http://informahealthcare.com/phd ISSN: 1083-7450 (print), 1097-9867 (electronic) Pharm Dev Technol, Early Online: 1–10 ! 2013 Informa Healthcare USA, Inc. DOI: 10.3109/10837450.2013.823991 RESEARCH ARTICLE Texturing formulations for uranium skin decontamination Corinne Belhomme-Henry 1 , Guillaume Phan 1 , Nicolas Huang 2 , Ce ´line Bouvier 1 , Franc ¸ois Rebie `re 1 , Michelle Agarande 1 , and Elias Fattal 2 1 IRSN, PRP-HOM/SDI, Fontenay-aux-Roses, France and 2 CNRS UMR 8612, Cha ˆtenay-Malabry, France Abstract Context: Since no specific treatment exists in case of cutaneous contamination by radionuclides such as uranium, a nanoemulsion comprising calixarene molecules, known for their good chelation properties, was previously designed. However, this fluid topical form may be not suitable for optimal application on the skin or wounds. Objective: To develop a texturing pharmaceutical form for the treatment of wounded skins contaminated by uranium. Materials and methods: The formulations consisted in oil-in-water (O/W) nanoemulsions, loaded with calixarene molecules. The external phase of the initial liquid nanoemulsion was modified with a combination of thermosensitive gelifying polymers: Poloxamer and HydroxyPropylMethylcellulose (HPMC) or methylcellulose (MC). These new formulations were characterized then tested by ex vivo experiments on Franz cells to prevent uranyl ions diffusion through excoriated pig ear skin explants. Results: Despite strong changes in rheological properties, the physico-chemical characteristics of the new nanoemulsions, such as the size and the zeta potential as well as macroscopic aspect were preserved. In addition, on wounded skin, diffusion of uranyl ions, measured by ICP-MS, was limited to less than 5% for both HPMC and MC nanoemulsions. Conclusions: These results demonstrated that a hybrid formulation of nanoemulsion in hydrogel is efficient to treat uranium skin contamination. Keywords Calixarene nanoemulsions, hydroxypropylmethylcellulose, methylcellulose, poloxamer, skin decontamination, uranium History Received 18 March 2013 Revised 24 May 2013 Accepted 5 July 2013 Published online 12 August 2013 Introduction Although protection means have been implemented in the nuclear industry, contamination of workers by actinides such as uranium is still occurring through inhalation 1 , ingestion or penetration through wounds or intact skin. The wound or cutaneous pathways represent very critical modes of contamination in terms of frequency inducing a risk of renal chemical toxicity and bone tumor formation 2–5 . No specific emergency treatment of wound or cutaneous contamination has been established so far. The current medical care in case of skin contamination only occurs after transfer of injured persons to a medical unit. It consists in local decontamination of the wound with soaped water or a Ca-DTPA solution (calcic salt of diethylene triamine pentaacetic acid). This procedure is often followed by an intravenous injection of Ca-DTPA to reduce the risks of tissue damage and induction of cancer 6 , and in the most serious wounds, a surgical excision is needed. However, the specificity of the treatment with DTPA is rather poor 7,8 . Some chelating agents more specific to uranium like biphosphonate molecule series were developed in preclinical studies 9–11 , but none of those chelating agents have resulted in pharmaceutical forms dedicated to skin decontamination or the specific uranium chelation within the proposed formulations was not demonstrated. In this context, we have developed a recent topical pharmaceutical form consisting in an oil-in-water (O/W) nanoemulsion displaying calixarene molecules, known for their actinides chelation properties 12,13 . The efficiency of the nanoe- mulsion for uranium extraction was demonstrated through in vitro 14–16 and ex vivo experiments 16 . Unfortunately, this formulation is not suitable for a topical delivery because of its liquid form. Therefore, the objective of the present study was to modulate the viscosity of the liquid nanoemulsion in order to obtain an efficient topical delivery system. We decided to design a hybrid formulation of nanoemulsion dispersed in thermosensitive hydrogels. In the present work both physico-chemical properties as well as the efficiency of several types of formulations were evaluated. Methods Materials Calixarene molecule (MW 1189.56 g/mol; Figure 1) was synthesized as previously described in the patent 17 . Other compounds used for preparing calixarene nanoemulsions were paraffin oil, (VWR, Fontenay-sous-Bois, France), non-ionic surfactants sorbitan monooleate (Span 80), polyoxyethylene glycol sorbitan monooleate (Tween 80), poloxamer 407 (Pluronic F-127 Õ ) and HydroxyPropylMethylCellulose (HPMC), purchased from Sigma-Aldrich (Saint-Quentin-Fallavier, France); MethylCellulose (MC) from VWR and water obtained from a Milli-Q Synergy 185 water purification system (Millipore, Saint- Quentin-en-Yvelines, France). Uranium-contaminated solutions were prepared by diluting a standard depleted uranium solution Address for correspondence: Guillaume Phan, PhD, PharmD, IRSN, PRP- HOM/SDI, 31 avenue de la Division Leclerc, Fontenay-aux-Roses, F-92260, France. E-mail: guillaume.phan@irsn.fr Pharmaceutical Development and Technology Downloaded from informahealthcare.com by IRSN on 08/26/13 For personal use only.