Abstract
Due to fast nasal mucociliary clearance, only the dissolved drug content can effectively permeate the mucosa and be pharmaceutically active after intranasal application of suspensions. Therefore, the aim of this study was to increase the budesonide concentration in solution of a nasal spray formulation. Budesonide, a highly water-insoluble corticosteroid, was successfully solubilized using a micellar formulation comprising escin, propylene glycol and dexpanthenol in an aqueous buffered environment (“Budesolv”). A formulation based on this micellar system was well-tolerated in the nasal cavity as shown in a good laboratory practice (GLP) local tolerance study in rabbits. Ex vivo permeation studies into porcine nasal mucosa revealed a faster and more efficient absorption. Budesolv with 300 µg/mL solubilized budesonide resulted in a budesonide concentration of 42 µg/g tissue after only 15 min incubation. In comparison, incubation with the marketed product Rhinocort® aqua 64 (1.28 mg/mL budesonide as suspension) led to 15 µg/g tissue. The in vivo tumor-necrosis-factor (TNF)-α secretion in an acute lung inflammation mouse model was significantly reduced (p < 0.001) following a prophylactic treatment with Budesolv compared to Rhinocort® aqua 64. Successful treatment 15 min after the challenge was only possible with Budesolv (40% reduction of TNF-α, p = 0.0012) suggesting a faster onset of action. The data reveal that solubilization based on saponin micelles presents an opportunity for the development of products containing hardly soluble substances that result in a faster onset and a better topical treatment effect.
Highlights
The rate and extent of drug absorption into a tissue after topical application determines the bioavailability and the effectivity of a locally acting drug
The data reveal that solubilization based on saponin micelles presents an opportunity for the development of products containing hardly soluble substances that result in a faster onset and a better topical treatment effect
Treatment was done in five mice per group with the following formulations: 0.9% NaCl as placebo; Budesolv, containing 300 μg budesonide solubilized in 0.03% w/v escin in a phosphate/citrate buffer and 5% v/v propylene glycol (PG); Rhinocort® aqua 64 micrograms nasal spray (AstraZeneca), containing 1.28 mg/mL dispersed budesonide; β-CD: 300 μg/mL budesonide solubilized in 2.86 mg/mL randomly methylated β-cyclodextrins in 0.9% NaCl
Summary
The rate and extent of drug absorption into a tissue after topical application determines the bioavailability and the effectivity of a locally acting drug. CDs are a well-established system for solubilization of lipophilic and amphiphilic substances [12] They are able to form water soluble complexes with lipophilic drugs in their core, which are reported to be released at a controlled [3] or slow rate [13]. We previously published the use of escin as part of our solubilization platform Marinosolv® for the development of tacrolimus-containing eye drops, which showed increased tissue concentrations of permeated tacrolimus in different eye compartments in a porcine ex vivo and in vivo eye model compared to a tacrolimus suspension [23]. Marinosolv® represents a proprietary platform of formulations that utilizes various saponins, a low concentration of pharmaceutically or cosmetically acceptable co-solvents and dexpanthenol as a general principle to solubilize hydrophobic, highly insoluble molecules, including active pharmaceutical ingredients. We proved the local tolerance of intranasally applied Budesolv in a four-week GLP study in rabbits
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