# Ecodesigned Formulations with Tomato Pomace Extracts

Aya Jamaleddine, Martine Urrutigoïty, Jalloul Bouajila, Othmane Merah,

Philippe Evon, Pascale de Caro

► To cite this version:

Aya Jamaleddine, Martine Urrutigoïty, Jalloul Bouajila, Othmane Merah, Philippe Evon, et al. Ecodesigned Formulations with Tomato Pomace Extracts. Cosmetics, 2023, 10 (1), pp.7. 10.3390/cosmetics10010007. hal-03921276

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Submitted on 3 Jan 2023

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Distributed under a Creative Commons Attribution 4.0 International License
# Ecodesigned Formulations with Tomato Pomace Extracts

Aya Jamaleddine, Martine Urrutigoïty, Jalloul Bouajila, Othmane Merah,

Philippe Evon, Pascale de Caro

<figure><img src="image_1.png" /></figure>

## To cite this version:

Aya Jamaleddine, Martine Urrutigoïty, Jalloul Bouajila, Othmane Merah, Philippe Evon, et al. "Ecodesigned Formulations with Tomato Pomace Extracts. Cosmetics, 2023, 10 (1), pp.7. 10.3390/cosmetics10010007." [hal-03921276v2]

HAL Id: hal-03921276

https://hal.inrae.fr/hal-03921276v2

Submitted on 7 Nov 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>
RMD
Open

Rheumatic &
Musculoskeletal
Diseases

SHORT REPORT

COVID-19 infection among patients
with autoinflammatory diseases: a study
on 117 French patients compared with
1545 from the French RMD COVID-19
cohort: COVIMAI – the French cohort
study of SARS-CoV-2 infection in
patient with systemic
autoinflammatory diseases

Rim Bourguiba,¹ Maeva Kyheng,² Isabelle Koné-Paut,³ Diane Rouzaud,⁴
Jerome Avouac,⁵ Mathilde Devaux,⁶ Nassim Ait Abdallah,⁷ Bruno Fautrel,⁸
Nicole Ferreira-Maldent,⁹ Vincent Langlois,¹⁰ Emmanuel Ledoult,¹¹
Hubert Nielly,¹² Viviane Queyrel,¹³ Jérémie Sellam,¹⁴ Nathalie Tieulie,¹⁵
Pascal Chazerain,¹⁶ Philippe Evon,¹⁷ Julien Labreuche,¹⁸ Léa Savey,¹
Veronique Hentgen,¹⁹ Gilles Grateau,¹ Sophie Georgin-lavialle,¹ FAI²R/SFR/SNFMI/SOFREMIP/CRI/IMIDIATE consortium and contributors

**To cite:** Bourguiba R, Kyheng M, Koné-Paut I, et al. COVID-19 infection among patients with autoinflammatory diseases: a study on 117 French patients compared with 1545 from the French RMD COVID-19 cohort: COVIMAI – the French cohort study of SARS-CoV-2 infection in patient with systemic autoinflammatory diseases. *RMD Open* 2022;8:e002063. doi:10.1136/rmdopen-2021-002063

► Additional supplemental material is published online only. To view, please visit the journal online (http://dx.doi.org/10.1136/rmdopen-2021-002063).

Received 27 October 2021
Accepted 4 February 2022

Check for updates

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

For numbered affiliations see
end of article.

**Correspondence to**
Dr Sophie Georgin-lavialle;
sophie.georgin-lavialle@aphp.fr

ABSTRACT

**Objective** There is little known about SARS-CoV-2 infection in patients with systemic autoinflammatory disease (SAID). This study aimed to describe epidemiological features associated with severe disease form and death. Mortality between patients with and without SAID hospitalised for SARS-CoV-2 infection was compared.

**Methods** A national multicentric prospective cohort study was conducted from the French Rheumatic and Musculoskeletal Diseases (RMD) COVID-19 cohort. Patients with SAID were matched with patients with non-SAID on age±7 years, gender and number of comorbidities to consider important confounding factors. Impact of SAID on severity of SARS-CoV-2 infection was analysed using multinomial logistic regression for severity in three classes (mild, moderate and severe with mild status as reference). Fine-Gray regression model for length of hospital stay and binomial logistic regression model for risk of death at 30 days.

**Results** We identified 117 patients with SAID (sex ratio 0.84, 17 children) and compared them with 1545 patients with non-autoinflammatory immune-mediated inflammatory disorders (non-SAID). 67 patients had a monogenic SAID (64 with familial Mediterranean fever). Other SAIDs were Behçet' disease (n=21), undifferentiated SAID (n=16), adult-onset Still disease (n=9) and systemic-onset juvenile idiopathic arthritis (n=5). Ten adults developed severe form (8.6%). Six patients died. All children had a benign disease. After matching on age±7

WHAT IS ALREADY KNOWN ABOUT THIS
SUBJECT?

⇒ As reported in the French RMD cohort, patients with inflammatory RMD are more likely to develop severe form when they have multiple comorbidities or they were under steroids over 10 mg/day.

WHAT DOES THIS STUDY ADD?

⇒ Children display more likely mild signs of COVID-19 with excellent prognosis.

⇒ When comparing patients with systemic autoinflam-
matory disease (SAID) and non-SAID after matching
on age, sex and number of comorbidities, no signifi-
cant difference in severity of COVID-19 between the
two groups was found.

⇒ Associated comorbidities are more important than the underlying SAID, for developing a severe form or dying.

⇒ Colchicine or biotherapies against Interleukine IL-6 or IL-1 do not seem to be associated with high risk of severe form of COVID-19.

HOW MIGHT THIS IMPACT ON CLINICAL
PRACTICE OR FUTURE DEVELOPMENTS?

⇒ In addition to common risk factors for severe COVID-19, patients with SAID on steroids should be considered of high risk for severe form.
<figure><img src="image_3.png" /></figure>

Article

# Ecodesigned Formulations with Tomato Pomace Extracts

Aya Jamaeddine <fnref n="1" />, Martine Urrutigoïty <fnref n="2" />, Jalloul Bouajila <fnref n="3" /> ID, Othmane Merah <fnref n="1" />,<fnref n="4" />,* ID, Philippe Evon <fnref n="1" /> ID and Pascale de Caro <fnref n="1" />,*

<figure><img src="image_4.png" /></figure>

check for
updates

**Citation:** Jamaeddine, A.; Urrutigoïty, M.; Bouajila, J.; Merah, O.; Evon, P.; de Caro, P. Ecodesigned Formulations with Tomato Pomace Extracts. *Cosmetics* **2023**, *10*, 7.
https://doi.org/10.3390/cosmetics10010007

Academic Editors: Christophe Hano,
Vasil Georgiev and Duangjai
Tungmunnithum

Received: 31 October 2022

Revised: 24 December 2022

Accepted: 26 December 2022

Published: 30 December 2022

<figure><img src="image_5.png" /></figure>

**Copyright:** © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).

**Abstract:** Tomato pomace (TP) has previously been identified as a coproduct that is rich in bioactive molecules, with potential beneficial effects for health. For tomato pomace that is composed of the skin, seeds and fibers, the challenge is to recover the molecules of interest trapped in the biopolymers. The use of deep eutectic solvents to extract metabolites from vegetable materials could present some advantages. Four natural deep eutectic solvents (NaDESs) were synthesized and characterized by infrared spectroscopy, thermogravimetry (TG) and differential scanning calorimetry (DSC). The TP was treated by maceration at moderate temperatures with the NaDESs. We identified 39 extracted molecules by HPLC-DAD, which revealed an abundance of hydroxy/methoxy flavones, flavanols, flavonols, phenolic acids, carotenoids and tannins, as well as a certain selectivity in the extracted molecules. Four cosmetic formulations that included the NaDESs were prepared. The NaDESs showed film-forming properties, which were harnessed for the final formulations, thanks to their biocompatibilities. Finally, the coupling of the extraction and formulation is a way to preserve the quality of the extracts and prepare ecodesigned formulations.

**Keywords:** tomato pomace; ecoextraction; bioactive molecules; formulation; ecodesign

## 1. Introduction

Currently, there is a strong market trend for products that are formulated with natural and healthier ingredients. This context presents an opportunity to develop innovative products using ecocompatible processes that can preserve the natural molecules. Residual biomass represents a significant source of secondary metabolites, which can be recovered by implementing green processes in accordance with the naturalness of the targeted formulations. Thus, the field of cosmetics is continuously looking for active plant ingredients to respond to the different specifications of skin care products. In this area, the raw materials are carefully selected according to their origins, qualities, properties and costs. A study by Soto et al. [1] showed that the ethanolic extracts of grape pomace, pine (*Pinus pinaster*) wood chips, *Acacia dealbata* flowers and shiitake (*Lentinus edodes*) meet the efficacy expectations when they are formulated for personal skin care products. Indeed, the use of agricultural byproducts represents a source of available metabolites, which avoids the use of dedicated cultures. These new supply chains have reduced ecological footprints and contributed to the better management of biomass waste. Obviously, the microbiological quality of the agricultural coproducts and the presence of pesticide residues must be controlled [2].

To illustrate the role of a coproduct in a formulation, Plainfossé et al. [3] used a hydroalcoholic extract of blackcurrant pomace to develop an antiaging cosmetic base. The work of Carriço et al. [4] has shown that phenolic acids extracted from *Quercus suber* bark,

<footnote n="1">1 Laboratoire de Chimie Agro-Industrielle (LCA), Université de Toulouse, INRAE, Toulouse INP, 31030 Toulouse, France</footnote>

<footnote n="2">2 Laboratoire de Chimie de Coordination (LCC), Université de Toulouse, CNRS, Toulouse INP, 31030 Toulouse, France</footnote>

<footnote n="3">3 Laboratoire de Génie Chimique, Université de Toulouse, CNRS, Université Paul Sabatier, 31062 Toulouse, France</footnote>

<footnote n="4">4 Département Génie Biologique, Université de Toulouse, Université Paul Sabatier, Institut Universitaire Technologique A, 32000 Auch, France</footnote>

<footnote>* Correspondence: othmane.merah@ensiacet.fr (O.M.); pascale.decaro@ensiacet.fr (P.d.C.)</footnote>
years, sex and number of comorbidities, no significant difference between the two groups in length of stay and the severity of infection was noted.

**Conclusion** As identified in the whole French RMD COVID-19 cohort, patients with SAID on corticosteroids and with multiple comorbidities are prone to develop more severe COVID-19 forms.

## INTRODUCTION

The pandemic related to SARS-CoV-2 infection has emerged since late 2019; Europe was affected in March 2020.¹ The virus caused many deaths in all countries. Patients with immune disorders were a concern of developing a severe form of COVID-19 especially those with systemic autoinflammatory diseases (SAIDs) in which, the innate immune system is improperly activated. The most frequent SAID worldwide is familial Mediterranean fever (FMF); three other monogenic diseases are also classified in the historical hereditary recurrent fevers: cryopyrin-associated periodic syndrome (CAPS), TNF receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD). Others are polygenic such as Behçet's disease and Still disease. It was initially difficult to predict if patients with SAID might develop an excessive inflammatory response when they contracted the virus.

To our knowledge, except few studies on FMF² and one on Behçet's disease,³⁻⁷ little is known about both the risk factors and the diseases at risk of contracting a severe form of COVID-19.

We took the opportunity of the French national prospective registry collecting cases of COVID-19 in patients with immune diseases including SAIDs.⁸ Our main question was to determine whether patients with SAIDs had an over-risk of severe form and death. Our secondary objectives were to assess whether the risk correlated to either the disease itself, the existence of comorbidities or the exposure to anti-inflammatory and immunosuppressive medications. In addition, we compared risk factors of patients with SAIDs with those with other inflammatory disorders included in the French RMD COVID-19 cohort.⁸

## PATIENTS AND METHODS

### Study design and patients

This multicentre, national cohort study (COVIMAI) analysed data from the French RMD COVID-19 cohort, which has been previously described.⁸ Briefly, the French RMD COVID-19 cohort included paediatric and adult patients with confirmed inflammatory rheumatic and musculoskeletal diseases and highly suspected or a confirmed diagnosis of COVID-19. SAIDs were defined by the international criteria and included the four historical monogenic SAIDs (FMF, TRAPS, CAPS, MKD), undifferentiated SAIDs,⁹ adult onset Still diseases (AOSDs) and Behçet's disease. We assessed and classified the severity of COVID-19 according to the level of care needed for each patient. Mild COVID-19 required ambulatory care;

moderate COVID-19 required non-intensive hospital treatment and severe COVID-19 required admission to an intensive care unit or led to death. The study started on March 2020 and was done in compliance with the research methodology MR-004 (research not involving humans connected to studies and evaluations in the field of health), received legal approval from Lille University Hospital ULR 2694-METRICS (Lille, France) and was declared to the Commission Nationale de l'Informatique et des Libertés (reference DEC20-107).

### Data collection

Cases of patients with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19 were reported retrospectively. The individual data regarding diagnosis and specific ongoing treatments for inflammatory rheumatic and musculoskeletal diseases were captured from physicians via an electronic Case Report Form available online through a secured access. Data collected from patients' medical records have previously been described elsewhere.⁸ All participants were followed until the worst COVID-19 outcome at the time of dataset lock. The present study was conducted on the database locked in 15 April 2021.

### Outcomes

The primary outcome was to compare the severity of COVID-19 in patients with SAID with patients with non-SAID included in the French RMD COVID-19 cohort. The secondary outcomes were to compare frequency of deaths and duration of hospital stay in patients with or without SAID.

### Statistical analysis

Quantitative variables were expressed as means (SD) in the case of normal distribution or medians (IQR) otherwise. Categorical variables were expressed as numbers (%). Normality of distributions was assessed using histograms and the Shapiro-Wilk test.

To consider important confounding factors, patients with SAIDs were matched with patients with non-SAID from the French RMD COVID-19 cohort on age±7 years, gender and number of comorbidities.

Impact of SAID on severity of SARS-CoV-2 infection was analysed, before and after matching, using multivariate logistic regression for severity in three classes (mild, moderate and severe with mild status as reference), Fine-Gray regression model for length of hospital stay (with death as competing event) and binomial logistic regression model (with link logit) for risk of death at 30 days.

All statistical tests were done at the two-tailed α level of 0.05. Data were analysed using SAS V.9.4 (SAS Institute).

This study is registered with ClinicalTrials.gov, NCT04353609.

## RESULTS

We included 117 patients with SAID and compared them with 1545 patients with non-SAID. The disease
which is a coproduct of the forestry industry, have interesting potential for preparing creams with antioxidant, antiaging and anti-inflammatory properties. Previous works have also identified tomato pomace as a source of bioactive molecules. For instance, Jамaeddine et al. [5] detected the in vitro bioactivities for fractions isolated by maceration in ethanol or ethyl acetate, and for an extract obtained with SC-CO₂. Lycopene extracted from tomato skins and added to an emulsion had a protective effect against photodamage to the skin induced by UVB rays [6]. Nonmarketable tomatoes, powdered after drying, are used in cosmetic formulations as sources of vitamins A, B and C, folic acid, and phytosterols [7].

The usual extraction methods consist of putting the plant material into contact with a solvent (water or organic). This step is followed by the separation of the residual material and the solvent (filtration, centrifugation, etc.), and then the evaporation of the solvent to obtain the extract. The latter, possibly purified, must then be resolubilized to be formulated. To reduce the number of steps and the problems of solubility, and to avoid costly safety requirements, volatile solvents are avoided. Salem et al. [8] obtained fractions rich in polyphenols via the hydroglycerin extraction of grape seeds (i.e., grape pomace) at 40 °C for 2 h. The glycerin medium was used for the formulation of a cream with antioxidant properties.

Among the promising green solvents, deep eutectic solvents (DESs) have some advantages, and some authors have started to test them for extractions of natural molecules [9]. The use of DESs for cosmetic formulations is interesting because of their viscosity and chemical stabilities. Odorless and colorless, they can positively contribute to a formulation's properties. We can cite the work of Huang et al. [10], who extracted rutin-rich fractions from wheat bran using a natural DES (NaDES) from the association between choline chloride and glycerol. Panic et al. [11] isolated anthocyanins from grape pomace using a NaDES composed of choline chloride and citric acid on a half-liter scale, and they succeeded at recycling it. These solvents have undergone significant developments in recent years [12]. Indeed, they have been adapted to cosmetic applications. They are nonvolatile, nontoxic, colorless and recyclable, with high thermal stability [13]. They can be easily prepared by mixing a hydrogen bond donor (HBD) compound and hydrogen bond acceptor (HBA) compound in a certain molar ratio [14]. For eutectic compositions, the mixtures have lower melting points compared with those of the compounds taken separately. Popovic et al. [15] tested a NaDES ("choline chloride: malic acid") combined with microwave activation to extract anthocyanins from cherry pomace. Regarding tomato pomace, we can cite four recent studies. First, Silva et al. [16] and Lazzarini et al. [17] improved the extraction yields of carotenoids using the mixtures "DL-menthol /lactic acid" or "ethyl acetate/ethyl lactate", following the nonthermal air-drying of the tomato pomace. Vorobyova et al. [18] used a choline chloride-based DES to extract phenolic acids from TP (65 °C, 60 min), and they assessed their antioxidant activities. Vasyliev et al. [19] showed that a second DES, which was rich in phenolic acids and flavanols, could be used in a cream formulation with antifungal properties. Chlorogenic acid was detected as the most abundant phenolic acid in the extracts.

The objective of this work was to use tomato pomace as a source of beneficial molecules by trapping them in NaDESs. These extracting matrices could optimize the bioavailability of pomace metabolites. Therefore, the performances of four NaDESs were compared. To avoid the separation of the metabolites from the NaDESs, the feasibility of keeping the NaDES components in the formulations was studied. The extracted metabolites were analyzed by HPLC before their integration into a film-forming formulation.

## 2. Materials and Methods

### 2.1. Reagents

The DL-menthol (2-isopropyl-5-methylcyclohexanol (95%)), lactic acid solution (2-hydroxypropionic acid (85–90%)), D-glucose (99%), L-proline (99%) and chitosan were purchased from Sigma Aldrich. The standard compounds used for identification
<table><caption>Table 1</caption><thead><tr><th></th><th>Non-Autoinflammatory diseases(n=1545)</th><th>Autoinflammatory diseases (n=117)</th></tr></thead><tbody><tr><td>Age (years)</td><td></td><td></td></tr><tr><td>Mean±SD</td><td>54.7±17.5</td><td>38.7±20.5</td></tr><tr><td>&lt;18</td><td>41/1545 (2.7)</td><td>17/117 (14.5)</td></tr><tr><td>18-54</td><td>700/1545 (45.3)</td><td>74/117 (63.2)</td></tr><tr><td>55-64</td><td>328/1545 (21.2)</td><td>8/117 (6.8)</td></tr><tr><td>65-74</td><td>260/1545 (16.8)</td><td>9/117 (7.7)</td></tr><tr><td>≥75</td><td>216/1545 (14.0)</td><td>9/117 (7.7)</td></tr><tr><td>Female gender</td><td>1038/1545 (67.2)</td><td>64/117 (54.7)</td></tr><tr><td>Comorbidities</td><td></td><td></td></tr><tr><td>Respiratory disease</td><td>204/1543 (13.2)</td><td>6/117 (5.1)</td></tr><tr><td>Interstitial lung disease</td><td>60/1543 (3.9)</td><td>0/117 (0.0)</td></tr><tr><td>COPD</td><td>61/1543 (4.0)</td><td>2/117 (1.7)</td></tr><tr><td>Asthma</td><td>95/1543 (6.2)</td><td>4/117 (3.4)</td></tr><tr><td>Cardiovascular disease</td><td>177/1543 (11.5)</td><td>11/117 (9.4)</td></tr><tr><td>Coronary heart diseases</td><td>146/1543 (9.5)</td><td>9/117 (7.7)</td></tr><tr><td>Stroke</td><td>42/1543 (2.7)</td><td>5/117 (4.3)</td></tr><tr><td>Diabetes</td><td>156/1543 (10.1)</td><td>8/117 (6.8)</td></tr><tr><td>BMI (kg/m²)</td><td>26.0 (22.0 ; 29.0)</td><td>23.0 (21.0 ; 26.0)</td></tr><tr><td>&lt;30</td><td>1054/1388 (75.9)</td><td>98/111 (88.3)</td></tr><tr><td>30-39.9</td><td>297/1388 (21.4)</td><td>10/111 (9.0)</td></tr><tr><td>≥40</td><td>37/1388 (2.7)</td><td>3/111 (2.7)</td></tr><tr><td>Hypertension</td><td>361/1543 (23.4)</td><td>12/117 (10.3)</td></tr><tr><td>Cancer</td><td>57/1543 (3.7)</td><td>3/117 (2.6)</td></tr><tr><td>Smoking</td><td>139/1543 (9.0)</td><td>8/117 (6.8)</td></tr><tr><td>Chronic renal failure</td><td>80/1543 (5.2)</td><td>5/117 (4.3)</td></tr><tr><td>Number comorbidities</td><td></td><td></td></tr><tr><td>0</td><td>674/1543 (43.7)</td><td>76/117 (65.0)</td></tr><tr><td>1</td><td>466/1543 (30.2)</td><td>26/117 (22.2)</td></tr><tr><td>2</td><td>230/1543 (14.9)</td><td>8/117 (6.8)</td></tr><tr><td>3</td><td>103/1543 (6.7)</td><td>4/117 (3.4)</td></tr><tr><td>4</td><td>58/1543 (3.8)</td><td>3/117 (2.6)</td></tr><tr><td>&gt;4</td><td>12/1543 (0.8)</td><td>0/117 (0.0)</td></tr><tr><td>Rheumatic or inflammatory Diseases treatments</td><td></td><td></td></tr><tr><td>Corticosteroid</td><td>460/1542 (29.8)</td><td>20/117 (17.1)</td></tr><tr><td>Systemic corticosteroid doses≥10mg/day</td><td>176/458 (38.4)</td><td>6/20 (30.0)</td></tr><tr><td>NSSAIDs</td><td>147/1542 (9.5)</td><td>2/117 (1.7)</td></tr><tr><td>Colchicine</td><td>10/1542 (0.6)</td><td>72/117 (61.5)</td></tr><tr><td>Hydroxychloroquine</td><td>146/1542 (9.5)</td><td>0/117 (0.0)</td></tr><tr><td>Methotrexate</td><td>553/1542 (35.9)</td><td>13/117 (11.1)</td></tr><tr><td>Leflunomide</td><td>66/1542 (4.3)</td><td>0/117 (0.0)</td></tr><tr><td>Salazopyrine</td><td>17/1542 (1.1)</td><td>0/117 (0.0)</td></tr><tr><td>Mycophenolate Mofetil /mycophenolic acid</td><td>41/1542 (2.7)</td><td>0/117 (0.0)</td></tr><tr><td>Azathioprine</td><td>18/1542 (1.2)</td><td>4/117 (3.4)</td></tr><tr><td>IgIV</td><td>10/1542 (0.6)</td><td>0/117 (0.0)</td></tr><tr><td>Targeted biologic or synthetic therapies</td><td></td><td></td></tr><tr><td>anti-TNF</td><td>469/1542 (30.4)</td><td>18/117 (15.4)</td></tr><tr><td>anti-IL6R</td><td>56/1542 (3.6)</td><td>5/117 (4.3)</td></tr><tr><td>anti-IL17A</td><td>51/1542 (3.3)</td><td>0/117 (0.0)</td></tr></tbody></table>

Continued
were purchased from Extrasynthese (Genay, France). Pharmaceutical-grade glycerin (>99%), xanthan gum and Cosgard (a preservative based on benzylic alcohol) were bought from Aroma-Zone.

## 2.2. Preparation of Tomato Pomace

Fresh tomato pomace was supplied by the "Les Jus du Soleil" cooperative (Marmande, France). The tomato pomace was oven-dried at 50 °C for 8 h to obtain a material with 2%. Before extraction, the TP was ground with an electric grinder to obtain particles with diameters between 1 and 2 mm (measured with optical microscopy (magnification: 10×)).

## 2.3. Extraction with Glycerol/Glucose Mixture

The DES "glycerol/glucose" preparation was adapted from Wils et al. [20]. Glycerol and glucose were weighed and mixed at the molar ratio (3:1) with 30% water in a 100 mL flask. The mixture was vigorously stirred at 80 °C until the formation of a homogeneous liquid (2 h). Briefly, 2 g of TP was placed in a bottom flask before adding 32 g of DES, and then it was stirred at 600 rpm at 40 °C for two hours. Centrifugation (12,300 rpm, 20 min) led to the separation of the pomace from the NaDES.

## 2.4. Extraction with DL-Menthol/Lactic Acid Mixture

The preparation of the NaDES "DL-menthol/lactic acid" (Men-Lac) was adapted from Silva et al. [16]. Solid DL-menthol and lactic acid solution was weighed in a glass vial at the molar ratio (8:1). The mixture was heated using a mechanical stirrer at 1200 rpm at 40 °C until the obtainment of a homogeneous medium. Briefly, 3.4 g of TP was added to 20 g of the Men-Lac mixture and mixed at 50 °C for 1.5 h in a water bath. After centrifugation (12,300 rpm, 20 min), the red-colored Men-Lac separated from the pomace particles.

## 2.5. Extraction with Lactic Acid/Glucose Mixture

The preparation of the "lactic acid/glucose" NaDES was adapted from Fernandez et al. [21]. The lactic acid and glucose, weighed according to the molar ratio (5:1), were mixed under the addition of 15% water and kept at 50 °C for 1 h with magnetic stirring until the formation of a homogeneous and transparent liquid. Briefly, 2 g of TP was suspended in 40 mL of the lactic acid/glucose mixture and homogenized by a vortex for 15 s. The suspension was subjected to ultrasound (power: 200 W; frequency: 20 kHz) at 40 °C for 1 h. Then, the mixture was centrifuged for 30 min to separate the TP particles.

## 2.6. Extraction with L-Proline/Glycerol Mixture

The NaDES "L-proline/glycerol" preparation was adapted from Wu et al. [22], with some modifications. The two compounds were mixed at the molar ratio (1:2.5) with 30% water and kept under magnetic stirring at 80 °C until the formation of a homogeneous and transparent liquid. Briefly, 2 g of TP was mixed with 20 mL of the prepared DES and kept at 40 °C, with an ultrasonic power of 320 W, for 1 h. The supernatant was obtained by centrifugation at 10,000 rpm for 10 min.

## 2.7. Thermal Analyses

The TGA/TDA analyses of the NaDESs were carried out with TGA/DSC 3+ equip-
ment (Mettler-Toledo, Viroflay, France). The differential scanning calorimetry (DSC) anal-
yses were performed with DSC Sirius equipment (Netzsch, Selb, Germany). A total of
10.5 mg of the material was placed in an aluminum pod. The nitrogen flow was set at
50 mL/min, with a temperature increase of 10 °C/min between 20 and 600 °C for the
thermograms, and between –100 and 20 °C for the calorimetry.
<figure><img src="image_2.png" /><figcaption>**Table 1** Continued</figcaption></figure>

<table><thead><tr><th></th><th>Non-Autoinflammatory diseases(n=1545)</th><th>Autoinflammatory diseases (n=117)</th></tr></thead><tbody><tr><td>anti-IL1</td><td>2/1542 (0.1)</td><td>12/117 (10.3)</td></tr><tr><td>abatacept</td><td>34/1542 (2.2)</td><td>1/117 (0.9)</td></tr><tr><td>JAK inhibitor</td><td>56/1542 (3.6)</td><td>1/117 (0.9)</td></tr><tr><td>Rituximab</td><td>83/1542 (5.4)</td><td>0/117 (0.0)</td></tr><tr><td>Other biologics</td><td>33/1542 (2.1)</td><td>1/117 (0.9)</td></tr></tbody><tfoot><tr><td colspan="3">Values are presented as no./total no. (%) unless otherwise indicated<br/>COPD, Chronic obstructive pneumopathy disease; IgIV, Intravenous immunoglobulins.</td></tr></tfoot></table>

distribution of the 117 patients with SAID was respectively: monogenic SAID (n=67; 57.3%) including FMF (n=64) and CAPS (n=3), Behçet's disease (n=21; 17.9%), undifferentiated SAID (n=15; 12.8%), AOSD (n=9; 7.7%) and Systemic Juvenile Idiopathic Arthritis (sJIA) (n=5; 4.3%) (online supplemental table 1). Seventeen children had COVID-19 at a median age of 12 years ranging from 3 to 16 years. Ten cases occurred during the first wave (March, April 2020) and seven cases from the second wave (September 2020 onwards). The diseases were FMF (n=7; 41%), PFAPA (n=2), CAPS (n=2), sJIA (n=3), unclassified SAID (n=2) and DADA2 (n=1). Symptoms of COVID-19 were benign in children; none had risk factors for severe COVID-19; seven patients were on colchicine; others were receiving biotherapies (anti-IL-1: n=4; anti-IL-6: n=1; anti TNF: n=2) (online supplemental table 2).

The mean age in each group was 38.7±20.5 for SAID versus 54.7±17.5 for non-SAID. Among the SAIDs, there was a clear predominance of adults (85.5%) with most patients aged between 18 and 54 years (63.2%). The proportion of women was 54.7% in the SAID cohort and 67.2% in the non-SAID cohort. The proportion of patients with SAID with at least one known comorbidity of severe SARS-CoV-2 infection was 35%. Most patients were on colchicine (61.5%) in line with the high proportion of FMF among patients with SAID (table 1). In the SAID group, at least one comorbidity was noted in 35% versus 57% in the non-SAID group. Colchicine and anti-IL-1 biotherapy were, respectively, 61.5% and 10.3%

in the monogenic SAID group, whereas in the non-SAID group, systemic corticosteroids under 10 mg/day (38.4%), methotrexate (35, 9%), anti-TNF (30.4%) and anti-IL-6R (3, 6%) were taken (table 1).

In the SAID group, 90 patients (76.9%) displayed mild form, 17 patients (14.5%) with moderate form and 10 patients (8.6%) with severe form. When comparing the severity between the two groups, the difference was closed to the significant level (with mild form as reference p=0.064), patients with SAID displayed a significantly lower proportion of moderate forms (14.5% vs 22.5%, OR 0.56, 95% CI 0.33 to 0.95). Severe forms were not different between the two groups (8.6% vs 11.2%, OR 0.66, 95% CI 0.34 to 1.29). The days of hospitalisation were similar between the two groups (HR 0.83, 95% CI 0.51 to 1.36) and there were no differences on the death rate (OR 1.00 (95% CI 0.43 to 2.35)). After matching on age±7 years, sex and number of comorbidities, we could not find any significant difference between the two groups (table 2).

Concerning the patients who died in the SAID group: two had severe FMF on colchicine and anakinra, one of them had AA amyloidosis; two had Behçet's disease, including a 35-year-old patient; one elderly patient had Still's disease and one had unclassified SAID. Half were on corticosteroids >10 mg/day. All had numerous comorbidities and 2/3 were over 65 years old (tables 3 and 4).

<table><caption>**Table 2**</caption><thead><tr><th rowspan="2"></th><th colspan="3">Before matching</th><th colspan="3">After matching</th></tr><tr><th>Autoinflammatory diseases (n=117)</th><th>non-Autoinflammatory diseases (n=1545)</th><th>Effect size (95% CI)</th><th>P-value</th><th>Autoinflammatory diseases (n=116)</th><th>non-Autoinflammatory diseases (n=116)</th><th>Effect size (95% CI)</th><th>P-value</th></tr></thead><tbody><tr><td>Severity of COVID-19 Infection</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mild</td><td>90 (76.9)</td><td>1025 (66.3)</td><td>1.00 (ref)</td><td>0.064</td><td>89 (76.7)</td><td>92 (79.3)</td><td>1.00 (ref)</td><td>0.86</td></tr><tr><td>Moderate</td><td>17 (14.5)</td><td>347 (22.5)</td><td>0.56 (0.33 to 0.95)</td><td></td><td>17 (14.7)</td><td>16 (13.8)</td><td>1.10 (0.52 to 2.31)</td><td></td></tr><tr><td>Severe</td><td>10 (8.6)</td><td>173 (11.2)</td><td>0.66 (0.34 to 1.29)</td><td></td><td>10 (8.6)</td><td>8 (6.9)</td><td>1.29 (0.49 to 3.42)</td><td></td></tr><tr><td>Length of hospital stay (days),</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>median (IQR)</td><td>8 (4 to NA)</td><td>10 (5 to 22)</td><td>0.83 (0.51 to 1.36)</td><td>0.45</td><td>8 (4 to NA)</td><td>11 (4 to NA)</td><td>0.99 (0.52 to 1.88)</td><td>0.96</td></tr><tr><td>Death</td><td>6 (5.1)</td><td>79 (5.1)</td><td>1.00 (0.43 to 2.35)</td><td>0.99</td><td>6 (5.2)</td><td>5 (4.3)</td><td>1.21 (0.36 to 4.08)</td><td>0.76</td></tr></tbody><tfoot><tr><td colspan="9">Values are presented as no./total no. (percentage) unless otherwise indicated.</td></tr><tr><td colspan="9">Matching on age+/- 7 years, sex and number of comorbidities. A 5-year-old male patient with asthma in autoinflammatory disease could not be matched with a control</td></tr></tfoot></table>
## 2.8. Fourier-Transform Infrared (FTIR) Analyses

The FTIR spectra of the NaDESs were performed in the range of 600–4000 cm⁻¹ with a PerkinElmer Spectrum 100 spectrophotometer using an ATR device. The baseline was corrected, and the absorbance was normalized between 0 and 1.

## 2.9. High-Performance Liquid Chromatography Analysis (HPLC-DAD)

The HPLC analyses were performed with a Thermo Fisher Scientific Spectra System C18 100 pump equipped with an ACCELA Detector PDA. The separations were achieved on a 150 × 2.1 mm RPC18 reverse phase column (Phenomenex, Le Pecq, France) with a particle size of 3 µm. The elution was performed at a flow rate of 1.2 mL/min, and using a mobile phase that consisted of acidified water at a pH of 2.6 (solvent A) and acidified water:acetonitrile (20:80 *v*/*v*) (solvent B). The samples were eluted with the following linear gradient: from 12% B to 30% B for 15 min; from 30% B to 50% B for 2 min; from 50% B to 99.9% B for 3 min; from 99.9% B to 12% B for 10 min. The samples were prepared by taking 0.5 g of the NaDES diluted in 1 mL of acetonitrile and filtered with a Millex-HA (0.45 µm pores) syringe filter (Sigma Aldrich, Saint Louis, MI, USA). Three hundred microliters of each sample were injected, and the detection was registered at 280 nm. The compounds were identified based on their retention times (RTs) and spectral characteristics relative to the standards.

## 2.10. Determination of Compositions of Extracts

### 2.10.1. Total Flavonoid Content (TFC)

The flavonoid contents of the extracts in the DESs were determined according to the aluminum chloride method as per Quettier-Deleu et al. [23], with some modifications. Two hundred microliters of the extract in the NaDES and eight hundred microliters of ethanol were put into a flask. One milliliter of a methanolic solution of aluminum chloride (2%) was added and mixed before incubation in the dark for 1 h at room temperature. The absorbance of the samples was measured at 415 nm using a UVD 1800 spectrophotometer (Shimadzu, Kyoto, Japan). A blank was prepared by replacing the extract solution with ethanol, before reading the absorbance. A calibration curve was prepared using rutin as a standard, with concentrations between 0 and 35 µg/mL in ethanol. Two hundred microliters of each DES were added to ensure the same ethanol/DES ratio. The aliquots of the rutin solution were put in contact with the aluminum chloride solution, using the same protocol. The concentrations in the flavonoids were expressed in milligrams of rutin equivalents (REs) per gram of byproducts.

### 2.10.2. Total Carotenoid Content (TCC)

A UV 1800 spectrophotometer (Shimadzu, Kyoto, Japan) was used to estimate the total carotenoid contents at 446 nm in a quartz cell with a path length of 1 cm. The absorbances at 446 nm of the solutions prepared with concentrations between 1.04 and 26 µg/mL of β-carotene in DES 2 (DL-menthol/lactic acid) were measured. The values obtained were used as a calibration curve. The total carotenoid content was calculated in milligrams of β-carotene equivalents per gram of byproducts.

### 2.10.3. Total Phenolic Content (TPC)

The total polyphenol contents of the extracts in the DESs were determined using the Folin–Ciocalteu reagent. In a 6 mL tube, 100 µL of 10% (*w*/*v*) Folin–Ciocalteu reagent was mixed with 1040 µL of DES 3 (lactic acid/glucose) after extraction. After a soft shaking (5 min), 800 µL of a sodium carbonate solution (2%) was added. After manual stirring, the medium was incubated in the dark at room temperature for 30 min. A blank was prepared in a similar manner by replacing the DES with ethanol. The absorbance was measured at 760 nm using a UVD 1800 spectrophotometer (Shimadzu, Kyoto, Japan). Gallic acid was used as a standard for the preparation of a calibration curve, with DES 3 concentrations between 0 and 100 µg/mL. The different solutions of gallic acid were mixed with 100 µL of
<table><caption>**Table 3**</caption><thead><tr><th rowspan="2"></th><th colspan="2">Monogenic recurrent fever</th></tr><tr><th>Non monogenic SAID (n=50)</th><th>Monogenic SAID (n=67)</th></tr></thead><tbody><tr><td>Patient's characteristics</td><td></td><td></td></tr><tr><td>Age (years)</td><td></td><td></td></tr><tr><td>Median (IQR)</td><td>44.0 (34.0 ; 59.0)</td><td>29.0 (19.0 ; 43.0)</td></tr><tr><td>&lt;18</td><td>4/50 (8.0)</td><td>13/67 (19.4)</td></tr><tr><td>18-64</td><td>37/50 (74.0)</td><td>45/67 (67.2)</td></tr><tr><td>≥65</td><td>9/50 (18.0)</td><td>9/67 (13.4)</td></tr><tr><td>Female gender</td><td>29/50 (45.3)</td><td>35/67 (54.7)</td></tr><tr><td>Comorbidities</td><td></td><td></td></tr><tr><td>Respiratory disease</td><td>3/50 (6.0)</td><td>3/67 (4.5)</td></tr><tr><td>Interstitial lung disease</td><td>0</td><td>0</td></tr><tr><td>COPD</td><td>1/50 (2.0)</td><td>1/67 (1.5)</td></tr><tr><td>Asthma</td><td>2/50 (4.0)</td><td>2/67 (3.0)</td></tr><tr><td>Cardiovascular disease</td><td>6/50 (12.0)</td><td>5/67 (7.5)</td></tr><tr><td>Coronary heart diseases</td><td>4/50 (8.0)</td><td>5/67 (7.5)</td></tr><tr><td>Stroke</td><td>4/50 (8.0)</td><td>1/67 (1.5)</td></tr><tr><td>Diabetes</td><td>5/50 (10.0)</td><td>3/67 (4.5)</td></tr><tr><td>BMI (kg/m²)</td><td>25.0 (21.0 ; 28.0)</td><td>22.0 (20.0 ; 25.5)</td></tr><tr><td>&lt;30</td><td>38/47 (80.9)</td><td>60/64 (93.8)</td></tr><tr><td>30-39.9</td><td>6/47 (12.8)</td><td>4/64 (6.3)</td></tr><tr><td>≥40</td><td>3/47 (6.4)</td><td>0/64 (0.0)</td></tr><tr><td>Hypertension</td><td>6/50 (12.0)</td><td>6/67 (9.0)</td></tr><tr><td>Cancer</td><td>2/50 (4.0)</td><td>1/67 (1.5)</td></tr><tr><td>Smoking</td><td>6/50 (12.0)</td><td>2/67 (3.0)</td></tr><tr><td>Chronic renal failure</td><td>2/50 (4.0)</td><td>3/67 (4.5)</td></tr><tr><td>Number comorbidities, median (IQR)</td><td></td><td></td></tr><tr><td>0</td><td>25/50 (50.0)</td><td>51/67 (76.1)</td></tr><tr><td>1</td><td>16/50 (32.0)</td><td>10/67 (14.9)</td></tr><tr><td>2</td><td>5/50 (10.0)</td><td>3/67 (4.5)</td></tr><tr><td>3</td><td>3/50 (6.0)</td><td>1/67 (1.5)</td></tr><tr><td>4</td><td>1/50 (2.0)</td><td>2/67 (3.0)</td></tr><tr><td>&gt;4</td><td>0</td><td>0</td></tr><tr><td>Rheumatic or inflammatory Diseases treatments</td><td></td><td></td></tr><tr><td>Corticosteroid</td><td>19/50 (38.0)</td><td>1/67 (1.5)</td></tr><tr><td>Systemic corticosteroid doses≥10 mg</td><td>6/19 (31.6)</td><td>0/1 (0.0)</td></tr><tr><td>NSSAIDs</td><td>1/50 (2.0)</td><td>1/67 (1.5)</td></tr><tr><td>Colchicine</td><td>15/50 (30.0)</td><td>57/67 (85.1)</td></tr><tr><td>Hydroxychloroquine</td><td>0</td><td>0</td></tr><tr><td>Methotrexate</td><td>13/50 (26.0)</td><td>0/67 (0.0)</td></tr><tr><td>Leflunomide</td><td>0</td><td>0</td></tr><tr><td>Salazopyrine</td><td>0</td><td>0</td></tr></tbody></table>

Continued

<table><caption>**Table 3** Continued</caption><thead><tr><th rowspan="2"></th><th colspan="2">Monogenic recurrent fever</th></tr><tr><th>Non monogenic SAID (n=50)</th><th>Monogenic SAID (n=67)</th></tr></thead><tbody><tr><td>Mycophenolate Mofetil / mycophenolic acid</td><td>0</td><td>0</td></tr><tr><td>Azathioprine</td><td>4/50 (8.0)</td><td>0/67 (0.0)</td></tr><tr><td>IgIV</td><td>0</td><td>0</td></tr><tr><td>Targeted biologic or synthetic therapies</td><td></td><td></td></tr><tr><td>anti-TNF</td><td>14/50 (28.0)</td><td>4/67 (6.0)</td></tr><tr><td>anti-IL6</td><td>5/50 (10.0)</td><td>0/67 (0.0)</td></tr><tr><td>anti-IL17A</td><td>0</td><td>0</td></tr><tr><td>anti-IL1</td><td>4/50 (8.0)</td><td>8/67 (11.9)</td></tr><tr><td>abatacept</td><td>1/50 (2.0)</td><td>0/67 (0.0)</td></tr><tr><td>JAK inhibitor</td><td>1/50 (2.0)</td><td>0/67 (0.0)</td></tr><tr><td>Other biologics</td><td>1/50 (2.0)</td><td>0/67 (0.0)</td></tr><tr><td>Severity of COVID-19 Infection</td><td></td><td></td></tr><tr><td>Mild</td><td>35/50 (70.0)</td><td>55/67 (82.1)</td></tr><tr><td>Moderate</td><td>9/50 (18.0)</td><td>8/67 (11.9)</td></tr><tr><td>Severe</td><td>6/50 (12.0)</td><td>4/67 (6.0)</td></tr><tr><td>Length of hospital stay (days), median (IQR)</td><td>12 (6 to NA)</td><td>5 (2 to NA)</td></tr><tr><td>Death</td><td>4/50 (8.0)</td><td>2/67 (3.0)</td></tr></tbody></table>

DISCUSSION

Patients of all ages with SAID can contract COVID-19 and without surprise, more frequently those with FMF, because it is the most frequent monogenic SAID worldwide and those with Behçet's disease, the most frequent polygenic SAID. Interestingly, neither patients with TRAPS nor MKD developed COVID-19 in this series, but some cases might be unreported.

Patients with SAID were younger compared with patients with non-SAID, and all children with SAID displayed a benign form of COVID-19 with excellent prognosis. Therefore, after matching with sex and age, there is no difference in the infection outcome: severe forms and deaths, between the two groups. Thus, the weight of comorbidities appeared more important than the underlying disease; indeed 41/117 (35%) patients with COVID-19+SAID displayed one or more comorbidities.

Colchicine, taken as a daily treatment by 72/117 patients with SAID (61.5%), was not associated with the severity of infection. Even though the number of patients is relatively low, there was no signal on a higher sensitivity to COVID-19 of patients receiving biotherapies targeting either TNF (n=4) or IL-1 (n=8). Interestingly, three patients receiving daily steroids >10 mg/day died including two patients with Behçet's disease. Chronic oral steroid intake has previously been reported to be associated with more severe COVID-19⁷.
Folin–Ciocalteu reagent and incubated in the dark for 30 min. The results are expressed in milligrams of gallic acid equivalents (GAEs) per gram of byproducts.

## 2.11. *Preparation of Cosmetic Emulsions*

### 2.11.1. Formulation of Peel-Off Mask

The “glycerol/glucose” mixture after extraction was used for the formulation of the peel-off mask. The water and polyvinyl alcohol were mixed at 80 °C with constant stirring until the gel formation. The mixture was cooled to 40 °C. Then, the polyethylene glycol 40 (PEG) and the extract in the NaDES were added. Finally, laurate monoglyceride, ethanol and Cosgard were added under vigorous stirring for a few minutes.

### 2.11.2. Formulation of Lip Balm

The “DL-menthol/lactic acid” mixture, including the extract, was used for the formulation of the lip balm. Candelilla wax, beeswax, NaDES, fractionated coconut oil (caprylis) and castor oil were mixed in a beaker and stirred in a water bath at 40 °C until the formation of a gel.

### 2.11.3. Formulation of Hydrosoluble Mask

The NaDES lactic acid/glucose, including the extract, was used for the formulation of the gel mask. Xanthan, glycerol, niacinamide and the NaDES were mixed at room temperature before adding the water and Cosgard. The formulation was mechanically stirred for 15 min until the formation of a homogeneous gel. Two drops of lemon essential oil can be added.

### 2.11.4. Formulation of Moisturizing Cream

The NaDES glycerol/L-proline, including the extract, was used in the formulation of the emulsion. The aqueous and oily phases were prepared separately. Water, the NaDES and xanthan gum were stirred at 80 °C until a homogeneous mixture was obtained. Jojoba oil, glycerin laurate, shea butter and carnauba wax were stirred at 80 °C until homogenization. The oily phase was gradually added to the aqueous phase under stirring at 80 °C for 10 min. After adding starch and ethanol under stirring, the medium thickened, leading to the final emulsion.

## 3. Results and Discussion

### 3.1. *Synthesis of Deep Eutectic Solvents*

We chose to synthesize four deep eutectic solvents to perform the extraction of metabolites from tomato pomace (Table 1). These NaDESs had already been used for the extraction of natural molecules, but two of them have never been applied to tomato pomace. The addition of water in some eutectic solvents helped to adjust the viscosity.

As shown in the table, the glucose/glycerol mixtures were used to extract fatty acids and pigments from spirulina microalgae, and the resulting mixture showed anti-inflammatory activity towards skin keratinocytes [20]. We used the hydrophobic DL-menthol/lactic acid mixture to extract the fractions rich in lycopene from the tomato pomace at 60 °C for 30 min [16]. Fernandez et al. [21] applied the glucose/lactic acid mixture with 15% water under ultrasound (60 min) to several industrial byproducts, including tomato pomace. These conditions represent the optimized solution found by the authors. The mixture allowed for the extraction of both polyphenols and low-polar molecules. We also selected the glycerol/L-proline mixture, which was previously used to extract a combination of phenolic compounds and flavonoids from *Moringa oleifera* L. leaves at 40 °C [22]. The same ratios between the hydrogen donor compound and hydrogen acceptor compound were maintained for our experiments.
<table><caption>Table 4</caption><thead><tr><th></th><th>Age at time of the survey</th><th>Sex</th><th>Body mass index (kg/m<fnref n="2" />)</th><th>Comorbidities* number type</th><th>Autoinflammatory disease</th><th>AA amyloidosis</th><th>Treatment</th><th>Biologics</th></tr></thead><tbody><tr><td>1</td><td>75</td><td>W</td><td>20</td><td>2 COPD</td><td>Behçet disease</td><td>No</td><td>Steroids >10mg</td><td>No</td></tr><tr><td>2</td><td>34</td><td>H</td><td>43</td><td>3 Obesity Diabetes HT</td><td>Unclassified autoinflammatory disease</td><td>No</td><td>Colchicine</td><td>No</td></tr><tr><td>3</td><td>84</td><td>M</td><td>20</td><td>4 CVD CKD AVC</td><td>Still disease</td><td>No</td><td>Steroids> 10 mg</td><td>No</td></tr><tr><td>4</td><td>74</td><td>W</td><td>27</td><td>3 Diabetes HT</td><td>Behçet disease</td><td>No</td><td>Steroids>10 mg</td><td>No</td></tr><tr><td>5</td><td>58</td><td>M</td><td>21.8</td><td>2 HT CKD**</td><td>FMF</td><td>Yes</td><td>Colchicine</td><td>IL1-inhibitor (Anakinra)</td></tr><tr><td>6</td><td>81</td><td>M</td><td>22.9</td><td>5 CVD CKD** COPD HT</td><td>FMF</td><td>No</td><td>Colchicine</td><td>IL1-inhibitor (Anakinra)</td></tr></tbody></table>

## CONCLUSION

In conclusion, COVID-19 affected more likely patients with FMF in our cohort. Severe forms occurred more frequently among patients with multiple comorbidities, and chronic intake of oral steroids.

## Author affiliations

**Collaborators** FAI²R / SFR/SNFMI/SOFREMIP/CRI/IMIDIATE Consortium And Contributors: Florence Aeschlimann, Paris; Christian Agard, Nantes; Nassim, Ait-Abdallah Paris; Jean-David Albert, Rennes; Didier Alcaix, Le Havre; Jean-Sébastien Allain, Rennes; Yannick Allanore, Paris; Zahir Amoura, Paris; Adamah Amouzougan, Aint-Priest-En-Jarez; Emma Andre, Paris; Aïnsi Arbault, Dijon; Jean-Benoît Arlet Paris; Laurent Arnaud, Strasbourg; Denis Arniaud, Marseille; Herliette Arty-Hue, Gap; Lucie Atlan, Amboise; Alexandra Audemard-Verger Tours; Christine Audoin-Pajot, Toulouse; Victor Audren, Paris; Gilles Avenel, Rouen; Jérôme Avouac, Paris; Maxime Bach-Bunner, Colmar; Hélène Bacquet-Deschryver, Dieppe; Brigitte Bader-Meunier, Paris; Nathalie Balandraud, Marseille; Jean-Charles Balblanc, Trevenans; Claire Ballot-Schmit, Besancon; Stéphane Bally, Chambery; Frédéric Banal, Saint-Mande; Béatrice Banneville, Paris; Pierre Barbery, Lisieux; Audrey Barrelet, Jossigny; Géraldine Bart, Rennes; André Basch, Caluire-Et-Cuire; Vincent Baumier, Clermont-Ferrand; Guillaume Bayer, Quincy-Sous-Senart; Sophie Bayle, Avignon; Catherine Beauvais, Paris; Rudie Beinat, Bordeaux; Véronique Belin, Thonon-Les-Bains; Rakiba Belkhir, Kremlin-Bicetre; Alexandre Belot, Bron; Aurélie Beltai, Narbonne; Ruben Benainous, Bobigny; Mohammed Benammar, Saint-Quentin; Chahinez Bendahmane, Pontoise; Mathilde Benhamou, Versailles; Ygal Benhamou, Rouen; Ahmed Benmansour, Chateauroux; Pascal Bennet, Bois-Guillaume; Brigitte Bernoux-Manat, Rennes; Elise Berthet, Clermont-Ferrand; Sabine Berthier, Dijon; Olivia Berthoud, Rennes; Emilie Berthoux, Lyon; Ewa Bertolini, annecy; Adrien Bigot, Tours; Aurélia Bisson-Vaivre, Castres, Gilles Blaison, Colmar; Gilles Bolla, Cannes; Olivier Bonidan, Agen; Christine Bonnet, Limoges; Raphaël Borie, Paris; Charlotte Borocco, Paris; Marie Bossert, Trevenans; Laurence Boudou, Saint-Chamond; Françoise Bouhour, Bron; Kévin Bouiller, Besancon; Laurence Bouillet, Grenoble; Bastien Bouldoires, Colmar; Thomas Bourree, Cholet; Ines Boussen, Paris; Karima Boussoualim, Saint-Priest-En-Jarez; Eric Bouvard, Paris; Brondino Regine, Pennes-Mirabeau; Pierre Buchlin, Mulhouse; Laurence Cabantous, Merignac; Patrice Cacoub, Paris; Simon Cadiou, Rennes; Alaine Cantagrel, Toulouse; Didier Caplanne, Bayonne; Aurélia Carbasse, Montpellier; Maurizio Carteni, Saint-Pierre-De-Coutances; Brice Castel, Tarbes; Pascal Cathebras, Saint-Priest-En-Jarez; Hervé Caumont, Troyes; Audrey Cayot-Bouillet, Dijon; Annalisa Celant, Metz; Aurélie Chaffin, Avranches; Benjamin Chaigne, Paris; Benoît Chailloux, Herbiers; Romuald Champy, Ecuelles; Agnès Charcot, Paris; Pierre Charles, Paris; Isabelle Charlot-Lambrecht, Reims; Caroline Charpin, Marseille; Emmanuel Chatelus, Strasbourg; Bernard Chaudier, Marseille; Pascal Chazerain, Paris; Pascale Chertok, Argenteuil; Xavier Chevalier, Creteil; Maximé Chevreau, Aix-Les-Bains; Emilie Chotard, Paris; Delphine Chu Miow Lin, Tours; Pascal Claudepierre, Creteil; Gaëlle Clavel, Paris; Cyril Clavel-Osorio, Saint-Martin; Marine Clay, Grenoble; Johanna Clet, Bordeaux; Fleur Cohen, Paris; Gregory Cohen, Avignon; Marie-Eve Colette-Cedoz, Bourgoin-Jallieu; Nived Collercandy, Tours; Antoine Colombey, Saint-Nazaire; Chloé Comarmond, Paris; Bernard Combe, Montpellier; Céline Comparon, Bobigny; Elodie Constant, Valence; Arnaud Constantin, Toulouse; Pascal Coquerelle, Beuvry; Justine Corli, Douai; Clémence Corre, Vannes; Nathalie Costedoat-Chalumeau, Paris; Marion Couderc, Lermont-Ferrand; Marie Couret, Bourg-En-Bresse, Natacha Courvoisier, Nogent-Sur-Marne; Fabienne Coury-Lucas, Pierre-Benite; Cécile Coutarel, Clermont-Ferrand; Fabrice Coutier, Vesoul; Richard Damade, Chartres; Laurence Daver-Malaterre, Marseille; Claire De Moreuil, Brest; Marijke Decrock, Perpignan; Michel Delahousse, Suresnes; Emilie Delattre Barrois, Quingey; Christophe Deligny, Fort-De-France; Delphine Denarie, Roanne; Amélie Denis, Le Mans; Camille Deprouw, Courbevoie; Emanuelle Dernis, Le Mans; Alban Deroux, Grenoble; Renaud Desbarbieux, Boulogne-Sur-Mer; Elise Descamps, Paris; Alexandra Desdoits, Caen; Chantal Deslandre, Paris; Marie Desmurs, Mulhouse; Jacques Despaux, Montelimar; Marie Desplats, Lambersart; Frédérick Detree, Reims; Valérie Devauchelle-Pensec, Brest; Mathilde Devaux, Poissy; Robin Dhote,

<footnote n="1">¹Sorbonne University, AP-HP, Tenon Hospital, Internal Medicine Department, 4 rue de la Chine, 75020, Paris, France; national Reference center for autoinflammatory diseases and AA amyloidosis (CEREMAIA), Tenon Hospital, Paris, France</footnote>

<footnote n="2">²Univ. Lille, CHU Lille, ULR 2694 - METRICS : évaluation des technologies de santé et des pratiques médicales, F-59000 Lille, France, CHU Lille, Département de Biostatistiques, F-59000 Lille, France, Université de Lille, Lille, France</footnote>

<footnote n="3">³Service de Rhumatologie Pédiatrique, Centre de Référence des Maladies Auto-Inflammatoires de l'enfant, Hôpital Bicêtre, AP HP, Université Paris Sud, Bicêtre, France</footnote>

<footnote n="4">⁴Department of internal medicine, Bichat hospital, Paris, France, Bichat Hospital, Paris, France</footnote>

<footnote n="5">⁵Université de Paris, Service de Rhumatologie, Hôpital Cochin, AP-HP.CUP, Paris, France, Hôpital Cochin, Paris, France</footnote>

<footnote n="6">⁶CHI Poissy-Saint-Germain-en-Laye, Saint-Germain-en-Laye, France</footnote>

<footnote n="7">⁷Unité de Médecine Interne: Maladies Auto-immunes et Pathologie Vasculaire (UF 04), Centre de Reference des Maladies autoimmunes systemiques Rares d'Ile-de-France MATHEC, AP-HP, Hôpital Saint-Louis, Paris, France, Université de Paris, IRSL, Recherche clinique appliquée à l'hématologie, EA, Paris, France, Hôpital Saint-Louis, Paris, France</footnote>

<footnote n="8">⁸Sorbonne Université – Assistance Publique Hôpitaux de Paris, Pitié Salpêtrière University Hospital, Dept of Rhumatology, Reference Center for Rare Diseases CEREMAIA (ERN RITA), Paris, France. ii) Pierre Louis Institute of Epidemiology and Public Health, INSERM UMRS 1136, PEPITES team, Assistance Publique-Hopitaux de Paris, Paris, France</footnote>

<footnote n="9">⁹Internal Medecine, CHU Tours, Tours, France</footnote>

<footnote n="10">¹⁰GH du Havre-Hôpital Jacques Monod, Le Havre, France</footnote>

<footnote n="11">¹¹Service de Médecine Interne, Centre de Référence des Maladies Auto-immunes et Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), CHU Lille, F-59000 Lille, France 2- Inserm, U1286, F-59000 Lille, France, CHRU de Lille, Lille, France</footnote>

<footnote n="12">¹²Hôpital d'Instructions des Armées Bégin, Saint Mande, France</footnote>

<footnote n="13">¹³Rheumatology department, CHU de Nice, Nice, France</footnote>

<footnote n="14">¹⁴Rheumatology, INSERM UMRS_938, Sorbonnes Université UPMC Univ Paris 06, St-Antoine Hospital, DHU I2B, Paris, France</footnote>

<footnote n="15">¹⁵Service de Rhumatologie, Hôpital Pasteur, Centre Hospitalier Universitaire, Université de Nice Sophia Antipolis, Nice, France</footnote>

<footnote n="16">¹⁶Internal Medicine and Rheumatology, Groupe Hospitalier Diaconesses Croix Saint Simon, Paris, France</footnote>

<footnote n="17">¹⁷Internal Medecine department, CH de Bar-Le-Duc, Bar-le-Duc, France</footnote>

<footnote n="18">¹⁸Univ Lille, Lille, France</footnote>

<footnote n="19">¹⁹CeReMAI-Departement of Pediatrics Department of general pediatrics, Andre Mignot hospital, Versailles, CEREMAIA, France, Hôpital Mignot, Le Chesnay, France</footnote>
<table><caption>**Table 1.** Compositions of selected DESs.</caption><thead><tr><th>No.</th><th>Composition</th><th>Molar Ratio</th><th>% of Water</th><th>Target Molecules/ Plant Matter</th><th>Ref.</th></tr></thead><tbody><tr><td>DES 1</td><td>Glycerol + glucose</td><td>3:1</td><td>30</td><td>Fatty acids and pigments/microalga spirulina</td><td>[20]</td></tr><tr><td>DES 2</td><td>DL-menthol + lactic acid</td><td>8:1</td><td>0</td><td>Lycopene/tomato pomace</td><td>[16]</td></tr><tr><td>DES 3</td><td>Glucose + lactic acid</td><td>5:1</td><td>15</td><td>Phenolic compound/tomato pomace, olive cake</td><td>[21]</td></tr><tr><td>DES 4</td><td>Glycerol + L-proline</td><td>1:2.5</td><td>30</td><td>Phenolic compound/moringa leaves</td><td>[22]</td></tr></tbody></table>

### 3.2. Extraction of Tomato Pomace by DESs

The ground tomato pomace was brought into contact with one of the DES under stirring and moderate heat (Figure 1). The solid material was separated by centrifugation before the analyses of the metabolites. The DESs containing the metabolites were then integrated into the formulations.

<figure><img src="image_6.png" /><figcaption>**Figure 1.** Strategy of extraction/formulation coupling.</figcaption></figure>

The extraction conditions gathered in Table 2 are based on the references in Table 1.

<table><caption>**Table 2.** Extraction conditions with DESs.</caption><thead><tr><th>No.</th><th>Method of Extraction</th><th>Amount of DES</th><th>Mass of TP (g)</th></tr></thead><tbody><tr><td>DES 1</td><td>Maceration (2 h, 40 °C)</td><td>32 g</td><td>2</td></tr><tr><td>DES 2</td><td>Maceration (30 min, 50 °C)</td><td>20 g</td><td>3.4</td></tr><tr><td>DES 3</td><td>Ultrasound (1 h, 40 °C)</td><td>40 mL</td><td>2</td></tr><tr><td>DES 4</td><td>Ultrasound (1 h, 40 °C)</td><td>20 mL</td><td>2</td></tr></tbody></table>
Bobigny; Harmonie Diaz, Narbonne; Philippe Dieude, Paris; Yannick Dieudonne, Strasbourg; Elisabeth Diot, Tours; Guillaume Direz, Le Mans; Djamal-Dine Djeddi, Amiens; Fanny Domont, Paris; Sarah Douvier, Aix-Les-Bains; Béatrice Drouet, Pau; Jean-Jacques Dubost, Clermont-Ferrand; Catherine Duc, Romans-Sur-Isere; Angélise Ducornet, Saint-Brieuc; Carine Dufaure-Lombard, Limoges; Cécile Dumaine, Paris; Anne-Elisabeth Dumel, Cernay; Chantal, Dumoulin-Richez Merignac; Agnès Duquesne, Bron; Géraldine Durand, Poitiers; Mariee Durandin-Truffinet, Paris; Pierre-Marie Duret, Colmar; Stéphanie Dürrieu-Mehlman, Saint_Cloud; Perrine Dusser-Benesty, Paris; Maika Duval, Antistes; Mikael Ebbo, Marseille; Esther Ebstein, Paris; Andra Economu-Dubosc, Sucy-En-Brie; Soumaya El Mahou, Tourcoing; Stéphanie Emilie, Villeneuve-Saint-Georges; Romain Euvrad, Bourg-En-Bresse; Philippe Evon, Bar-Le-Duc; Claire Eymard-Gibert, Lyon; Sylvie Fabre, Montpellier; Dorothée Fagedet, Gap; Dominique Farge-Bancel, Paris; Meryem Farhat, Lille; Marion Fauconier, Reims; Bruno Fautrel, Paris; Jacques Echtenbaum, Pantin; Renaud Felten, Strasbourg; Nicole Ferreira-Maldent, Tours; Elodie Feurer, Lyon; Amandine Fichet, Trevenans; Françoise Flaisler, Nimes; René-Marc Flipo, Lille; Nans Florens, Lyon; Violaine Foltz, Paris; Elisabeth Fontanges, Lyon; Jennifer Foret, Dax; Anne-Claire Fougerousse, Saint-Mande; Anne Fouque-Aubert, Lyon; Catherine Foutrier-Morello, Plan-De-Cuques; Hélène Francois-Pradier, Paris; Léa Frantzen, Mulhouse; Marie-Louise Fremond, Paris; Pierre Fritz, Paris; Antoine Froissart, Creteil; Jean Fulpin, Piera Toulon; Fuzibet, Orleans; Francis Gaches, Toulouse; Laurence Gagneux-Lemoussu, Reims; Mélanie Gahier Penhoat, Saint-Nazaire; Joris Galland, Paris; Frédérique Gadjbakhch, Paris; Ansâi Gardette, Vichy; Nicole Garnier, Plaisance-Du-Touch; Thomas Gararra, Nantes; Jean-François Garrot, Semur-En-Auxois; Romain Gastaldi, Grenoble; Philippe Gaudin, Grenoble; Véronique Gaud-Listair, Saint-Michel-Sur-Orge; Maud Gauthier-Prieur, Louviers; Lorraine Gauzere, Saint-Denis; Dana Georgescu, Vienne; Sophie Georgin-Lavialle, Paris; Nathalie Gerard, Dijon; Elisabeth Gervais, Poitiers; Christelle Gibert, Valence; Eric Gibert, Paris; Ghislaine Gill, Paris; Jérôme Gillard, Lons-Sa-Leu-Saunier; Mélanie Gilson, Grenoble; Pauline Gimonnet, Epernay; Jeanine-Sophie Giraudet-Le Quintrec, Paris; Aude Giraud-Morelet, Ecully; Baptiste Glace, Vichy; Camille Glanowski, Saint-Mande; Bertrand Godeau, Creteil; Bruno Gombert, La Rochelle; Camille Gonnet-Gracia, La Rochelle; Tiphance Goulenok, Paris; Philippe Goupille, Tours; Olivier Gourmelen, Aix-Les-Bains; Sophie Govindaraju-Audouard, Vesoul; Franck Grados, Amiens; Martine Grall-Lerosey, Rouen; Bruno Grardel, Arras; Anne Grasland, Colombes; Gilles Gateau, Paris; Monica Groza, Colmar; Pascal Guggenbuhl, Rennes; Isabelle Guichard, Saint-Priest-En-Jarez; Constance Guillaud, Creteil; Sévenrine Guillaume-Czitrom, Kremlin-Bicetre; Caroline Guillbert, Marseille; Xavier Guillot, Saint-Denis; Philippe Guilpain, Montpellier; Aline Gury, Angers; Pauline Guyader, Ploemeur; Marie-Hélène Guyot, Roubaix; Eric, Hachulla Lille; Cécile Hacquard-Bouder, Yvetot; Marie-Noelle Havar, Argenteuil; Jean-Pierre Hellier, Arles; Pascal Hennequin, Epinal; Basile Henriot, Dinan; Julien Henry, Kremlin-Bicetre; Véronique Hentgen, Le Chesney; Marion Hermet, Vichy; Julie Hernandez, Montauban; Miguel Hie, Paris; Pascal Hilliquin, Corbele-Essonne; Olivier Hinschberger, Mulhouse; Ambre Hittinger-Roux, Reims; Jan Holubar, Montpellier; Elsa How Shing Koy, Saint-Priest-En-Jarez; Charlotte Hua, Nimes; Christophe Hudry, Paris; Serge Huguenel, Sarrebourg; Clara Jaccard, Clermont-Ferrand; Jean-Michel Jacquemier, Cornebarriieu; Bénédicated Jamard, Toulouse; Catherine Jan, Bar-Le-Duc; Sylvie Jean, Rennes; Laurie Joffres, Jean-Benoît; Sandrine Jousse-Joulin, Brest; Mathieu Jouvray, Arras; Pierre-Antoine Juge, Paris; Trauen Juillard, Lyon; Denis Jullien, Lyon; Abdelkrim Kabchou, Vichy; Ludovic Karkowski, Lyon; Françoise Karman, Pontault-Combault; Farid Kemiche, Pontoise; Jérémy Keraen, Quimper; Pierre Kieffer, Mulhouse; Isabelle Kone-Paut, Kremlin-Bicetre; Abdeldajallil Koreichi, Lorient; Marie Kostine, Bordeaux; Stéphanie Krebs, Ploemer; Sylvain La Batide Alanore, Paris; Valentin Lacombe, Angers; Pierre Lafforgue, Marseille; Sophie Halhalle, PARIS; M arc Lambert, Lille; Isabelle Lambrecht, Reims; François Lamer, Rennes; Vincent Langlois, Le Havre; Sylvain Lanot, Alencon; Aurélia Lanteri, Antibes; Jean-Paul Larbre, Ierre-Benite; Augustin Latourte, Paris; Christian Lavigne, Angers; Noémie Le Goueluc, Valenciennes; Sophie Le Guen Guegan, Contamine-Sur-Arve; Guillaume Le Guenno, Clermont-Ferrand; Agnès Lebrun, Paris; Emmanuel Ledoult, Tourcoing / Lille; Nathalie Legoupil, Paris; Erick Legrand, Angers; Diane Leguy, Roubaix; Olivier Leloir, Ronchin; Christophe Leroux, Dreux; Rémi Leroy, Dunkerque; Marie Leroy-Gouix, Vannes; Charles Leske, Cholet; Tifenn Léturcq, Paris; Amélie Leurs, Dunkerque; Céline Leveque Michaud, Valence; François-Xavier Limbach, Saverne; Frédéric Liote, Paris; Anne, Lohse Trevenans; Pierre Lozac'h, Le Mans; Charlotte Lucas, Rennes; Etienne Mabrut, Pierre-Benite; Aurélie Madelon, Grenoble; Nadine Magy-Bertrand, Besancon; Matthieu Mahevas, Creteil; Hélène Maillard, Lille; Thibault Maillet, Macon; François Maillot, Tours; Sandrine Malochet-Guinamand, Clermont-Ferrand; Quentin Mangon, Aurillac; Julie Mankikian, Tours; Sylvie Marchou_Lopez, Crolles; Nathalie Margarit, Portet-Sur-Garonne; Thierry Marhadour, Brest; Alexandre Maria, Montpellier; Xavier Mariette, Kremlin-Bicetre; Hubert Marotte; Saint-Priest-En-Jarez; Claire Martin, A Rochelle; Thierry Martin, Strasbourg; Alexis Mathian, Paris; François Maurier, Metz; Frédéric Maury, Beuvry; Betty Mazet-Guillaume, Angers; Arnaud Mazouyez, Contamine-Sur-Arve; Hassan Mazyad, Poissy; Nadia Mehsen-Cetre, Bordeaux; Arsène Mekinian, Paris; Isabelle Melki, Paris; Jean-Camille Meric, Ales; Laurent Messer, Colmar; Martin Michaud, Toulouse; Catherine Michel, Mulhouse; Matthias Michel, Sangatte; Mathilde

Michon, Courbevoie; Anne-Marie Milesi-Lecat, Vichy; Anna Molto, Paris; Olivier Moranne, Nimes; Gautier Morel, Valenciennes; Hugo Morel, Dijon; Jacques Morel, Montpellier; Franck Morin, Saint-Pierre-De-Coutances; Laurence Moulinier, Paris; Guillaume Moulis, toulouse; Bertrand Moura, Paris; Claudine Naude, Saint-Jean-De-Maurienne; Minh Nguyen, Paris; Sabine Nicolas-Vullierme, Chatillon; Hubert Nielly, Saint-Mande; Gaétane Nocturne, Kremlin-Bicetre; Aurore Nottez, Dunkerque; Henri-Olivier Ollagnon, Tourvillebanne; Eric Oziol, Beziers; Isabelle Paud-Vitoux, Guilherand-Granges; Guillaume Padern, Montpellier; Anne Pagnier, Grenoble; Caroline Paris, Marseille; Antoine Parrot, Paris; Tristan Pascart, Lille; Yasmina Pascaud-Mansour, Angers; Lætitia Paulin, Bourgoing-Jallieu; Stephan Pavy, Kremlin-Bicetre; Judith Payet, Saint-Denis; Laurent Perard, Lyon; Céline Pereira-Gillion, Tours; Yves-Marie Pers, Montpellier; Edouard Pertuiset, Pontoise; Micheline Pha, Paris; Thao Pham, Marseille; Maud Pichon, Argenteuil; Audrey Pierreisnard, Merignac; Gabrielle Pizana, Fougeres; Sylvaine Poignant, Nantes; Elsa Poix, Quint-Fonsegrives; Agnès Portier, Paris; Jacques Pouchot, Paris; Antoine Poulet, Marseille; Nicolas Poursac, Bordeaux; Grégory Pugnet, Toulouse; Déborah Puyraimond-Zemmour, Paris; Pierre Quartier-Dit-Maire, Paris; Quenet Marion, Saint-Brieuc; Viviane Queyrel, Nice; Loïc Raffray, Saint-Denis; Jérôme Razanamahery, Dijon; Philippe Remy, Creteil; Myriam Renard, Aix-Les-Bains; Jessica Rene, Tours; Sabine Revuz, Met; Bénédicated Rey, Lyon; Gaëlle Richard-Colmant, Lyon; Olivier Richer, Bordeaux; Christophe Richez, Bordeaux; Elodie Riviere, Kremlin-Bicetre; Etienne Riviere, Bordeaux; Sébastien Riviere, Paris; Sophie Robin, Elbeuf; Julien Rohmer, Suresnes; Isabelle Roit, Perpignan; Michel Selland, Paris; Etienne-Rozin, Agen; Carole Rosenberg, Argenteuil; Linda Rossi, Kremlin-Bicetre; Olivier Roth, Marseille; Sid-Ahmed Rouidi, Dreux; Mathilde Roumier, Suresnes; Mickaël Rousiere, Paris; Clémentine Ousselin, Valenciennes; Bénédicated Rouviere, Brest; Christian Roux, Nice; Fabienne Roux, Paris; Marielle Roux, Bourgoing-Jallieu; Nicolas Roux, Met; Diane Rouzaud, Paris; Sylvie Rozenberg, Paris; Ruyssen-Witrand Adeline, Toulouse; Sacco Isabelle, Paris; Sadji Fatima, Poissy; Laurent Sailler, Toulouse; Carine Salliot, Orleans; Jean-Hugues Salmon, Reims; Charlotte Samaille, Lille; Maxime Samson, Dijon; Alain Saraux, Brest; Léa Savey, Paris; Jean Schmidt, Amiens; Julie Seguier, Marseille; Jérémy Rolland, Paris; Eric Senbel, Marseille; Thomas Sene, Paris; Patricia Senet, Paris; Raphaèle Seror, Kremlin-Bicetre; Amélie Servettaz, Reims; Pascal Seve, Lyon; Aurélie Sicaud, Le Pont-De-Beauvoisin; Nadia Sivova, Tourcoing; Smets, Clermont-Ferrand; Vincent Sobanski, Lille; Christelle Sordet, Strasbourg; Elisabeth Sornay-Rendu, La Tour-Du-Pin; Martin Soubrier, Clermont-Ferrand; Odile Souchaud-Debouverie, Poitiers; Gaëlle Sourisseau-Diverres, Gujan-Mestras; Lætitia Sparca, Mulhouse; Lionel Spielmann, Colmar; Chloé Stavris, Marseille; Sarah Steib, Marseille; Catherine Straus, Elancourt; Victor Strotz, Antony; Sylvain Mathieu, Clermont-Ferrand; Séverine Taffignon-Clave, Ecully; Débora Talmud, Orleans; Chloé Taraud, Niot; Nora Tenenbaum, Paris; Claire Theillac, Benoît Pierre-Benite; Thomachot, Gardanne; Thierry Thomas, Saint-Priest-En-Jarez; Nathalie Tieulie, Nice; Soizic Tiriau, Nantes; Alice Tison, Bordeaux; Anne Tournadre, Clermont-Ferrand; Eric Toussirot, Besancon; Ludovic Trefond, Clermont-Ferrand; Sophie Trijau, Marseille; Sébastien Troullier, Aurillac; Anne-Priscille Trouvin, Paris; Marie-Elise Truchetet, Bordeaux; Florence Uettwiller, Tours; Florence Ulrich, Valenciennes; Yurdaguz Uzunhan, Bobigny; Isabelle Valls-Bellec, Brest; Jacques Vaquier, Limoges; Eric Veillard, Saint-Malo; Laurent Veillon, Orleans; Guillaume Vial, Bordeaux; Jean-François Viallard, Bordeaux; Judith Victor, Bordeaux; Claire Vidon, Aix_Les_Bains; Vidon, Creteil; Camille Vigne, Pierre-Benite; Alexandre Virone, Kremlin-Bicetre; Ursula Warzocha, Bobigny; Daniel Wendling, Besancon; Claude Werle, Haguenau; Cécile Wibaux, Seclin; Michel Wisniewski, Saint-Amand-Les-Eaux; Juliette Woessner, Avignon; Bernadette Xerri-Campano, Saint-Maur-Des-Fosses.

**Funding** The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

**Competing interests** None declared.

**Patient consent for publication** Not applicable.

**Ethics approval** This study involves human participants and was approved by CNIL DEC20-107. Participants gave informed consent to participate in the study before taking part.

**Provenance and peer review** Not commissioned; externally peer reviewed.

**Open access** This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

**ORCID iDs**

Rim Bourguiba http://orcid.org/0000-0002-7352-9074
Isabelle Koné-Paut http://orcid.org/0000-0001-8939-5763
Bruno Fautrel http://orcid.org/0000-0001-8845-4274
Emmanuel Ledoult http://orcid.org/0000-0002-3925-9541
### 3.3. Characterization of Synthesized NaDESs

#### 3.3.1. Infrared Analyses

The infrared spectra of the NaDESs allowed for the identification of the bands representative of the electronic interactions between the two compounds (Table 3).

<table><caption>**Table 3.** Formula of molecules used in composition of synthesized NaDESs.</caption><thead><tr><th>Formula</th><th>Molecule</th></tr></thead><tbody><tr><td><img src="image_0_0.png" alt="Chemical structure of DL-menthol"></td><td>DL-menthol</td></tr><tr><td><img src="image_0_1.png" alt="Chemical structure of L-proline"></td><td>L-proline</td></tr><tr><td><img src="image_0_2.png" alt="Chemical structure of Lactic acid"></td><td>Lactic acid</td></tr><tr><td><img src="image_0_3.png" alt="Chemical structure of D-Glucose"></td><td>D-Glucose</td></tr><tr><td><img src="image_0_4.png" alt="Chemical structure of Glycerol"></td><td>Glycerol</td></tr></tbody></table>

The formation of the NaDESs was highlighted by the shift in the vibration bands of the bonds that involve heteroatoms. These shifts were due to the electronic interactions between the components in the NaDESs. For DES 1 and DES 3, a band due to the angular deformation of the OH group of water molecules appeared at 1645 cm⁻¹. This peak was observed by Santana et al. [24] for several NaDESs containing water. For DES 1, DES 3 and DES 4, the formation of hydrogen bonds involving the OH groups (and NH groups for DES 4) within the NaDESs resulted in shifts in the OH (or NH) extension vibration bands towards lower frequencies. For DES 3 and DES 4, the vibration bands of the C=O bond were widened by the formation of hydrogen bonds with the oxygen atom, which is a phenomenon that was observed by Ali et al. [25] for a DL-menthol/caprylic acid mixture. It was observed for v(C=O) = 1716 cm⁻¹ of lactic acid, and for v(C=O) = 1609 cm⁻¹ (amide II) of L-proline.

The infrared spectra of each NaDES helped to verify that the crystalline structure of the precursors had changed into a glassy nonordered phase.

#### 3.3.2. Thermal Analyses

To synthesize the NaDESs and use them for the extraction, it was necessary to know their stabilities as a function of the temperature. The thermal properties are influenced by the nature of the precursors, the water content and the strength of the interactions
<figure><img src="image_3.png" /></figure>

Sophie Georgin-lavialle http://orcid.org/0000-0001-6668-8854

REFERENCES

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2 Kharouf F, Ishay Y, Kenig A, et al. Incidence and course of COVID-19 hospitalizations among patients with familial Mediterranean fever. *Rheumatology* 2021;60:keab577.

3 Bourguiba R, Delplanque M, Vinit C, et al. Clinical course of COVID-19 in a cohort of 342 familial Mediterranean fever patients with a long-term treatment by colchicine in a French endemic area. *Ann Rheum Dis* 2020. doi:10.1136/annrheumdis-2020-218707. [Epub ahead of print: 02 Nov 2020].

4 Güven SC, Erden A, Karakaş Özlem, et al. COVID-19 outcomes in patients with familial Mediterranean fever: a retrospective cohort study. *Rheumatol Int* 2021;41:715-9.

5 Nas K, Eryilmaz N, Geyik MF, et al. COVID-19 in patients with familial Mediterranean fever treated with colchicine: case based review. *Rheumatol Int* 2021;41:811-7.

6 Stella A, Lamkanfi M, Portincasa P. Familial Mediterranean fever and COVID-19: friends or Foes? *Front Immunol* 2020;11:574593.

7 Zouboulis CC, van Laar JAM, Schirmer M, et al. Adamantiades-Behçet's disease (Behçet's disease) and COVID-19. *J Eur Acad Dermatol Venereol* 2021;35:e541-3.

8 FAI2R /SFR/SNFMI/SOFREMIP/CRI/IMIDIATE consortium and contributors. Severity of COVID-19 and survival in patients with rheumatic and inflammatory diseases: data from the French RMD COVID-19 cohort of 694 patients. *Ann Rheum Dis* 2021;80:527-38.

9 Papa R, Penco F, Volpi S, et al. Syndrome of undifferentiated recurrent fever (surf): an emerging group of autoinflammatory recurrent fevers. *J Clin Med* 2021;10:10.
between the molecules. The decomposition temperatures ($T_d$) determine the temperature range of use. Differential scanning calorimetry indicates the characteristic glass transition temperatures ($T_g$).

Ribeiro et al. [26] studied the mixture DL-menthol:lactic acid (2:1), for which they measured a decomposition temperature of 229 °C and a glass transition temperature of –61 °C. Craveiro et al. [27] observed a reduction in the glass transition by adding water to a mixture of choline chloride:xylose (2:1) (approximately 4 °C for 5% of added water).

The thermograms of the four NaDESs prepared were carried out between 20 and 600 °C to obtain the mass loss profiles as a function of the temperature. Differential scanning calorimetry covers a temperature range from –100 to 40 °C. The information related to the temperature profiles is presented in Table 4.

<table><caption>**Table 4.** Results of thermal analyses of NaDESs.</caption><thead><tr><th>NaDES</th><th>Composition</th><th>% of Water</th><th>T<sub>d</sub> (°C)</th><th>T<sub>g</sub> (°C)</th><th>T<sub>c</sub> (°C)</th><th>T<sub>m</sub> (°C)</th></tr></thead><tbody><tr><td>DES 1</td><td>Glycerol/glucose (3:1)</td><td>30</td><td>180</td><td></td><td></td><td></td></tr><tr><td>DES 2</td><td>DL-menthol/lactic acid (8:1)</td><td>0</td><td>120</td><td>-54</td><td>-15</td><td>≈10</td></tr><tr><td>DES 3</td><td>Glucose/lactic acid (5:1)</td><td>15</td><td>130</td><td>-75.1</td><td></td><td></td></tr><tr><td>DES 4</td><td>Glycerol/L-proline (1:2.5)</td><td>30</td><td>180</td><td>-66.4</td><td></td><td></td></tr></tbody></table>

$T_d$: decomposition temperature; $T_c$: crystallization temperature; $T_g$: glass transition temperature; $T_m$: melting temperature.

The synthesized NaDESs were stable up to 120, 130 or 180 °C, depending on the constituents. The highest thermal stability was measured for DESs 1 and 4, with $T_d$ = 180 °C. Delgado-Mellado et al. [28] observed that this temperature is generally intermediate between the decomposition temperatures of the pure constituents. As reported by Dai et al. [13], NaDESs that contain sugars, such as DES 1 and DES 3, have decomposition temperatures below 200 °C. DES 2 of the composition 8:1 had a glass transition temperature close to –54 °C, and a subsequent exothermic crystallization peak at –15 °C (–7.8 J/g). We also observed a melting point at 10 °C (7.7 J/g), which is the temperature below the two melting points of the DL-menthol (27 and 34 °C for the polymorphic forms α and β) mentioned by Ribeiro et al. [26].

The glass transition temperatures determined for DES 2, DES 3 and DES 4 were below –50 °C and constituted evidence of synthesized NaDESs. These temperatures attest that NaDESs are supramolecular complexes with stable liquid phases over a fairly wide temperature range [24].

### 3.4. Analysis of Extracts

The total contents of phenols (TCP) were determined in the DESs after extraction (Table 5). Some components of the DESs reacted with the Folin's reagent (the solution turned blue), which invalidated the measurements for DES 1 (glycerol/glucose), DES 2 (DL-menthol/lactic acid) and DES 4 (glycerol/L-proline). For DES 3, it was observed that the level of polyphenols extracted (1915.5 µg/g of TP) was higher than that measured in an extract made with ethyl acetate (786.7 µg polyphenols/g TP), but it was significantly lower than those obtained with a polar solvent and supercritical CO₂.

<table><caption>**Table 5.** Comparison of extracted polyphenol rates from tomato pomace.</caption><thead><tr><th>Solvent of Extraction</th><th>Rate of Extracted Polyphenols<br>(µg Gallic Acid Equivalent/g of Dried TP)</th></tr></thead><tbody><tr><td>DES 3 (lactic acid/glucose)</td><td>1915.5 ± 15.1</td></tr><tr><td>Ethanol *</td><td>3489.5 ± 23.3</td></tr><tr><td>Ethanol + water *</td><td>3251.8 ± 19.4</td></tr><tr><td>Supercritical CO<sub>2</sub> *</td><td>3062.9 ± 21.6</td></tr><tr><td>Ethyl acetate *</td><td>786.7 ± 8.3</td></tr></tbody></table>

<footnote>* Values obtained from [5].</footnote>
The total flavonoid contents (TFCs) presented in Table 6 show that DES 3 (lactic acid/glucose) had the highest level of extracted flavonoids (1410.9 µg/g TP) compared with the other DESs. DES 2 is better suited to the extraction of apolar molecules. According to the results obtained, ethanol remained the most appropriate solvent for extracting this category of compounds (3479 µg of flavonoids/g of TP).

<table><caption>**Table 6.** Comparison of extracted flavonoid rates from tomato pomace.</caption><thead><tr><th>Extraction Solvent</th><th>Rate of Extracted Flavonoids (µg Rutin Equivalent/g of TP)</th></tr></thead><tbody><tr><td>DES 1</td><td>439.5 ± 8.3</td></tr><tr><td>DES 2</td><td>50.5 ± 5.3</td></tr><tr><td>DES 3</td><td>1410.9 ± 15.3</td></tr><tr><td>DES 4</td><td>893.5 ± 10.8</td></tr><tr><td>Ethanol</td><td>3479 ± 25.5</td></tr><tr><td>Ethanol + ethyl acetate</td><td>1853.2 ± 13.4</td></tr><tr><td>Supercritical CO<sub>2</sub></td><td>1174.8 ± 12.3</td></tr></tbody></table>

Fernandez et al. [21] found DES 3 interesting for phenolic acid extraction. Indeed, the HPLC analyses confirmed that DES 3 is particularly rich in gallic acid and chlorogenic acid. The DES "choline chloride: lactic acid" was also reported to be efficient with 51.7 mg GAE/g extract from tomato pomace [18]. Nevertheless, the NaDES did not improve the rate of extraction obtained with ethanol (Table 6).

The levels of carotenoids extracted were determined using spectrophotometry (Table 7). DES 2 (DL-menthol/lactic acid) is suitable for the extraction of carotenoids, as confirmed by the COSMO-RS predictions of Vasiliev et al. [19]. We found a rate of 96.4 µg carotene/g TP with this DES, which is lower than the 1446.6 µg lycopene/g MS obtained by Silva et al. [16] under similar conditions. Lazzarini et al. [17] showed the influence of the drying process of tomato pomaces on the extraction rates of carotenoids, which could explain this difference. The extraction made using SC-CO₂ had the highest rate of carotenoid extraction.

<table><caption>**Table 7.** Comparison of extracted carotenoid rates from tomato pomace.</caption><thead><tr><th>Extraction Solvent</th><th>Rate of Extracted Carotenoids (µg β-Carotene Equivalent/g of TP)</th></tr></thead><tbody><tr><td>DES 2</td><td>96.4 ± 4.1</td></tr><tr><td>Supercritical CO<sub>2</sub></td><td>2895.1 ± 26.2</td></tr><tr><td>Ethanol + ethyl acetate</td><td>1521.0 ± 17.4</td></tr><tr><td>Ethyl acetate</td><td>1293.7 ± 15.5</td></tr><tr><td>Ethanol</td><td>849.6 ± 12.3</td></tr></tbody></table>

The metabolites extracted by the DESs were also analyzed via HPLC-DAD at 280 nm (Figure 2). The 39 molecules identified are listed in Table 8. The comparison of the area unit of the peaks for the same molecule indicated that DES 4 was dominated by flavanols/flavonols (molecules 2, 8, 11 and 17), flavones (molecules 20, 24, 28, 31, 34 and 37) and naringenin (flavanone). In the same way, the total phenolic content (TPC) of DES 3 can be attributed to its high contents of chlorogenic acid (molecule 6) and gallic acid (molecule 1). Compared with the other DESs, DES 1 is characterized by high contents of ferulic acid, p-coumaric acid, tannins (molecules 9, 10, 15 and 39), flavones (molecules 14 and 30) and flavonols (myricetin and quercetin). As expected, the content of carotenoids was higher in DES 2, which also contained some flavones (for instance, molecule 38).
<figure><img src="image_7.png" /><figcaption>**Figure 2.** HPLC-DAD chromatograms at 280 nm of media after extraction (extracts in NaDESs).</figcaption></figure>

Many of these molecules confer antioxidant or anti-inflammatory properties (kaempferol, cinnamic acid derivatives, some phenolic acids), which are beneficial for the skin. For example, ferulic acid is not only a free radical scavenger, but it is also an inhibitor of the enzymes that catalyze the generation of free radicals. It has a protective role for the main structures of the skin, and it is interesting for its anti-inflammatory, antioxidant and antimicrobial properties, even if it tends to oxidize quickly [29]. Lycopene is the most abundant carotenoid in tomato pomace, and it has antioxidant properties that act to inhibit UV effects. Moreover, the phytosterols contained in tomato seed oil have restorative and healing properties that are interesting for lip balm [30].

### 3.5. Methodology of Formulations

For the present work, we chose to keep the whole extracting medium for the formulations to avoid the separation of the molecules from the DESs. This strategy avoided the usual difficulties of resolubilizing an extract into a formulation. The compositions of the selected NaDESs (Table 3) are compatible with cosmetic formulations, as the compounds are listed in the INCI Beauty database. Moreover, they are authorized as organic ingredients by the international COSMOS standard. The role of each compound is specified in Tables 8–10. In a formulation, antioxidant molecules help to delay the oxidation of other molecules by inhibiting chain reactions. They can be endogenous or exogenous molecules. Antioxidants also fight against the formation of reactive oxygen species (ROS) that are produced by metabolism and involved in the skin aging mechanism. In galenic formulations, the use of lycopene, which is a powerful antioxidant, is a very recent approach. Indeed, the changes in the colors and fragrances of the formulations that contain lycopene are no longer perceived as disadvantages, according to a sensory analysis conducted by Costa et al. [31]. As for phenolic acids, they can inhibit the activities of collagenase and elastase, which are enzymes that are involved in the degradation of collagen and elastin, respectively [4]. The same author showed that cork extracts rich in phenolic acids and tannins help to regulate sebum production. Among these compounds (i.e., phenolic acids and tannins), some have shown antimicrobial properties, such as the gallic acid present in NaDESs 2 and 3, which is interesting for the preservation of emulsions.
<table><caption>**Table 8.** Identification of molecules in tomato pomace extracts by HPLC-DAD (a.u.: area unit).</caption><thead><tr><th>No.</th><th>RT (min)</th><th>Compound</th><th>DES 1 (a.u.)</th><th>DES 2 (a.u.)</th><th>DES 3 (a.u.)</th><th>DES 4 (a.u.)</th></tr></thead><tbody><tr><td>1</td><td>2.04</td><td>Gallic acid</td><td>-</td><td>30.4</td><td>193.3</td><td>-</td></tr><tr><td>2</td><td>2.21</td><td>(-)-Epicatechin (flavanol)</td><td>-</td><td>-</td><td>-</td><td>456.0</td></tr><tr><td>3</td><td>2.51</td><td>Methyl 3,5-dihydroxybenzoate</td><td>-</td><td>17.9</td><td>-</td><td>-</td></tr><tr><td>4</td><td>2.70</td><td>Ferulic acid</td><td>465.7</td><td>16.9</td><td>66.4</td><td>124.8</td></tr><tr><td>5</td><td>3.15</td><td>Caffeic acid</td><td>158.7</td><td>-</td><td>-</td><td>285.8</td></tr><tr><td>6</td><td>3.65</td><td>Trans-3-hydroxycinnamic acid (chlorogenic acid)</td><td>-</td><td>27.5</td><td>72.0</td><td>-</td></tr><tr><td>7</td><td>3.85</td><td>p-Coumaric acid</td><td>212.8</td><td>-</td><td>-</td><td>-</td></tr><tr><td>8</td><td>5.43</td><td>Myricetin (flavonol)</td><td>237.0</td><td>13.0</td><td>44.6</td><td>199.7</td></tr><tr><td>9</td><td>6.21</td><td>6-Hydroxycoumarin (tannin)</td><td>105.8</td><td>6.1</td><td>45.1</td><td>-</td></tr><tr><td>10</td><td>9.18</td><td>2-Hydroxycinnamic acid (tannin)</td><td>28.8</td><td>-</td><td>-</td><td>32.7</td></tr><tr><td>11</td><td>9.63</td><td>Quercetin (flavonol)</td><td>40.0</td><td>0.9</td><td>9.3</td><td>21.3</td></tr><tr><td>12</td><td>10.61</td><td>3,4-Dihydroxycinnamate</td><td>-</td><td>0.1</td><td>-</td><td>14.6</td></tr><tr><td>13</td><td>10.94</td><td>trans-Cinnamic acid</td><td>-</td><td>0.4</td><td>-</td><td>-</td></tr><tr><td>14</td><td>11.17</td><td>Naringenin (flavanone)</td><td>-</td><td>-</td><td>-</td><td>81.6</td></tr><tr><td>15</td><td>11.77</td><td>α-Cyano-4-hydroxycinnamic acid</td><td>144.2</td><td>4.7</td><td>37.0</td><td>-</td></tr><tr><td>16</td><td>12.66</td><td>Vitamin E (tocopherol)</td><td>9.7</td><td>0.1</td><td>4.1</td><td>5.4</td></tr><tr><td>17</td><td>13.8</td><td>Kaempferol (flavonol)</td><td>0.4</td><td>0.1</td><td>3.3</td><td>3.3</td></tr><tr><td>18</td><td>14.68</td><td>3-Cyano-7-hydroxy-4-methyl coumarin</td><td>-</td><td>0.3</td><td>3.8</td><td>-</td></tr><tr><td>19</td><td>14.99</td><td>2,4-Dihydroxy-3,6-dimethyl benzoic acid</td><td>10.1</td><td>-</td><td>-</td><td>2.8</td></tr><tr><td>20</td><td>15.58</td><td>6-Hydroxy flavone</td><td>-</td><td>-</td><td>1.4</td><td>1.2</td></tr><tr><td>21</td><td>16.22</td><td>5,6,7-Hydroxy flavone (baicalein)</td><td>0.9</td><td>0.1</td><td>0.1</td><td>-</td></tr><tr><td>22</td><td>18.1</td><td>7-Hydroxy-4-phenylcoumarin</td><td>-</td><td>0.3</td><td>-</td><td>-</td></tr><tr><td>23</td><td>18.53</td><td>Ethyl trans-2-hydroxy cinnamate</td><td>31.7</td><td>1.3</td><td>-</td><td>-</td></tr><tr><td>24</td><td>18.70</td><td>5-Hydroxy-4'-methoxy flavone</td><td>14.9</td><td>-</td><td>15.7</td><td>42.8</td></tr><tr><td>25</td><td>19.61</td><td>7-Hydroxy flavone</td><td>-</td><td>0.2</td><td>-</td><td>-</td></tr><tr><td>26</td><td>19.79</td><td>β-Carotene</td><td>9.2</td><td>24.5</td><td>7.3</td><td>-</td></tr><tr><td>27</td><td>19.81</td><td>Lutein</td><td>0.1</td><td>11.1</td><td>7.3</td><td>-</td></tr><tr><td>28</td><td>20.28</td><td>5,7-Dihydroxy-3',4',5'-trimethoxy flavone</td><td>2.9</td><td>0.2</td><td>-</td><td>15.0</td></tr><tr><td>29</td><td>20.62</td><td>5,7-Dihydroxy-4-propyl coumarin</td><td>-</td><td>0.3</td><td>0.8</td><td>-</td></tr><tr><td>30</td><td>20.75</td><td>3'-Hydroxy-6-methyl flavone</td><td>3.2</td><td>-</td><td>-</td><td>-</td></tr><tr><td>31</td><td>20.99</td><td>5-Hydroxy flavone</td><td>-</td><td>-</td><td>-</td><td>0.1</td></tr><tr><td>32</td><td>21.12</td><td>3,3'-Dimethoxy flavone</td><td>0.2</td><td>-</td><td>0.2</td><td>-</td></tr><tr><td>33</td><td>21.49</td><td>3,6,3'-Trimethoxy flavone</td><td>0.6</td><td>-</td><td>0.6</td><td>-</td></tr><tr><td>34</td><td>21.50</td><td>7-Hydroxy-3',4',5'-trimethoxy-α-naphthoflavone</td><td>-</td><td>-</td><td>-</td><td>0.6</td></tr><tr><td>35</td><td>21.83</td><td>3,7-Dimethoxyflavone</td><td>1.0</td><td>1.4</td><td>-</td><td>-</td></tr><tr><td>36</td><td>22</td><td>5-Hydroxy-3'-methoxy flavone</td><td>-</td><td>-</td><td>1.2</td><td>-</td></tr><tr><td>37</td><td>22.03</td><td>5-Hydroxy-4'-methoxy flavone</td><td>-</td><td>-</td><td>-</td><td>0.9</td></tr><tr><td>38</td><td>22.54</td><td>4',5'-Dimethoxy-2'-hydroxy-4-methyl chalcone</td><td>-</td><td>-</td><td>-</td><td>0.2</td></tr><tr><td>39</td><td>23.39</td><td>Hamamelitannin</td><td>10.2</td><td>5.1</td><td>5.02</td><td>-</td></tr></tbody></table>
<table><caption>**Table 9.** Composition of peel-off mask.</caption><thead><tr><th>Ingredient</th><th>Composition (% w)</th><th>Function</th></tr></thead><tbody><tr><td>Polyvinyl alcohol</td><td>15.0</td><td>Film-forming agent (viscosity control)</td></tr><tr><td>Water</td><td>69.1</td><td>Solvent</td></tr><tr><td>DES 1 with extract</td><td>11.4</td><td>Antioxidant and purifying agent</td></tr><tr><td>Polyethylene glycol 40</td><td>2.1</td><td>Film-forming and thickening agent</td></tr><tr><td>Glycerol monolaurate</td><td>1.0</td><td>Emollient and emulsifier agent</td></tr><tr><td>Ethanol</td><td>1</td><td>Solubilizer and inhibitor of microbial activity</td></tr><tr><td>Cosgard</td><td>0.4</td><td>Preservative</td></tr></tbody></table>

<table><caption>**Table 10.** Composition of lip balm.</caption><thead><tr><th>Ingredient</th><th>Composition (% w)</th><th>Function</th></tr></thead><tbody><tr><td>Candelilla wax</td><td>10.4</td><td>Film-forming agent</td></tr><tr><td>Beeswax</td><td>10.0</td><td>Emulsifying, film-forming and perfuming agent</td></tr><tr><td>Fractionated coconut oil (caprylis)</td><td>46.3</td><td>Softener</td></tr><tr><td>DES 2 with extract</td><td>2.3</td><td>Coloring (lycopene) and regenerating agent</td></tr><tr><td>Castor oil</td><td>30.2</td><td>Nourishing and repairing agent</td></tr><tr><td>Raspberry extract</td><td>7 drops</td><td>Natural origin, accepted by ECOCERT</td></tr></tbody></table>

In cosmetics, there are several ways to protect and beautify the skin. The formulations depend on the part of the face concerned (i.e., skin, lips or eyes).

A **mask** offers an effective way to provide the skin with nutrients and ensure the hyperhydration state of the epidermis for an improvement in the skin texture [32]. It can be a water-washable mask or the “peel-off” type, the adhesion of which removes impurities from the skin.

A **lip balm** should moisturize, repair and protect against the cold. Its texture should be pleasant and not sticky. Balms have lipid bases, such as coconut oil. Azmin et al. [33] used this oil to extract lycopene by macerating powdered dried tomatoes.

A **moisturizing cream** has the properties of protecting the skin from external aggressions, such as cold, pollution and UV rays.

The analyses carried out showed that the NaDESs were appropriate for the concentration of some of the bioactive molecules that were present in the tomato pomace. The NaDESs with extracted metabolites were incorporated into two different mask formulations: a cream and a balm (Figure 3).

<figure><img src="image_8.png" /><figcaption>**Figure 3.** Cosmetic formulations from left to right: peel-off mask (DES 1); lip balm (DES 2); water-soluble mask (DES 3); cream (DES 4).</figcaption></figure>
Glycerol is a moisturizing agent and glucose is a humectant agent, which means that DES 1 (glycerol/glucose) was compatible with the preparation of a mask (Table 9). The antioxidant and anti-inflammatory activities of the bioactive molecules from the tomato pomace provided the mask with some of the properties that are sought after to cleanse and regenerate the skin. The formulation of the peel-off mask also included a synthetic polymer that is soluble in water so that the mask can form a homogeneous film that adheres to the skin and can be easily removed after the application time.

DES 2 (DL-menthol/lactic acid) was chosen to prepare a lip balm (Table 10) because menthol can be introduced in low doses into lip balm formulations, which provides a refreshing effect. The lactic acid produced by a fermentation process using *Lactobacillus* helped to regulate the pH and bacterial colonization of the preparation. DES 2 is rich in carotenoids and hydroxy flavones, the antioxidant properties of which protect and repair the lips. The texture was solid, and the melting was sufficient to mold it into a stick. It can be easily spread, and it forms a smooth film.

DES 3 (lactic acid/glucose) is suitable for formulating a water-soluble mask (Table 11). The lactic acid helps to adjust the pH for gentle exfoliation. The glucose present in the DES acts as a humectant. The formulation spreads on the skin and forms a film with moderate adhesion [33]. DES 3 is rich in gallic acid and chlorogenic acid, the antioxidant properties of which keep the skin in good condition.

<table><caption>**Table 11.** Composition of hydrosoluble mask.</caption><thead><tr><th>Ingredient</th><th>Composition (% w)</th><th>Function</th></tr></thead><tbody><tr><td>Xanthan gum</td><td>7.5</td><td>Gelling agent and emulsifier</td></tr><tr><td>DES 3 with extract</td><td>5.3</td><td>Film-forming agent and antioxidant</td></tr><tr><td>Glycerol</td><td>20.5</td><td>Moisturizing agent</td></tr><tr><td>Water</td><td>55.7</td><td>Solvent</td></tr><tr><td>Niacinamide</td><td>10</td><td>Vitamin B3 and smoothing agent</td></tr><tr><td>Cosgard</td><td>1.0</td><td>Preservative</td></tr></tbody></table>

In DES 4 (glycerol/L-proline), glycerol is a moisturizing agent, and L-proline is one of the 20 amino acids that make up our body's proteins. This amino acid is involved in collagen metabolism and is used as a skin care agent. According to the composition of the cream (Table 12), DES 4 contains powerful antioxidants (such as epicatechin and myricetin, caffeic acid, naringenin), which confer antiaging properties to the cream.

<table><caption>**Table 12.** Composition of moisturizing cream.</caption><thead><tr><th>Ingredient</th><th>Composition (% by Mass)</th><th>Function</th></tr></thead><tbody><tr><td>Water</td><td>40.7</td><td>Solvent</td></tr><tr><td>DES 4 with extract</td><td>18.5</td><td>Antioxidant, regenerating properties</td></tr><tr><td>Xanthan gum</td><td>0.3</td><td>Gelling agent, emulsifier</td></tr><tr><td>Jojoba oil</td><td>11.1</td><td>Emollient, skin protection</td></tr><tr><td>Carnauba wax</td><td>0.9</td><td>Emollient</td></tr><tr><td>Glycerin laurate</td><td>4.1</td><td>Softener and emulsifier</td></tr><tr><td>Shea butter</td><td>3.4</td><td>Texturizing agent, skin care</td></tr><tr><td>Starch</td><td>3.6</td><td>Viscosity control</td></tr><tr><td>Ethanol</td><td>17.2</td><td>Solvent</td></tr></tbody></table>

### 3.6. Application of Formulations

Formulation pH values between 5 and 7 respect the pH of the skin [3]. The drying times were measured on films spread on contrast cards from a deposit of a known mass. They were evaluated for between 5 and 10 min. A spreading test was carried out by depositing 0.07 g of the formulation between two glass slides (Figure 4).
<figure><img src="image_9.png" /><figcaption>**Figure 4.** Tests of formulation spreading (0.07 g). From left to right: peel-off mask; water-soluble mask; cream; lip balm.</figcaption></figure>

The spreading diameters of each formulation are shown in Table 13. Logically, the cream, being more fluid, had the highest spreading diameter. The masks had thicker textures, but they formed homogeneous and translucent films. The texture of the balm was more consistent (a solid wax-like formulation), but it melted sufficiently to hug the surface. A drop of the NaDES was also brushed onto a contrast card (2 cm²), which showed the initial film-forming properties of the NaDES, which probably contributed to the final texture of the formulation (Table 12). The characteristics of the four NaDESs seem favorable for the elaboration of film-forming formulations that include active molecules. The polar molecule solubilization abilities were better for NaDESs 3 and 4. It should also be noted that the costs of NaDESs 1 and 3 (based on the glucose, glycerol and lactic acid) were rather moderate. It is necessary to assess whether the added value of L-proline (for the cream) and DL-menthol (for the balm) can compensate for the respective costs of NaDESs 2 and 4.

<table><caption>**Table 13.** Film-forming properties of NaDESs and their resulting formulations.</caption><thead><tr><th>Property</th><th>Peel-Off Mask</th><th>Water-Soluble Mask</th><th>Hydrating Cream</th><th>Lip Balm</th></tr></thead><tbody><tr><td>Aspects of dry film of NaDESs on contrast cards</td><td>Glossy film</td><td>Soft film</td><td>Mat film</td><td>Mat and smooth film</td></tr><tr><td>Spread diameters of formulations (cm) *</td><td>1.5</td><td>2</td><td>3</td><td>1.2</td></tr></tbody></table>

## 4. Conclusions

In this article, four eutectic solvents with different polarities and compositions were synthesized. The syntheses were carried out at moderate temperatures (50–80 °C). The NaDES were characterized by infrared spectroscopy and thermal analyses, which highlighted the interactions between the molecules and the formation of a stable liquid phase up to a decomposition temperature > 120 °C). These NaDESs have already been used for the extraction of natural molecules, but two of them have never been applied to tomato pomace.

The results showed that the selected NaDES were suitable for the extraction of the metab-olites present in the tomato pomace. From HPLC data, the extraction ability of NaDES were compared and defined their selectivity towards each molecule. Thus, the DL-menthol/lactic acid mixture (DES 2) preferentially trapped low-polar compounds (carotenoids, lipids, to-copherol), while the glucose/ glycerol mixture (DES 1) showed affinity with some phenolic acids, flavones, flavonols and tannins. The glucose/lactic acid

<footnote>* According to Figure 4.</footnote>
mixture (DES 3) was particu-larly selective towards some phenolic compounds, while the
glycerol/ L-proline (DES 4) was efficient for the extraction of some flavones, flavonols
and flavanones. The possibility of com-bining the extraction and formulation steps was
achieved, while maintaining the quality of the ingredients. The biocompatibility of these
NaDES made it possible to incorporate them into the cosmetic formulations, which rep-
resents a new strategy for the ecoconception of formulations. Moreover, the bioactive
molecules extracted by the NaDES can really generate beneficial effects for the facial skin
and lips, based on the synergetic effects of the metabolites. Further tests should be consid-
ered to check the skin tolerance and to assess the antiaging properties of formulations by
measuring the inhibition of elastase, collagenase and hyaluron-idase.

**Author Contributions:** Conceptualization, A.J., P.d.C., M.U. and O.M.; methodology, A.J., M.U., P.d.C., P.E. and J.B.; software, A.J., J.B., P.d.C., P.E. and O.M.; validation, P.d.C., M.U. and O.M.; formal analyses, A.J., P.d.C. and M.U.; investigation, A.J., P.d.C., O.M. and J.B.; resources, M.U., P.E., P.d.C. and O.M.; data curation, A.J., P.E., P.d.C. and M.U.; writing—original draft preparation, A.J., P.d.C. and P.E.; writing—review and editing, O.M., M.U., J.B. and P.d.C.; supervision, P.d.C., P.E., M.U. and O.M.; project administration, O.M. and P.d.C.; funding acquisition, O.M. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was financially supported by the Hubert Curien-Cèdre program 42232RE (French Foreign Ministry).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

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