| Abstract | Azelatna kiselina (AZA) topikalno se primjenjuje u liječenju vulgarne akne (VA), rozaceje i hiperpigmentacija kože. Cilj
ovog rada bio je ispitati može li se AZA nanonizirati metodom vlažnog mljevenja i uklopiti u hidrogel za topikalnu primjenu
namijenjen liječenju indiciranih kožnih bolesti. AZA je uspješno nanonizirana metodom niskoenergetskog vlažnog
mljevenja s malim udjelom, 0,3 % (m/m) površinski aktivne tvari, polisorbata 60, P60. Veličina nanokristala AZA u
optimiranoj nanosuspenziji, leNS-AZA, iznosila je 59,2±3,8 nm (PDI 0,142±0,112). Uzorci nanosuspenzija prevedeni su u
suhi oblik, leLNS-AZA, liofilizacijom te su karakterizirani s obzirom na termička svojstva i intrinzičnu brzinu otapanja i
uklapani u hidrogelove, leLNS-AZA-PHA, koji su pripravljeni mehaničkim miješanjem Pluronic®-a F-127 (10-20 %, m/m)
(P) i hijaluronske kiseline (1 %, m/m) (HA) (PHA hidrogel) u količini koja odgovara masenom udjelu od 10 % AZA.
Hidrogelovima su određena reološka svojstva, brzina oslobađanja AZA in vitro te penetracija AZA u rožnati sloj kože in
vivo. Termičkom analizom je potvrđena kristalna struktura AZA u leLNS-AZA uzorcima s udjelom od oko 13 % amorfne
strukture. Potvrđena je i interakcija nanokristala AZA s P60. Nanonizacijom je postignuto povećanje brzine otapanja leLNSAZA
u odnosu na neprocesuirani oblik AZA, npAZA, od 36,0 %, a 16,4 % u odnosu na liofilizirani oblik suspenzije npAZA
i polisorbata 60, L-npAZA. Povećanjem koncentracije P povećavala se viskoznost leLNS-AZA-PHA hidrogelova i
smanjivala temperatura faznog prijelaza (Tsol-gel). Postotni udio oslobođene AZA iz leLNS-AZA-PHA hidrogelova bio je
približno 10 puta veći u odnosu na komercijalno dostupnu Skinoren® kremu dok je brzina oslobađanja AZA iz hidrogelova
bila neovisna o udjelu P. Koncentracijski profili ovisnosti količine AZA po jediničnoj površini o dubini penetracije u rožnati
sloj kože uzoraka hidrogela leLNS-AZA-PHA-15 i leLNS-AZA-PHA-20 gotovo su identični s profilom Skinoren® kreme.
Hidrogelu s udjelom P od 15 % (m/m), HA od 1 % (m/m) i AZA od 10 % (m/m) u obliku nanokristala procijenjena je
učinkovitost u odnosu na Skinoren® kremu u bolesnika s blagim do umjerenim oblikom VA na koži lica. U tu svrhu
nanosuspenzija AZA pripravljena je metodom visokoenergetskog vlažnog mljevenja, heNS-AZA, s veličinom nanokristala
AZA od 148,1±6,5 nm (PDI 0,399±0,020) te uspješno prevedena u suhi oblik, heLNS-AZA, liofilizacijom i uklopljena u
PHA hidrogel, heLNS-AZA-PHA. Teksturnom analizom je određena čvrstoća heLNS-AZA-PHA hidrogela od 510,8±20,0
g uz rad pri opterećenju silama smicanja od 467,9±28,0 g s što ukazuje na prikladnu razmazivost hidrogela. U
provedenom randomiziranom, dvostruko-slijepom kliničkom ispitivanju potvrđena je bolja ili jednaka učinkovitosti
heLNS-AZA-PHA hidrogela u liječenju VA i rozaceje u odnosu na Skinoren® kremu. |
| Abstract (english) | Azelaic acid (AZA) is used topically to treat acne vulgaris (VA), rosacea, and hyperpigmentation of the skin.
The aim of this study was to investigate whether AZA could be nanonized by wet milling and incorporated into a
topical hydrogel intended for the treatment of the above skin conditions. AZA was successfully nanonized by
low-energy wet milling method with a low content, 0.3 % (w/w) of surfactant, polysorbate 60, P60. The size of
AZA nanocrystals in the optimized nanosuspension, leNS-AZA, was 59.2±3.8 nm (PDI 0.142±0.112). Samples
of the nanosuspensions were converted to the dry form, leLNS-AZA, by lyophilization and characterized by
thermal properties and intrinsic dissolution rate and incorporated into hydrogels, leLNS-AZA-PHA, prepared by
mechanical mixing of Pluronic® F-127 (10-20 %, w/w) (P) and hyaluronic acid (1 %, w/w) (HA) (PHA hydrogel)
in an amount equivalent to 10 wt % AZA. The hydrogels were used to determine the rheological properties, the
rate of AZA release in vitro, and the penetration of AZA into the stratum corneum in vivo. Thermal analysis
confirmed the crystal structure of AZA in the leLNS-AZA samples, with approximately 13 % of the structure
being amorphous. The interaction of AZA nanocrystals with P60 was also confirmed. Nanonization resulted in a
36 % increase in the dissolution rate of leLNS-AZA compared to the unprocessed form of AZA, npAZA, and a
16.4 % increase compared to the lyophilized form of npAZA suspension and P60, L-npAZA. The increase in P
concentration increased the viscosity of leLNS-AZA-PHA hydrogels and decreased the phase transition
temperature (Tsol-gel). The percentage of AZA released from leLNS-AZA-PHA hydrogels was approximately 10-
fold higher than that of commercial Skinoren® cream, while the rate of AZA release from hydrogels was
independent of P. The concentration profiles of AZA per unit area as a function of depth of penetration into the
stratum corneum of the leLNS-AZA-PHA-15 and leLNS-AZA-PHA-20 hydrogel samples were nearly identical
to that of Skinoren® cream.
The efficacy of hydrogel with a P content of 15 % (w/w), HA of 1 % (w/w) and AZA of 10 % (w/w) in the form
of nanocrystals was studied in comparison with Skinoren® cream in patients with mild to moderate VA on facial
skin. For this purpose, an AZA nanosuspension was prepared by high-energy wet milling, heNS-AZA, with an
AZA nanocrystal size of 148.1±6.5 nm (PDI 0.399±0.020) and successfully converted to a dry form by
lyophilization, heLNS-AZA, and incorporated into a PHA hydrogel, heLNS-AZA-PHA. Texture analysis
revealed strength of the heLNS-AZA-PHA hydrogel of 510.8±20.0 g with a shear work of 467.9±28.0 g s,
indicating suitable spreadability of the hydrogel. A randomized, double-blind clinical trial confirmed better or
equal efficacy of heLNS-AZA-PHA hydrogel in the treatment of VA and rosacea compared to Skinoren® cream. |
