# Paediatric formulation: budesonide 0.1 mg/mL viscous oral solution for eosinophilic esophagitis using cyclodextrins

Caroline Ey, Christel Hosselet, Benjamin Villon, Frédéric Marçon

► To cite this version:

Caroline Ey, Christel Hosselet, Benjamin Villon, Frédéric Marçon. Paediatric formulation: budesonide 0.1 mg/mL viscous oral solution for eosinophilic esophagitis using cyclodextrins. Pharmaceutical Technology in Hospital Pharmacy, 2018, 3 (2), pp.71 - 77. 10.1515/pthp-2018-0004. http://hal.science/hal-03677498

HAL Id: hal-03677498

https://hal.science/hal-03677498

Submitted on 24 May 2022

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_1.png" /></figure>
Caroline Ey, Christel Hosselet, Benjamin Villon and Frédéric Marçon*

# Paediatric formulation: budesonide 0.1 mg/mL viscous oral solution for eosinophilic esophagitis using cyclodextrins

https://doi.org/10.1515/pthp-2018-0004

Received January 17, 2018; revised February 23, 2018; accepted February 26, 2018

## Abstract

**Background:** Viscous oral solutions of budesonide (dose range: 1 mg to 2 mg) have long been used to treat eosinophilic oesophagitis in children. The objective of the present study was to provide a convenient paediatric pharmaceutical formulation of a viscous budesonide solution at a dose level of 0.1 mg/mL, using cyclodextrin as a solubilizer.

**Methods:** Solubility studies were performed with γ-cyclodextrin and hydroxypropyl-β-cyclodextrin, and viscosity was tested with a Brookfield viscometer. The stability of the final formulation was tested in a climatic chamber. Levels of budesonide, budesonide impurities and degradation products were assayed using the HPLC–UV method described for the budesonide-related substance assay in the European Pharmacopoeia monograph.

**Results:** The solubility of budesonide increased linearly with both cyclodextrins. Gamma cyclodextrin (complexation efficiency: 0.147) was preferred to hydroxypropyl-β-cyclodextrin (complexation efficiency: 0.064) as a solubilizing agent. Hydroxypropylcellulose (1% m/v) was added to increase viscosity, and sucralose was added to improve palatability. The sterilized, filtered, final formulation was stable for at least 3 months when packed aseptically in sterile 15 mL type 1 amber glass vials.

**Conclusions:** We have developed a convenient, stable, preservative-free, viscous formulation of a budesonide solution for the hospital- and home-based treatment of paediatric patients.

**Keywords:** budesonide, cyclodextrins, eosinophilic oesophagitis, pediatrics

## Introduction

Budesonide (Figure 1) is an anti-inflammatory corticosteroid that is notably used to treat asthma, allergic rhinitis and Crohn's disease. Powders/suspensions for inhalation, nasal sprays, and enteric solid dosage forms are administered locally to act on the lung, nose or digestive tract, respectively. Budesonide has a low systemic bioavailability (<30%, due to extensive pre-systemic metabolism) but is generally well tolerated; systemic side effects are rare [1].

Oral viscous budesonide has been used to treat eosinophilic oesophagitis in children at dose levels ranging from 1 to 2 mg [2, 3]. Due to the lack of availability of a dedicated formulation of budesonide in this indication, an extempora- neous formulation is generally prepared by mixing water, five to ten 1 g packets of an artificial sweetener (1.1% m/m sucralose in maltodextrin/glucose; SPLENDA®, Heartland Food Products Group, Indianapolis, IN, USA) and a bude- sonide suspension for inhalation [4, 5]. Even though these extemporaneous formulations have been successfully tested against a placebo in a small clinical trial and con- stitute a standard treatment for eosinophilic oesophagitis [2], they are not practical for daily use. Furthermore, there are few published data on the formulations' physicochem- ical characteristics (e. g. stability). We therefore decided to compound and study a budesonide formulation suitable for oral administration to children in an indication of eosino- philic oesophagitis.

We considered that the above-mentioned extempora- neous formulation could be improved. The intrinsic solu- bility of budesonide in water is around 20 mg/L which may hamper its efficiency; hence, solubilizing it may improve the drug's topical action [6, 7]. As eosinophilic oesophagi- tis is an allergic disease, we also wanted to limit the use of preservatives such as parabens or benzoic acid, which are known to cause allergies [8]. Given that the oesophageal transit time ranges from 1.5 to 6 s in children aged between 6 days and 16 years [9], we reasoned that adding a viscous

<footnote>*Corresponding author: Frédéric Marçon, Pharmacie à Usage Intérieur, Groupe de Recherche en Pharmacotechnie Pédiatrique, Centre Hospitalier Universitaire d'Amiens-Picardie, Amiens, France; LG2A UMR CNRS 7378, Amiens, France, E-mail: marcon.frederic@chu-amiens.fr</footnote>

<footnote>Caroline Ey, Christel Hosselet, Benjamin Villon, Pharmacie à Usage Intérieur, Groupe de Recherche en Pharmacotechnie Pédiatrique, Centre Hospitalier Universitaire d'Amiens-Picardie, Amiens, France, E-mail: c.ey@ch-beauvais.fr; c.hosselet@ch-beauvais.fr; Villon.Benjamin@chu-amiens.fr</footnote>
<figure><img src="image_2.png" /><figcaption>**Figure 1:** The chemical formula of budesonide; * indicates the chiral centre responsible for the two epimeric forms.</figcaption></figure>

mucoadhesive might also improve the formulation's effectiveness [5]. To enhance palatability, we kept sucralose in the formulation at doses compatible with the FDA's acceptable daily intake of 5 mg/kg/day.

The objective of the present study was to provide a convenient, paediatric pharmaceutical formulation of budesonide 0.1 mg/mL for the treatment of eosinophilic oesophagitis, using cyclodextrins as a solubilizer.

## Materials and methods

Experiments were performed in a stepwise manner; each step enabled us to validate the choice of an excipient and its quantity.

### Materials

All excipients were of pharmaceutical grade. Hydroxypropyl-β-cyclodextrin (CAVASOL W7 HP PHARMA), γ-cyclodextrin (CAVAMAX W8 PHARMA) and hydroxypropylcellulose (KLUCEL GF PHARM) was purchased from Ashland (Alizay, France). Micronized budesonide (manufactured by Farmabios) and Sucralose (manufactured by Vitasweet) were purchased from INRESA (Bartenheim, France). Suitable analytical-grade reagents were used for stability testing.

### Solubility testing

Solubility studies were performed in the presence and absence of cyclodextrins in purified water (at 24 °C, and protected from light). Increasing concentrations of cyclodextrin (0.2, 0.4, 0.7, and 2 mM) were added to a large excess of budesonide in a 10 mL volumetric flask. The suspensions were sonicated for 1 h, stirred overnight (for 16 h, protected from light) and then centrifuged twice (5000 rpm for 10 min) before measurements. The supernatants were carefully pipetted and diluted in methanol

(from 1:2 to 1:4). The budesonide concentration was then measured at 240 nm with an UV spectrophotometer (UV2600, Shimadzu) vs. a calibration curve prepared daily. Cyclodextrins were selected on the basis of the phase diagram and the complexation efficiency (CE, as described elsewhere) [10].

### Viscosity testing

The viscosity of 1% hydroxypropylcellulose solutions (n = 3) at 22 °C was measured in a 500 mL beaker using a rotational viscometer (VR 3000, Myr); the L1 spindle was used. Glycerol (10 % m/v) was used to facilitate the preparation of solutions. The cyclodextrins' influence on the solution's viscosity was assessed. Viscosity was measured after 2 h without agitation. The formulations' non-Newtonian fluid properties (e. g. shear thinning and thixotropy) were investigated at various rotational speeds (from 10 to 200 rpm) and various experiment durations.

### Stability testing

Budesonide, budesonide impurities and degradation products were assayed using the European pharmacopoeia (EurPh) high-performance liquid chromatography method, as described in the budesonide-related substance assay (EurPh 01/2010:1075). Briefly, samples were diluted 1:5 in purified water, and 20 µL of these solutions were eluted on an octadecyl column (4.6 x 150 mm, 3.5 µm; Symmetry®, Waters) at 50 °C, using an ethanol, acetonitrile, phosphate buffer (pH 3.2) gradient (Table 1) and a flow rate of 1 mL/min with an ultra-high-performance liquid chromatograph (Nexera®, Shimadzu). The method's performance in our hands was checked against the chemical reference substance (budesonide for system suitability, Y0001148, European directorate for the Quality of Medicines and Healthcare). The budesonide level was measured at 240 nm against a three-point calibration curve (80%, 100% and 120% of the nominal concentration) prepared daily.

<table><caption>**Table 1:** Gradient of mobile phase A (anhydrous ethanol, acetonitrile, phosphate buffer pH 3.2, 2:32:68, v/v/v) and mobile phase B (acetonitrile, phosphate buffer pH 3.2, 50:50, v/v).</caption><thead><tr><th>Time (min)</th><th>Phase A (% v/v)</th><th>Phase B (% v/v)</th></tr></thead><tbody><tr><td>0 – 38 min</td><td>100</td><td>0</td></tr><tr><td>38 – 50 min</td><td>100 → 0</td><td>0 → 100</td></tr><tr><td>50 – 60 min</td><td>0</td><td>100</td></tr></tbody></table>
Forced degradation studies were performed on the final formulation in type I transparent glass vials placed in a climatic chamber (KBF, Binder) at 24 °C/60% relative humidity with 1.1 W/m² UV/visible exposure, according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q1B guidelines to ease the detection of degradation products on final stability testing. Final stability testing was performed on the formulation in type I amber glass vials placed in climatic chamber (KBF, Binder) at 24 °C/60% relative humidity for 3 months.

# Results

## Solubility

The intrinsic solubility of budesonide increased 5-fold with a 1:5 molar ratio of γ-cyclodextrin and a 1:12 molar ratio of hydroxypropyl-β-cyclodextrin (Figure 2). The CE was 0.147 for γ-cyclodextrin and 0.064 for hydroxypropyl-β-cyclodextrin. According to the binary phase diagram, around 1.7 mg/mL of γ-cyclodextrin and around 4.5 mg/mL of hydroxypropyl-β-cyclodextrin are needed to solubilize 1 mg/mL of budesonide.

## Viscosity testing

The mean ± SD viscosity of a 1% (m/v) hydroxypropyl-cellulose and 10% (m/v) glycerol solution in purified water with and without 0.2% (m/v) of γ-cyclodextrin was 47 ± 2 mPa·s and 48 ± 2 mPa·s, respectively, using the L1 spindle at 100 rpm. No major changes in viscosity were observed at the various speeds used (10, 20, 50, 100, and 200 rpm).

## Stability testing

### The final formulation

To improve palatability (as judged by the investigators), sucralose was added to the viscous budesonide solution within the manufacturer's recommended range of concentrations (i. e. 0.03–0.24% (m/v)). The final formulation (Table 2) was sterilized by filtration through a 0.2 µm polyethersulphone membrane (STERICUP, Millipore), and then 10 mL were dispensed under aseptic conditions into sterile 15 mL type I amber glass vials (unidose).

<figure><img src="image_3.png" /><figcaption>**Figure 2:** Solubility of budesonide (mean ± SD) as a function of the amount of hydroxypropyl-β-cyclodextrin (blue squares) or γ-cyclodextrin (red diamonds). The target budesonide concentration is indicated by a red, dashed line.</figcaption></figure>
<table><caption>**Table 2:** Final formulation of the budesonide 0.1 mg/mL viscous oral solution.</caption><thead><tr><td>Ingredients</td><td>Quantity (mg)</td></tr></thead><tbody><tr><td>Budesonide</td><td>10</td></tr><tr><td>γ-cyclodextrin</td><td>200</td></tr><tr><td>Hydroxypropylcellulose</td><td>1000</td></tr><tr><td>Glycerol</td><td>10,000</td></tr><tr><td>Sucralose</td><td>400</td></tr><tr><td>Purified water</td><td>QS 100 mL</td></tr></tbody></table>

## Shelf-life

The budesonide content remained stable for at least 3 months (Figure 3), no significant degradation was detected on the HPLC chromatogram (Figure 4, Table 3) and there was no change regarding the solution's colour, clarity or pH (around 4.7). Conversely the chromatogram corresponding to forced degradation shows many degradation products (Figure 4).

## Discussion

Cyclodextrin complexation is one of the most widely used techniques for improving the solubility [11], palatability [12] and topical delivery [13] of lipophilic compounds. Hydroxypropyl-β-cyclodextrin [14, 15] and γ-cyclodextrin [16] have already been successfully used to enhance the dissolution rate and solubilization of budesonide. Indeed,

hydroxypropyl-β-cyclodextrin reportedly forms an inclusion complex with budesonide [15]. In the present study, budesonide's solubility increased linearly with both cyclodextrins in the tested range [0.2 – 2 mM]. The calculated CE was greater for γ-cyclodextrin (0.147) than for hydroxypropyl-β-cyclodextrin (0.064), confirming that γ-cyclodextrin was a better water solubilizer for budesonide than hydroxypropyl-β-cyclodextrin at the concentrations tested here. Even though we did not obtain a formal proof that budesonide and γ-cyclodextrin had formed an inclusion complex, we hypothesize that γ-cyclodextrin's wider cavity reduces steric hindrance and thus increases the complexation efficiency. When used with Biopharmaceutics Classification System class II compounds like budesonide, cyclodextrins may improve bioavailability [17, 18] and so dose adjustment may be needed. It has previously been reported that the oral bioavailability of budesonide is primarily restricted by pre-systemic metabolism after complete absorption of the drug [1]. Thus, cyclodextrin is not expected to improve oral bioavailability. Conversely, we considered that sequestration and thus limitation of budesonide's topical action were unlikely because (i) γ-cyclodextrin is rapidly hydrolysed by salivary amylase [19], and (ii) cyclodextrin complexes of budesonide [15] and compounds with similar structures (e. g. dexamethasone [20]) have already been used successfully for topical administration. Further studies need to be done to confirm it. Although all the investigators considered that the palatability of the solution was good, this parameter was not rigorously tested. The addition of sucralose improved palatability enough to avoid the need for further adjunction of aromas.

<figure><img src="image_4.png" /><figcaption>**Figure 3:** Budesonide content of formulations (n = 3 at each time point) when stored in type 1 amber glass vials at 24 °C/60 % relative humidity.</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>**Figure 4:** Typical HPLC-UV chromatograms of budesonide raw material freshly dissolved in methanol (top), the final formulation stored in type 1 amber glass vials for 3 months at 24°C/60% relative humidity (middle), and the final formulation stored in type 1 transparent glass vials under forced photodegradation conditions (bottom).</figcaption></figure>

<table><caption>**Table 3:** Typical table of compounds of the chromatogram obtained with the final formulation stored 3 months at 24°C/60% relative humidity; *: retention time of minor degradation products present in less than 0.1% on other chromatogram, AU: arbitrary units, epi: epimer, % budesonide: percentage of total budesonide area (area/sum of the two budesonide epimers' areas).</caption><thead><tr><th>Retention time (min)</th><th>Area (AU)</th><th>Area (% budesonide)</th><th>Identification</th></tr></thead><tbody><tr><td>3,543</td><td>85</td><td>0,02</td><td></td></tr><tr><td>4,351</td><td>383</td><td>0,11</td><td></td></tr><tr><td>4,901</td><td>102</td><td>0,03</td><td></td></tr><tr><td>5,375</td><td>324</td><td>0,09</td><td></td></tr><tr><td>6,006</td><td>111</td><td>0,03</td><td></td></tr><tr><td>9,089*</td><td>0</td><td>0,00</td><td></td></tr><tr><td>12,637</td><td>750</td><td>0,21 Imp. D epi</td><td></td></tr><tr><td>14,057</td><td>256</td><td>0,07 Imp. D epi</td><td></td></tr><tr><td>16,539*</td><td>0</td><td>0,00</td><td></td></tr><tr><td>18,339*</td><td>0</td><td>0,00</td><td></td></tr><tr><td>20,969</td><td>189,762</td><td>52,40 Budesonide epi B</td><td></td></tr><tr><td>22,415</td><td>172,357</td><td>47,60 Budesonide epi A</td><td></td></tr><tr><td>27,049</td><td>261</td><td>0,07</td><td></td></tr></tbody></table>

We also chose to add a cellulose hydrocolloid to the solution, since it provides a good compromise between viscosity enhancement and mucoadhesion, and was compatible with the use of cyclodextrins [21]. Furthermore, it has been shown that drug/cyclodextrin/cellulosic hydrocolloid complexes may enhance the topical action of drugs [22]. We kept the viscosity under 150 mPa·s (i. e. the viscosity of a simple syrup) because higher values impeded the filtration step. When tested separately, the adjunction of 0.2% (m/v) γ-cyclodextrin neither increased the viscosity nor modified the non-Newtonian properties of a 1% hydroxypropylcellulose solution. The hydroxypropylcellulose KLUCEL GF PHARM has a nominal viscosity of 150 – 400 mPa·s as a 2% (m/w) aqueous solution (data from the manufacturer), and halving its concentration reduced its nominal viscosity by more than half in our experiments.

Lastly, no significant loss of content was observed during a 3-month stability study, and no significant degradation (i. e. > 0.5% of the total budesonide) was
observed. Rapid photodegradation was observed when the final formulation was stored in transparent glass vials in the light – confirming previous reports and emphasizing the need for photoprotection [23].

## Conclusion

We provided a convenient, stable formulation of budesonide for treating our paediatric patients in hospital and then at home, if required. The formulation was as simple as possible, and special efforts were made to limit the number and quantity of excipients in the final formulation because eosinophilic esophagitis mainly has an allergic aetiology. Consequently, the patients' exposure to potential allergens was limited by our exclusion of aroma or preservatives. Further studies of the efficacy and safety of our new formulation may now be warranted. Given that budesonide's bioavailability is mainly limited by pre-systemic metabolism, complexation with cyclodextrins is unlikely to remove this obstacle. Hence, the previously tested budesonide doses could be used for further studies.

**Conflict of interest statement:** Authors state no conflict of interest. All authors have read the journal's Publication ethics and publication malpractice statement available at the journal's website and hereby confirm that they comply with all its parts applicable to the present scientific work.

## References

1. Edsbäcker S, Andersson T. Pharmacokinetics of budesonide (Entocort EC) capsules for Crohn's disease. Clin Pharmacokinet 2004;43:803-21.

2. Dohil R, Newbury R, Fox L, Bastian J, Aceves S. Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial. Gastroenterology 2010;139:418-429.e1.

3. Gupta SK, Vitanza JM, Collins MH. Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol 2015;13:66-76.e3.

4. Aceves SS, Bastian JF, Newbury RO, Dohil R. Oral viscous budesonide: a potential new therapy for eosinophilic esophagitis in children. Am J Gastroenterol 2007;102:2271-79.

5. Dellon ES, Sheikh A, Speck O, Woodward K, Whitlow AB, Hores JM, et al. Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis. Gastroenterology 2012;143:321-324.e1.

6. Mota FL, Carneiro AP, Queimada AJ, Pinho SP, Macedo EA. Temperature and solvent effects in the solubility of some pharmaceutical compounds: measurements and modeling. Eur J Pharm Sci 2009;37:499-507.

7. Ali HSM, York P, Blagden N, Soltanpour S, Acree WE, Jouyban A. Solubility of budesonide, hydrocortisone, and prednisolone in ethanol + water mixtures at 298.2 K. J Chem Eng Data 2010;55:578-82.

8. Cashman AL, Warshaw EM. Parabens: a review of epidemiology, structure, allergenicity, and hormonal properties. Dermat Contact Atopic Occup Drug 2005;16:57-66-6.

9. Guillet J, Wynchank S, Basse-Cathalinat B, Christophe E, Ducassou D, Blanquet P. Pediatric esophageal scintigraphy. Results of 200 studies. Clin Nucl Med 1983;8:427-33.

10. Loftsson T, Hreinsdóttir D, Másson M. The complexation efficiency. J Incl Phenom Macrocycl Chem 2007;57:545-52.

11. Loftsson T, Brewster ME. Pharmaceutical applications of Cyclodextrins. 1. Drug solubilization and stabilization. J Pharm Sci 1996;85:1017-25.

12. Szejtli J, Szente L. Elimination of bitter, disgusting tastes of drugs and foods by cyclodextrins. Eur J Pharm Biopharm 2005;61:115-25.

13. Merkus FWHM, Verhoef JC, Marttin E, Romeijn SG, Phm VDK, Hermens WAJJ, et al. Cyclodextrins in nasal drug delivery. Adv Drug Deliv Rev 1999;36:41-57.

14. Kim J-E, Cho H-J, Kim D-D. Budesonide/cyclodextrin complex-loaded lyophilized microparticles for intranasal application. Drug Dev Ind Pharm 2014;40:743-48.

15. Dufour G, Bigazzi W, Wong N, Boschini F, De Tullio P, Piel G, et al. Interest of cyclodextrins in spray-dried microparticles formulation for sustained pulmonary delivery of budesonide. Int J Pharm 2015;495:869-78.

16. Kinnarinen T, Jarho P, Järvinen K, Järvinen T. Pulmonary deposition of a budesonide/y-cyclodextrin complex in vitro. J Control Release 2003;90:197-205.

17. Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutical drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995;12:413-20.

18. Loftsson T. Cyclodextrins and the biopharmaceutics classification system of drugs. J Incl Phenom Macrocycl Chem 2002;44:63-67.

19. Athj DB, Van Ommen B, Bär A. Disposition of [14C]y-Cyclodextrin in germ-free and conventional rats. Regul Toxicol Pharmacol 1998;27:150-58.

20. Usayapant A, Karara AH, Narurkar MM. Effect of 2-Hydroxypropyl-β-cyclodextrin on the ocular absorption of dexamethasone and dexamethasone acetate. Pharm Res 1991;8:1495-99.

21. Loftsson T, Masson M. The effects of water-soluble polymers on cyclodextrins and cyclodextrin solubilization of drugs. J Drug Deliv Sci Technol 2004;14:35-43.

22. Loftsson T, Masson M. Cyclodextrins in topical drug formulations: theory and practice. Int J Pharm 2001;225:15-30.

23. Bhutnar A, Khapare S, Desai A, Dsouza S. Isolation and Characterization of Photodegradation Impurity in Budesonide Drug Product Using LC-MS and NMR Spectroscopy. Am J Anal Chem 2017;8:449-61.
Bionotes

<figure><img src="image_6.png" /><figcaption>**Caroline Ey**</figcaption></figure>

Pharmacie à Usage Intérieur, Groupe de
Recherche en Pharmacotechnie Pédiatrique,
Centre Hospitalier Universitaire d'Amiens-
Picardie, Amiens, France,
c.ey@ch-beauvais.fr

Caroline Ey is a pharmacy resident. She took up her pharmaceutical studies at the Faculty of Montpellier before starting her residency in different hospitals attached to the University of Picardie Jules Verne. She has worked at the University Hospital of Amiens in the department of pharmaceutical technology for a semester where she helped to develop pediatric and other formulations.

<figure><img src="image_7.png" /><figcaption>**Christel Hosselet**</figcaption></figure>

Pharmacie à Usage Intérieur, Groupe de
Recherche en Pharmacotechnie Pédiatrique,
Centre Hospitalier Universitaire d'Amiens-
Picardie, Amiens, France,
c.hosselet@ch-beauvais.fr

Christel Hosselet is a pharmacist in the sector of radiopharmaceuticals drugs at Beauvais hospital's pharmacy. He completed his PharmD degree at the University of Picardy Jules Verne and his Master's degree in radiopharmaceutical drug synthesis at the University Francois Rabelais (Tours). He has been resident in the department of pharmaceutical technology at Amiens University hospital's pharmacy.

<figure><img src="image_8.png" /><figcaption>**Benjamin Villon**</figcaption></figure>

Pharmacie à Usage Intérieur, Groupe de
Recherche en Pharmacotechnie Pédiatrique,
Centre Hospitalier Universitaire d'Amiens-
Picardie, Amiens, France,
Villon.Benjamin@chu-amiens.fr

Benjamin Villon is an analytical engineer working at the University Hospital of Amiens. He received his engineering degree in chemistry at the Ecole Nationale Supérieure de Chimie de Rennes (ENSCR) in 2016. He is focused on analytical chemistry and contributes to the development and the study of paediatric age-appropriate drugs through the development of analytical methods and stability testing among others.

<figure><img src="image_9.png" /><figcaption>**Frédéric Marçon**</figcaption></figure>

Pharmacie à Usage Intérieur, Groupe de
Recherche en Pharmacotechnie Pédiatrique,
Centre Hospitalier Universitaire d'Amiens-
Picardie, Amiens, France; LG2A UMR CNRS
7378, Amiens, France,
marcon.frederic@chu-amiens.fr

Frédéric Marçon is assistant professor at the University of Picardy Jules Verne and pharmacist responsible of the pharmaceutical technology department at Amiens University hospital. As former resident at Amiens University Hospital, he obtained his PharmD degree in 2009 and completed his PhD in biopharmacy and pharmaceutical sciences in 2013. His work and research is focused on the development of paediatric medicines (age-appropriate formulations, pharmacokinetic study, efficacy and safety study). He is a cofounder of the GREPP research group.