Nanoparticles – the hype and the decline? Why?


Nanoparticles – the hype and the decline? Why?

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1. What is a nanoparticle – the Babylonian babel

Just to make sure that we are talking about the same thing, at the beginning of this article a short excursion is necessary to the definition of nanoparticles or the understanding what is a nanoparticle. Based on the pure dimension nanometer, nanoparticles range from 1 nm/a few nm to just below 1,000 nm (= 1 µm, borderline to microparticles) [1].  The range is identical to the colloidal particles, sometimes colloidal particles are defined from 1-500 nm (roughly borderline of the visible light). The terms “colloidal particles” and “colloid science” were used before the terms nanoparticles and nanotechnology became fashionable in the 1990ies.

Sometimes nanoparticles are defined having a size 1-100 nm [1]. Definition of a nanoparticle by IUPAC: a particle of any shape with dimensions in the 1 × 10−9 and 1 × 10−7 m range" [2]. The European Union (EU) legal definition in cosmetics is close to this definition. Nanoparticles are particles having – based on their number distribution – more than 50% of the particles below 100 nm [3]. If this is the case, the material needs to be identified as nano in the INCI on the packing of a cosmetic product (e.g. “zinc oxide (nano)” in sunscreens).

In summary, the technical/scientific definition of nanoparticles based on the dimensional range is different to the legal definition, e.g. the EU. To circumvent this Babylonian babel, one suggestion is to call particles 1-100 nm nanoparticles, and particles >100 nm to <1,000 nm (= 1 µm) “submicron particles”. It should be noted, there are also various definitions based on the product class. Actually, one could spend one article just about the different definitions of nanoparticles and nanomaterials, scientifically and legally, and in different areas of the world (e.g. EU vs. USA). In this article, the term nanoparticle is applied to particles from a few nm to < 1,000 nm. Nanoparticles include solid but also liquid particles with appropriate size.

2. What makes nanoparticles so interesting?

Richard Feynman is considered as the father of nanotechnology, based on his presentation „There’s Plenty of Room at the Bottom“ [4]. The Japanese Norio Taniguchi introduced the term “nanotechnology” in 1974, defining it: “Nano-technology mainly consists of the processing of separation, consolidation, and deformation of materials by one atom or one molecule” [5, 6]. Nanoparticles are a part of nanotechnology.

What makes nanoparticles so interesting for science but also for industrial products? It is the fact, that physico-chemical properties of materials change when they are being transferred into the nanodimension. This allows to generate new properties to products. The change occurs approx.. below 1 µm, and the change is often more pronounced the smaller the particles get. Examples are the increase in saturation solubility Cs of materials. Cs increases exponentially with decreasing size.

Also the adhesiveness of particles to surfaces increases with decreasing size (increase in contact area). For cosmetic and pharmaceutical products the most interesting properties are:

1. increase in saturation solubility Cs of poorly soluble cosmetic actives/drugs (increase in concentration gradient during absorption process)

2. increase in dissolution velocity dc/dt (e.g. faster absorption)

3. increase in adhesiveness to surfaces (e.g. particles to skin or gut wall, increased retention time with prolonged release)

4. change in colour (e.g. gold sols, cosmetic appearance effects)

3. Where everything started – the breakthrough in cosmetics

Based on the definition, the parenteral emulsion Intralipid from 1962 was already a nanoparticle product [7]. The bulk droplet sizes in parenteral emulsions are typically 200 to 300 nm. However, as the start of the “nano age” one considers the introduction of the liposomes in products on the cosmetic market. Developed around 1965 by Bangham [8], they appeared about 20 years later on the cosmetic market – the product Capture by DIOR in 1986, presented in Barcelona. It was an anti-aging product, the company announced it as “The victory of science over time”. The liposomes were a great market success. It was really amazing, most of the consumers did not really know what a liposome was, but there was the assoziation liposome = quality, efficiency, thus there was a great market success (despite high price). By the way, Capture is in various variations still on the market – more than 30 years after market introduction. This is amazing for cosmetic industry, an industry with often relatively short product life times. In competition, L´Oreal developed the niosomes, first product introduced in 1987. Niosomes are vesicles made from non-ionic surfactants. Since this time, the liposomes or other vesicles have their place in dermal cosmetic products.

Fig. 1: Advertisement of liposome product Capture by DIOR in 1986

4. Liposomes in pharma

The appearance of liposomes in cosmetic products on the market can be considered as stimulus for pharma. It demonstrated that liposomes could be produced on large industrial scale, and are sufficiently stable for products. Beginning of the 1990ies the first pharma products appeared on the Market, e.g. Alveofact by Dr. Karl Thomae, Ambisome (Gilead) and Doxil (Ben Venue Laboratories, Inc., Ohio). They had clear advantages compared to previous formulations/treatments. Alveofact proved highly efficient in the treatment of infant respiratory distress syndrome (IRDS), replacing missing lung surfactant. The clinical results were so convincing that a very fast registration and market introduction took place. Ambisome liposomes with Amphotericin B reduced the nephrotoxicity, Doxil the cardiotoxicity of doxorubicin. From treatment efficiency and reduction of side effects, the liposomal pharma products can be considered as break through. Analogous to cosmetics, the liposomes appeared also in dermal pharma products (e.g. Epipevaryl Lipogel with econazole, Germany).

5. Follow up generation: nanocrystals in pharma

Liposomes are nanoparticles for water soluble or lipid soluble actives, but there was a need for poorly soluble drugs, poorly soluble at the same time in aqueous and in lipidic media (e.g. oils). In industrial advertisements these drugs were called “insoluble rocks”. The delivery solution were the nanocrystals, developed by NanoSystems (in 1999 élan, since 2011 Alkermes plc) in the US, by Gary Liversidge and co-workers [9]. Crystalline drug was reduced in size by bead milling to typically below 400 nm. Such nanocrystals show a distinct increase in saturation solubility Cs (up to factor 10-100). In addition, they are highly adhesive to surfaces, e.g. mucosa in the gastrointestinal tract (= prolonged duration at site of absorption). Both effects lead to an increase in oral bioavailability. In addition, the adhesiveness also reduced the variability between non-fed and fed state, making products independent on nutritional state of the patient.

The nanocrystals were a real success story. The liposomes needed about 20 years from invention around 1965 to the market, the nanocrystals made it in about 10 years from 1991 (patent filing year) to the first oral product Rapamune (sirolimus) in 2000 by Wyeth. The next products followed: Emend (aprepitant) as anti-emetic by Merck in 2001, fenofibrate as Tricor by Abbott 2004 and Triglide by Sciele Pharma, Megace ES (megestrol acetate) as anti-anorexic by Par Pharmaceuticals 2006. They were all oral products. The first injectable was approved by the US Food and Drug Administration in 2012: Invega Sustenna, the first monthly antipsychotic i.m. injection of paliperidone palmitate with nanocrystals. The injectable product was an important milestone for this technology. It is a stable, low viscosity, high drug-loaded formulation in a small injection volume with long-lasting action. The action for one month improves the compliance for schizophrenic patients.

A nice example for the market performance of nanocrystals is the block buster Tricor by Abbott. One reason to develop the product was the upcoming of generic fenofibrate products. The nanocrystalline fenofibrate in Tricor showed an up to 35% higher oral absorption, and a reduced difference between fed/non-fed state, thus could limited the market share of the old formulation as generics.

6. Nanocrystals in cosmetics

In 2006 the use of nanocrystals was transferred from the oral administration route to dermal application [10]. In contrast to the liposomes, they appeared in cosmetic products after their intensive use in pharma. Products on the market contain anti-oxidants (rutin, hesperidin) and whitening agents (e.g. glabridin). The molecules are all characterized by their poor solubility, both in water and in lipidic media (oils). In vivo studies showed an increase in bioactivity up to a factor 1,000. Manufacturer and distributor in Germany is Dr. Rimpler GmbH ( Nanocrystals in cosmetics open the use of poorly soluble plant molecules, which were not really effective by now due to their poor dermal penetration.

7. Solid lipid nanoparticles (SLN)

In parallel to the nanocrystals, in 1991 the solid lipid nanoparticle (SLN) were developed, by Prof. Rainer Müller Free University of Berlin (Germany) and Prof. Maria Rosa Gasco, Turin University (Italy). The SLN are derived from the oil-in-water (o/w) nanoemulsions. The liquid lipid (oil) was simply replaced by a solid lipid (glyceride or wax). The difference between the Müller and the Gasco SLN was the production technology, high pressure homogenization (HPH) vs. microemulsion technique. Due to the solid state of the particle matrix, labile molecules are protected against degradation, and their release can be controlled (not possible with nanoemulsion). Routes of administration are manyfold, preferentially oral and dermal, but also e.g. injection.

In 1999 the second generation was developed, the nanostructured lipid carriers (NLC) [11], in 2014 the third generation, the smartLipids [12]. The NLC consist of a blend of solid and liquid lipids (oils), but are still solid. The more complex structure increases the number of imperfections in the particle matrix, thus increases the drug loading. The smartLipids are even more complex lipid mixtures, creating a very chaotic particle matrix with highest drug loading capacity.

Identical to the liposomes, the lipid nanoparticles are on the market in cosmetics (first product in 2006, Nanorepair Q10/Dr. Rimpler GmbH Germany). They appeared in products world-wide, e.g. in Korea (e.g. company AmorePacific, line IOPE). Lipid nanoparticle suspensions as concentrates can simply be admixed to creams or lotions. The company Berg+Schmidt (Hamburg/Germany) supplies concentrates of the third-generation technology smartLipids to cosmetic manufacturers. Available are Bergacare SmartLipids with Retinol, coenzyme Q10 and whitening agents (lemon grass oil, glabridin).

To my knowledge, the lipid nanoparticles are not yet as pharma products on the market (classical drugs), but were candidates for clinical trials. An exception are formulations for gene therapy/gene delivery. In August 2018 the FDA approved Patisiran/ONPATTRO (marketed by Alnylam). It is an siRNA‐delivering lipid‐based nanoparticle, containing e.g. cholesterol. It is the first clinically approved RNAi therapy‐delivering nanoparticle for i.v. injection.

8. What differentiates commercially successful nanoparticles versus “academic” nanoparticles”

A successful nanoparticle from my point of view is a nanoparticle which made it into products on the market – for the benefit of the consumer and the patient. There are many nanoparticle systems invented in the academic labs, for example many “somes” (ethosomes, cubosomes, exosomes etc.). A famous example are the polymeric nanoparticles, Prof. Peter Speiser (†) from ETH Zurich/Switzerland is considered as the father of the pharmaceutical polymeric nanoparticles. He started developments at the beginning of the 1970ies. Despite thousands of publications about polymeric nanoparticles in the last almost 50 years, very few products are on the market. The same being valid for particles from other macromolecules, e.g. proteins. Abraxane is an example for albumin particles (130 nm) loaded with paclitaxel.

The obstacle for entering the market is the lack of fulfilling industrial requirements, often these requirements are completely neglected when starting an academic development. Important requirements are regulatory acceptance of the excipients used, physical and chemical long-term stability, non-toxicity/tolerability, possibility of large-scale production, and very important cost-efficiency (the health systems cannot afford too expensive medicines). Most important is, that the new nanoparticle delivery systems perform distinctly better than existing products. A health system normally does not pay for just 10 or 20% improvement in therapy. These are some of the reasons why many scientifically very interesting nanoparticle systems never left the academic labs.

9. What did lead to the decline in nanoparticles?

At the end of the 1990ies and at the turn of the millennium, there was a lot of euphory in nanoparticles, both in the academic world and in industry. Looking at conference programs of scientific societies, one had the impression that only nanoparticles were the hot topic. This euphoria, and the commercial successes of the first nanoparticle products, stimulated nanoparticle product developments in industry. No price was too high, when acquiring a promising technology. The overview article by Patra et al. [14] from 2018 contains a list of nanomedicines with their year of approval. The majority of 34 products was approved until 2004, only 15 products after.  In case of an advancing technology, one would expect just the opposite.

What are the reasons? In 2001, 9/11 happened in New York – having also tremendous impact on economy and industry. In 2008, the financial crisis starting with Lehmann Brothers happened. Again an economic crisis. In these years major pharma companies were re-thinking/eliminating their investment plans, cancelled product developments and the aim was just to consolidate the company by saving money. Companies re-considered if it was really worthwhile to develop a successor product, or simply continuing to sell the presently marketed product – and having no development costs. Especially investment in nanoparticle technology was cut down, large scale production lines not built, clinical phases not conducted etc. An impact had also the continuing takeover of companies by big pharma. After the takeover, sometimes nanoparticle development plans were terminated in the company acquired. Or the company taken over was dashed and sold piece by piece – also destroying product development plans.

So far pharma, but what happened with nanoparticles in cosmetics? Products with liposomes continued. Liposomes can be bought from the stock, and simply incorporated in any product. However, there is a standstill in nanoparticle technology, only in a limited number of products with new nanoparticle technologies appeared – one example being nanocrystals. However, nanocrystals are distinctly more expensive than liposomes. They are highly effective, but they are limited to higher priced products. In contrast to pharma, cosmetic products only need to list the ingredients on the packaging – they are not forced to prove that they are active in the skin. Thus e.g. curcumin can be listed as ingredient but having as microcrystal little/no effect in the skin – in contrast to curcumin nanocrystals. But the “normal” microcrystals are the more cost-effective solution for a product. Thus cost considerations hinder the use of nanotechnology. The story is very different for cosmetic products when the consumer can clearly judge the efficiency – e.g. whitening products. The consumer can see if dark spots lighten/disappear or not. Glabridin suspension (µm-sized) will have no/little effect – in contrast to highly effective glabridin nanocrystals or BergaCare SmartLipids Glabridin. In addition, cosmetics changes very fast the topic for advertising. Liposomes are meanwhile yesterday´s story, not exiting any more. The hot topics in cosmetics are nowadays anti-pollution and the skin microbiome. Nanoparticles will have perspectives when they can be part of the product strategy within these new topics, and of course part of the marketing strategy.

10. A look into the crystal ball – the next 10 years

Predicting the future of nanoparticles is like looking into the magic crystal ball. At present we have the next crisis – corona – with extremely high impact on the world-wide economy. This critical economic situation will last for 3-4 years – being not a good environment for development of novel delivery systems. From my point of view, on the short term only nanoparticle products will be developed with high profit perspective, thus the number of products per year will remain on a low level. For the coming 5 years I agree with the conclusion by Patra et. al [14] saying: “Despite the overwhelming understanding of the future prospect of nanomedicine and nano-drug delivery system, its real impact in healthcare system, even in cancer therapy/diagnosis, remains to be very limited”. Afterwards in a better economic environment, the situation will change, one can expect an increasing number of nanoparticle products after 2030.



2. Vert, M. et al. (2012). "Terminology for biorelated polymers and applications (IUPAC Recommendations 2012)". Pure and Applied Chemistry. 84 (2): 377 410. doi:10.1351/PAC-REC-10-12-04.

3. European Comission: Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products, 2009.

4. Richard P. Feynman: Viel Spielraum nach unten. Eine Einladung in ein neues Gebiet der Physik. In: Deutsches Museum (Ed.): Kultur & Technik. Nr. 1, 2000 ( [PDF; 6,0 MB; down loaded 8. December 2017] englisch: There's Plenty of Room at the Bottom. 1960. Engineering and Science, S. 20 ff., lecture on 29. December 1959)

5. N. Taniguchi: On the basic concept of nanotechnology. In: Proc. Intl. Conf. Prod. Eng. Tokyo, Part II, Japan Society of Precision Engineering. 1974.



8. Bangham AD: Membrane models with phospholipids. Prog Biophys Mol Biol 1968;18:29–95.

9. Liversidge, Cundy, Bishop, Czekai, US patent 5,145,684 (1992)

10. Müller, R. H. et al., Nanocrystals for Passive Dermal Penetration Enhancement, in: Percutaneous Penetration Enhancers. Chemical Methods in Penetration Enhancement, (N. Dragicevic, H. I. Maibach, eds.), Springer, 283-295, 2016

11. Souto, E. B., Müller, R. H., Lipid nanoparticles (SLN and NLC) for drug delivery, in: Nanoparticles for pharmaceutical applications (A. Domb, Y Tobata, R. Kumar, S. Farber, eds.), American Scientific Publishers, 103-122, 2007

12. Ding, Y. et al., smartLipids as third solid lipid nanoparticle generation – stabilization of retinol for dermal application, Die Pharmazie 72, 728-735 (doi: 10.1691/ph.2017.7016), 2017

13. Anselmo, A.C. and Mitragotri, S. Nanoparticles in the clinic: an update, Bioeng. Transl. Med. 4(3) (doi: 10.1002/btm2.10143), 2019

14. J.K. Patra et al., Nano based drug delivery systems: recent developments and future prospects, Journal of Nanobiotechnology volume 16, Article number: 71 (2018)