1. ** Laboratório Edol, Produtos Farmacêuticos, S.A.Lisboa, Portugal
HYDROCORTISONE EMULSIONS WITH A HIGH PERCENTAGE OF FATTY ACIDS, STEROLS, CHOLESTEROL AND CERAMIDES: STABILITY AND PERMEATION STUDIES
Rita Carneiro**, Ana Salgado*, Sara Raposo*, Paula Machado*, Alexandra N. Silva*, Aida Duarte*, Manuela Urbano**, Helena M. Ribeiro*
*iMed.UL (Research Institute for Medicines and Pharmaceutical Sciences) - Laboratórios de Tecnologia e de Microbiologia da Faculdade de Farmácia da Universidade de Lisboa, Portugal
** Laboratório Edol, Produtos Farmacêuticos, S.A.Lisboa, Portugal

2. AIM Formulate O/W emulsions Repair skin barrier
Ceramides, cholesterol, fatty acids
hydrocortisone
Repair skin barrier
Treat Atopic Dermatites
Studies performed:
Physicochemical and microbiological characterization stability;
Skin permeation.

3. Stratum corneum (SC) corneocytes lipid matrix
Several layers of keratinized cells
corneocytes
Ceramides
Cholesterol
Fatty acids
lipid matrix
Major barrier to percutaneous penetration and to transephitelial water loss

4. Atopic dermatitis (AD)
Chronic disease
Major symptom is pruritus
Main signs are: skin xerosis and eczematous lesions
Alteration of the skin barrier

5. Atopic dermatitis (AD)
Key factors in the management of AD are:
skin hydration and barrier repair;
use of effective topical anti-inflammatory agents, such as corticosteroids ;
avoidance of allergenic triggers.

6. FORMULATIONS PROCESSING
Non ionic O/W emulsions containing 1% of hydrocortisone were prepared:
CerEmulsion with 5% of SK Influx®
NoCerEmulsion without SK Influx®
SK Influx ® (INCI: Ceramide 3, Ceramide 6 II, Ceramide 1, Phytosphingosine, Cholesterol, Sodium Lauroyl Lactylate, Carbomer, Xanthan Gum)

7. PHYSICO-CHEMICAL CHARACTERIZATION
Macroscopic organoleptic characteristics pH
(potentiometric method)
Apparent viscosity and rheological profile
(Brookfield rotational viscometer)
Assay by HPLC
(Deionised water: methanol (50:50, v/v) flow rate ml/min, Injection volume - 10 ml, UV detection at 240 nm)

8. STABILITY EVALUATION
Guideline on stability testing of existing active substances and related finished products CPMP/QWP/122/02 (EMEA, 2007)
3 Batches
Real-time, 25ºC  2 ºC / 60%  5% humidity
Oven at 40ºC  2 ºC / 75%  5% humidity
Stored
Amount of hydrocortisone of %
Microbiological stability according to European Pharmacopeia

9. IN VITRO STUDIES Apparatus: vertical Franz diffusion cell
Membranes: silicone and human epidermis
Donor phase: 200 mg of each formulation
Receptor phase: PBS pH 7.4
Sampling: six replicated cells for each formulation
Results: Data was expressed as the cumulative amount of hydrocortisone permeated per cm2 in order to time.

10. RESULTS AND DISCUSSION
The emulsions were white glossy and mobile
pH:
viscosity : CerEmulsion mPas NoCerEmulsion mPas;
suitable for skin application
Ceramides, which may increase the viscosity by acquiring a lamellar structure

11. STABILITY EVALUATION
Hydrocortisone amount - did not change significantly over time.
Microbiological studies - formulations were within recommended limits specifications.

12. IN VITRO STUDIES
No significant differences were found among the formulations
No steady-state flux was observed
Nevertheless, the permeation of HC was higher for CerEmulsion
Possible interaction between the solvents of the emulsions and the membrane
Volatile ingredients might had evaporated changing the thermodynamic activity of the drug
Existence of HC reservoir within the SC
Fig. 1: Permeation profile of HC from the two emulsions through the silicone membrane (CerEmulsion - ○; NoCerEmulsion - ●) (mean  SD, n = 6).

13. IN VITRO STUDIES
No significant difference among the formulations tested
Ceramides had only a modest non significant effect
This is probably due to the small concentration of SK Influx®.
Fig. 2: Permeation profile of HC through the biological membrane - human epidermis - (CerEmulsion - ○; NoCerEmulsion - ●) (mean  SD, n = 6).

14. Conclusions Emulsions presented:
Organoleptic characteristics suitable for topical treatment of atopic dermatitis.
Chemical, physical and microbiological stability.
The formulation containing ceramides showed a better release/permeation profile.