention to these new findings, but through different, often less scientific approaches. Magical ingredients were often put forward… And it is the effect of babyboom that triggered it all. Indeed, this both sociological and scientific phenomenon was at the core of the first developments: it encouraged the cosmetics industry to take a new look at consumer expectations. At that very tech-oriented time, people expected a lot from science and technique, and significant pressure was put on laboratories to find anti-ageing solutions in the technical and scientific arsenal. Serum Night Repair by Estée Lauder had been a pioneer, as it was developed based on the emerging chronobiology approach. This aqueous gel was mainly claimed to stimulate skin repair during sleep through complex biological, i.e. scientific, complexes. In Europe, the solution was also derived from science and technique through the use of emerging technologies. The most technically advanced brands developed new products involving these multiphase technologies. And liposomes were candidates.
According to the people involved in these programmes, at first, it was quite tricky to formulate products with liposomes, because these structures were rather fragile and could be destroyed very quickly during the process, or due to incompatibilities. This resulted in many studies being conducted using specific characterization techniques, like laser granulometry or electronic microscopy, which required more development – they were not much used then. The preparation methods used for these specialties were also paid much attention depending on the specificities of techniques and manufacturers. It is in these fields that the cosmetics industry contributed to making progress.
Be it as it may, interestingly, products based on these technologies appeared on the market right at the same time. It was 1986, and two brands emerged as pioneers:
- Dior, LVMH, with Capture® Résultante
- Lancôme, L’Oréal, with Niosomes®
Product presentation
Capture®
@Dior
CAPTURE: the Product is a suspension of Liposomes (size of about 100nm) on the basis of non-hydrogenated soy phospholipids and a phytosterol encapsulating natural peptides and stabilized in a hyaluronic acid gel, and Carbomer and all perfumed.
@Dior
Many works will accompany the development of this product. Publications Capture Résultante bear witness to this.
The commercial launch will be accompanied by additional information such as efficiency results: DP Capture Résultante FR – 1986 et visuels.
Niosome®
This white cream looks like a standard cream, but it was actually structured based on the new formulation concept. The brand claimed it was the very first anti-ageing cream and it made Lancôme enter the very high-tech skincare era!
The commercial launch will be supported by numerous publications and adds. Press review Niosome
Why were these products major innovations?
They actually helped make simultaneous progress in different areas. Before that period, scientists used to create comprehensive ranges including several products: makeup remover, lotion, day cream, night cream, and others. And then, all of a sudden, products called “monadic” emerged, consisting in single products only much later completed with others for marketing purposes. This is how what would be called anti-ageing creams and the anti-ageing market emerged – a real driver in the next decades. Other specific elements enhanced these launches, confirming their innovative character:
- Product names: the new products bore names that marked a break with the usual, conventional ones. For the first time, most probably, “Capture” and “Niosomes” were derived from the technology involved in the development process.
- Communication, deliberately oriented towards their technical and scientific origin
- Ingredient “starification”: marketing arguments were much more focused on advanced technologies
- Scientific sponsorship, by making research institutes provide test and demonstration results – this approach soon became widespread
- Specific characterization techniques
How did this technology evolved
As technological watch developed, manufacturers upstream soon started investing in these new technologies. Taking into account the constraints of intellectual property, several manufacturers banked on this emerging, but promising technique, which is how the offering gradually multiplied, as could be seen with leading active manufacturers, three of the most proactive being Sederma – the company developed products starting from 1988 – and, a little later, Coletica and Laboratoires Sérobiologiques. It was truly relevant of the simultaneous innovation theory: the technology very quickly got widespread in various fields. Based on the initial products, the offering boomed very fast, so that the technology soon became a new standard in the industry. The 1990s Sederma catalogue gives a clear idea of the ranges that would develop in the following years.
Manufacturing techniques gradually got less complex and the technical progress made in developing stable formulas based on liposomal suspensions helped market a great number of products. Other than liposomes and Niosomes, many products were made available for formulators to develop specialties: Ufasome ® which was based on unsaturated fatty acids, Sphingosomes ® their sphingolipid envelope, Glucosomes ® the list is not exhaustive. The success of these various forms of liposomes contributed to creating a whole R&D branch dedicated to other micro and nanocarriers. Several products similar to liposomes or derived from these technologies emerged, like Lipomicrons ,®500 nm vesicles exclusively based on lipids, Biovecteurs® whose core was gelled, and Glycospheres®
As for Keratosomes® they contained keratin in their reticulated cores and were used to obtain a sort of corneocyte for “second-skin” applications. Dermosomes®, an aqueous dispersion of empty liposomes, were introduced as moisturizing actives – an original way to diffuse a bit of water in the stratum corneum to plastify it and make it suppler. A specific technology known as Spherulites® is also worth mentioning: it helped sort of design multilayer liposomes in a dry form, or more specifically in the form of a concentrated paste. This technology was invented by CAPSULIS, a company founded in 1994 to develop industrial applications for a micro-encapsulation process designed by CNRS at the Paul Pascal Research Centre (CRPP) in Bordeaux, France. Derived from fundamental research on liquid crystal physics, this patented technology consisted in incorporating actives into microvesicles. Spherulites® are microvesicles of a diameter of about 1 mm. Composed of surfactants in lamellar phases, these structures encapsulate hydrophilic or lipophilic actives with a very good yield to protect them and enhance their performance by means of a targeted action, slow release, or stimulated absorption. They were real innovative galenic forms. This technology led to the emergence of a new cosmetics positioning, Medicosmetics, starting from 2006 – Filorga soon became its standard bearer.
What about this technology today?
After a whole period during which the first encapsulation technologies (first-generation liposomes) prevailed, formulation systems evolved towards techniques that helped structure lamellar forms similar to liposomes directly in the aqueous phase. Natterman (formerly known as Rhône-Poulenc) developed “Preliposomes”, a concentrated paste of phospholipids which “made it possible for formulators to make their own liposomes”, much to the distress of liposome suspension suppliers. But, back then, the invention did not gain much popularity on the market. Lucas Meyer Cosmetics were a bit more successful. These approaches were based on the idea of directly forming lamellar structures similar to liposomes in the aqueous phase to confine actives and enhance their bioavailability. Lucas Meyer Cosmetics kept improving their systems to eventually develop the PRO-LIPO ® system, which still represents a simple and efficient way to work on this technology.
This technically rich period was followed by a “niche” era. Liposomes were almost forgotten. This phenomenon is typical of the cosmetics industry which, after praising a technology, often quickly shelves it. It is most probably due to the tyranny of novelty, which implies that anything that is not new has no longer any value. However, this technology did not completely disappear: a few functional ingredient manufacturers kept using this system to be able to use actives with enhanced bioavailability for more efficacy. Today, liposomes can be found again in many contexts, although they are not or very little put forward, as can be seen with Actifs Mibelle Biochemistry: most of the actives in their range are actually in the form of liposomes. To a lesser extent, Greentech follows the same logic with several actives: RETIMINE III®, ROSAMINE®and ACEROMINE®. Very recently, in 2019, Oléos Hallstar launched an active, Look Oléoactif ® also in the form of liposomes, and it is Cosmos-certified! Lastly, it is worth mentioning the work done by Strand Cosmetics, who developed a specific system Prez-liposomes-Strand-Cosmetics , according to them, makes it possible to use and activate actives incorporated into specialties developed for subcontracting companies.
Targeted liposomes
At some point, scientists considered using these structures for targeting purposes, which led to the development of a few specialties. The guiding principle involved adding a substance to the lipid envelope – a substance which could be recognized by specific tissue structures. This approach did not become widespread, although it still generates some interest, and a few manufacturers have become specialists.
Conclusion: innovation described by the players involved!
These technologies undoubtedly emerged during a transitional period for the cosmetics industry. Beyond the technical and scientific aspect of this episode, it may be interesting to take into account the collateral effects and impacts on the whole sector to measure the value of this type of phenomenon. And to the perennial question of whether it is the technology that leads to innovation or the contrary, we prefer to let you answer in your own way, based on these elements. As a conclusion, why not give those who make innovation happen an opportunity to express themselves and tell us more Liposomes JCL ? They make us understand what innovation really is, in all its aspects: flair, scientific culture, motivation, sometimes obstinacy, execution quality, role of the leader, etc.
That’s it for this saga. We only gave a partial account of it, so if you want to learn more, do not hesitate to have a look at the attached references Bibliographie, and maybe at other texts as well. Thank you to all great witnesses and those who helped us. Have a good read.
Well done to you all.
Jean Claude LE JOLIFF
I thank all those who helped me in the preparation of this file, the great witnesses of course, but also all those who provided me with elements and or re-read my prose. Thanks again. Do not hesitate to complete this file if you have any more information regarding this saga.
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