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. 2021 Dec;28(1):2289-2300.
doi: 10.1080/10717544.2021.1989089.

Spironolactone hyaluronic acid enriched cerosomes (HAECs) for topical management of hirsutism: in silico studies, statistical optimization, ex vivo, and in vivo studies

Rofida Albash  1 , Abdurrahman M Fahmy  2 , Mohammed I A Hamed  3 , Khaled M Darwish  4 , Rania Moataz El-Dahmy  5
Affiliations

Spironolactone hyaluronic acid enriched cerosomes (HAECs) for topical management of hirsutism: in silico studies, statistical optimization, ex vivo, and in vivo studies

Rofida Albash et al. Drug Deliv. 2021 Dec.

Abstract

Spironolactone (SP) is a potassium sparing diuretic with antiandrogenic properties. This study aimed at formulating SP into hyaluronic acid enriched cerosomes (HAECs) for topical management of hirsutism. HAECs were prepared by ethanol injection method, according to D-optimal design, after a proper in silico study. HAECs were evaluated by measuring their entrapment efficiency (EE%), particle size (PS), and polydispersity index (PDI). Optimal hyaluronic acid enriched cerosomes (OHAECs) were subjected to further in vitro and ex-vivo and in-vivo studies. The in silico study concluded better interactions between SP and phosphatidyl choline in presence of hyaluronic acid (HA) and high stability of their binding in water. The prepared HAECs had acceptable EE%, PS, and PDI values. The statistical optimization process suggested OHAEC containing 10.5 mg ceramide III and 15 mg HA, utilizing Kolliphor® RH40. OHAEC had EE% and PS of 89.3 ± 0.3% and 261.8 ± 7.0 nm, respectively. OHAEC was stable for up to 3 months. It also showed a mixed tubular and vesicular appearance under transmission electron microscope. The ex vivo and in vivo studies concluded better skin deposition and accumulation of SP from OHAEC. The histopathological study demonstrated the safety of OHAEC for topical application. Therefore, OHAEC could be considered as effective system for topical application of SP to manage hirsutism, with prolonged action, coupled with minimized side effects.

Keywords: In silico study; dermatokinetic; hirsutism; local accumulation efficiency index; spironolactone.

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Conflict of interest statement

The authors report no conflicts of interest.

Figures

Figure 1.
Figure 1.
Binding poses of the spironolactone phosphatidyl choline docked complex. (a) In absence of the hyaluronic acid monomer. (b) In combination with the hyaluronic acid monomer (magenta sticks) serving as an anionic formulation additive. Predicted binding interactions are illustrated between the drug molecule; spironolactone (yellow sticks) and of the hyaluronic acid monomer; phosphatidyl choline (green sticks). More favored complex stability was assigned for the spironolactone–phosphatidyl choline in combination with hyaluronic acid. Polar interactions (hydrogen bonding), discussed within the text, are depicted as black dashed lines.
Figure 2.
Figure 2.
Conformation alterations time evolution of SPH ternary complex throughout the explicit molecular dynamics simulation at different solvation system. The thermodynamic movements and stability of formulation components; spironolactone (yellow sticks), hyaluronic acid monomer (magenta sticks), and phosphatidyl choline (green sticks) were monitored over MD simulation trajectories within (a) 100% chloroform; (b) combined chloroform/alcohol; (c) 100% water solvated systems at captured at different snapshots (1) 0.2 ns; (2) 0.4 ns; (3) 0.6 ns; (4) 0.8 ns; and (5) 1 ns. Polar interactions (hydrogen bonding) are depicted as black dashed lines. (d) Molecular surface 3 D representation of the cone micellar configuration of optimized SPH in chloroform: alcohol (1:1) combination (left panel), as well as the inverted cone micellar configuration of 100% water (right panel). Molecular surface representations were illustrated in colors being previously assigned for the optimized SPH components; yellow, magenta, and green are for spironolactone, hyaluronic acid monomer, and phosphatidyl choline, respectively.
Figure 3.
Figure 3.
Effect of formulation variables on EE% of SP-HAECs (a–c), PS (d–f), while (g–i) show the effect of significant interactions on PS. Abbreviations: EE%, Entrapment efficiency percentage; PS, Particle size; SP, spironolactone; HAECs, Hyaluronic acid enriched cerosomes.
Figure 4.
Figure 4.
Transmission electron micrographs of SP OHAEC showing mixed vesicular and tubular appearances. Abbreviation: OHAEC, optimal hyaluronic acid enriched cerosomes.
Figure 5.
Figure 5.
Ex vivoprofile of SP from OHAEC, compared to its aqueous suspension. Abbreviation: SP: spironolactone, OHAEC: optimal hyaluronic acid enriched cerosomes.
Figure 6.
Figure 6.
Light microscope photomicrographs showing histopathological sections (hematoxylin and eosin stained) of rat skin normal control (group I), rat skin treated with SP suspension (group II) and rat skin treated with OHAEC (group III) with magnification power of 16X to illustrate all skin layers (Left side) and magnification power of 40X to identify the epidermis and dermis (Right side). Abbreviation: SP: spironolactone, OHAEC: optimal hyaluronic acid enriched cerosomes.
Figure 7.
Figure 7.
In vivo skin deposition profile of SP from OHAEC, compared to its aqueous suspension. Abbreviation: SP: spironolactone, OHAEC: optimal hyaluronic acid enriched cerosomes.
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