Formulating fluticasone propionate in novel PEG-containing nanostructured lipid carriers (PEG-NLC)

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Abstract

The aim of this study was to develop nanostructured lipid carriers (NLC) for topical delivery of fluticasone propionate (FP) with the aim to further improve the safety profile and decrease the adverse-side effects commonly reported in topical corticotherapy. NLC are colloidal drug-carriers consisting of a blend of a solid lipid and a small amount of liquid lipid since these carriers have proved to be effective in epidermal targeting in particular of glucocorticoids. NLC consisting of glyceryl palmito-stearate, and PEG-containing medium chain triglycerides mixture, stabilised by polysorbate 80 and soybean phosphatidylcholine were prepared. A mean particle size between 380 and 408 nm and entrapment efficacy of 95% were obtained for FP-loaded NLC. The crystallinity and polymorphic phase behaviour of FP-free and FP-loaded NLC were examined by differential scanning calorimetry and wide angle X-ray diffraction. Results revealed a low-crystalline structure and confirmed the incorporation of FP into the particles. The suitability of PEG-containing liquid lipids to form the lipid matrix of NLC was also confirmed.

Introduction

Topical therapy of skin diseases by means of glucocorticoids requires assuring not only the administration of adequate dose of the drug on the desired area of the skin, but also preventing the possibility of undesired effects of these potent drugs. Skin atrophy, skin-irritation, and photosensitivity have been commonly reported as side effects associated with topical glucocorticoid therapy. Moreover, there is always present a possibility of systemic uptake of the drug upon application on skin. Advanced formulations which would help eliminating these effects are still on demand. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) have been tested as effective carriers of a variety of drugs for topical therapy of skin diseases [1].

Solid lipid nanoparticles (SLN) are colloidal carriers composed of lipid matrix solid at room temperature [2]. Being composed of well tolerable and physiological materials, these carriers are well tolerated, compatible and non-toxic. Controlled release of incorporated drugs and protection of labile compounds could be achieved by means of SLN.

Nanostructured lipid carriers (NLC) [3] were designed to overcome some of the drawbacks of SLN, namely the limited drug payload. NLC consist of a mixture of solid lipid and liquid lipid and are in particular appropriate for drugs with higher solubility in oils than in solid lipids. A blend of a liquid and solid lipid creates a less perfect crystalline structure with many imperfections providing thus more space for drug accommodation. Examples of solid lipids are triglycerides (tristearine, tripalmitine, trimiristine), fatty acids (stearic acid, palmitic acid), waxes (carnauba, cetyl palmitate), whereas liquid lipids include e.g. medium chain triglycerides, oleic acid, isopropyl miristate. Their suitability for dermatological applications was also confirmed by successful formulations of drugs for skin disease treatment [1]. Epidermal targeting can be achieved with SLN and NLC formulations [4], [5], which may help preventing side effects typical during topical glucocorticoid treatment (skin thinning and atrophy [6]) as they are associated with deeper layers of the skin. Furthermore, risk of systemic absorption could be eliminated. In fact, lipid nanoparticles (SLN, NLC) have been reported as suitable colloidal carrier systems to control the penetration/permeation of drugs throughout the skin layers [7]. Depending on the lipid matrix composition, different release profiles may be obtained including a prolonged/controlled release of the drug which can decrease the risk of burst effect, commonly reported by the use of conventional drug solutions. Aqueous SLN formulations were proposed for topical delivery of various glucocorticoids, e.g. clobetasol propionate [8], dexamethasone [9] or betamethasone valerate [10].

Fluticasone propionate (FP) is a trifluorinated glucocorticoid used in management of symptoms of asthma and skin disorders connected with inflammation and itching, such as atopic dermatitis [11] or psoriasis [12]. Being highly lipophilic, this corticosteroid is an excellent candidate for NLC encapsulation. In comparison with older glucocorticoid molecules, FP has lower potential for systemic side effects as its degradation product is an inactive carboxylic acid [13]. In dermatological application, FP is a useful drug with anti-inflammatory, antipruritic and vasoconstrictive properties. Topical formulations for application on skin containing FP include ointment (Cutivate ointment 0.005%), cream and lotion (Cutivate cream 0.05% and Cutivate lotion 0.05%) [14]. The selection of suitable vehicle is of high importance in glucocorticoid therapy, as it influences the bioavailability and subsequently the strength of corticotherapy [6].

This study describes the development of a suitable NLC-based formulation for FP for application on skin. Based on the outcomes of pre-formulation studies, the developed NLC are composed of a PEG-containing liquid lipid. The physicochemical characterisation of the developed formulations confirms the possibility to prepare such PEG-containing NLC.

Section snippets

Materials

Fluticasone propionate was obtained from Sigma Aldrich (Germany), Precirol ATO 5 (glyceryl palmito-stearate) and Labrasol (PEG-6 caprylic/capric triglycerides) were gift samples from Gattefosse (France), Softigen 767 (PEG-8 caprylic/capric triglycerides) was a gift sample from Sasol GmbH (Germany). Tween 80 (Polysorbate 80) was from Vaz Pereira S.A. (Portugal), soybean lecithin from Acopharma (Spain). Water of double distilled quality was obtained from MiliQ Plus systems (Millipore, Germany).

Selection of components

Characterisation of the formulations

Four NLC formulations with two different liquid lipids were prepared by modified microemulsion method. Composition of these formulations is given in Table 1. Although FP is highly lipophilic, its solubility in a wide array of solid lipids and liquid lipids was insufficient (<0.3% FP). FP was found soluble only in PEG-medium chain triglycerides, namely in Labrasol (PEG-6 caprylic/capric triglycerides) and Softigen 767 (PEG-8 caprylic/capric triglycerides). Neither medium chain triglycerides

Conclusion

Two formulations of nanostructured lipid carriers for topical application of Fluticasone propionate were developed. Particles with size less than 1 μm, maintained over 60 days were obtained, and high entrapment efficacy of the Fluticasone propionate was achieved. The feasibility of PEG-containing lipids to form the lipid matrix of nanostructured lipid carriers was shown. The presence of PEG in NLC composition may also improve the physicochemical stability of the developed NLC. The present paper

Acknowledgements

This work was supported by the Slovak Research and Development Agency under the contract Nr. VVCE-003-07.

References (29)

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