Semi-Solid Dosage Forms Containing Pranoprofen-Loaded NLC as Topical Therapy for Local Inflammation: In Vitro, Ex Vivo and In Vivo Evaluation

Abstract

Pranoprofen (PRA)-loaded nanostructured lipid carriers (NLC) have been dispersed into blank gels composed of 1% of Carbomer 940 (PRA-NLC-Car) and 3% of Sepigel^® 305 (PRA-NLC-Sep) as a novel strategy to refine the biopharmaceutical profile of PRA, for dermal administration in the treatment of skin inflammation that may be caused by possible skin abrasion. This stratagem intends to improve the joining of PRA with the skin, improving its retention and anti-inflammatory effect. Gels were evaluated for various parameters such as pH, morphology, rheology, and swelling. In vitro drug release research and ex vivo permeation through the skin were carried out on Franz diffusion cells. Additionally, in vivo assays were carried out to evaluate the anti-inflammatory effect, and tolerance studies were performed in humans by evaluating the biomechanical properties. Results showed a rheological profile common of semi-solid pharmaceutical forms for dermal application, with sustained release up to 24 h. In vivo studies using PRA-NLC-Car and PRA-NLC-Sep in Mus musculus mice and hairless rats histologically demonstrated their efficacy in an inflammatory animal model study. No signs of skin irritation or modifications of the skin's biophysical properties were identified and the gels were well tolerated. The results obtained from this investigation concluded that the developed semi-solid formulations represent a fitting drug delivery carrier for PRA's transdermal delivery, enhancing its dermal retention and suggesting that they can be utilized as an interesting and effective topical treatment for local skin inflammation caused by a possible abrasion.

Keywords: Carbomer 940; Sepigel® 305; biomechanical properties; drug delivery; inflammation; nanostructured lipid carriers; pranoprofen.

Figure 1

pH values for at 4 °C, 25 °C, and 40 °C for (A) PRA-NLC-Car; and (B) PRA-NLC-Sep.

Figure 2

Autocorrelation function plot for the gel formulations at 4 °C, 25 °C, and 40 °C: (A) PRA-NLC-Car and (B) PRA-NLC-Sep. The blue dotted lines represent a 95 confidence limit of the autocorrelation and partial autocorrelation representations.

Figure 3

SEM photomicrographs of the dried (A) PRA-NLC-Car (magnification ×30,000); and (B) PRA-NLC-Sep (magnification ×15,000). Scale bar = 100 nm and 1 µm, respectively.

Figure 4

Fourier-transform infrared spectroscopy (FTIR) of PRA-NLC-Car, PRA-NLC-Sep, and PRA.

Figure 5

Flow curves and viscosity curves for (A) PRA-NLC-Car and (B) PRA-NLC-Sep formulations.

Figure 6

Surface area (cm²) on the basis of the tested mass (g) at 25 °C of (A) PRA-NLC-Car and (B) PRA-NLC-Sep. Mean ± standard deviation (SD) (n = 3).

Figure 7

(A) The swelling ratio of PRA-NLC-Car; (B) swelling ratio of PRA-NLC-Sep, both upon being submerged in PBS; (C) representation of the percentage of weight reduction degradation in PRA-NLC-Car; (D) percentage of weight loss degradation of PRA-NLC-Sep, both in PBS (pH = 5.5) (n = 3).

Figure 8

In vitro release profiles of PRA from gels (A) PRA-NLC-Car and (B) PRA-NLC-Sep.

Figure 9

Plots of the biomechanical properties: (A) stratum corneum hydration and (B) evolution of the skin thickness of the mice ears over time.

Figure 10

Representative images of histological sections of mice ears treated with different formulations: (A) negative control; (B) positive control, (C) PRA-NLC-Car; and (D) PRA-NLC-Sep. The asterisk indicates leucocyte infiltrate, the arrow indicates disruption due to edema, e is the epidermis, d is the dermis, and ac is the auricular cartilage, 200× magnification. Scale bar = 100 µm.

Figure 11

Representative images of histological sections of rat skin treated with different formulations: (A) negative control; (B) PRA-NLC-Car; and (C) PRA-NLC-Sep. Asterisk indicates a scar-increased epidermis and loss of stratum corneum. SC is the stratum corneum, e is the epidermis, and d is the dermis. Images at 100× magnification. Scale bar = 200 µm.

Figure 12

Biomechanical parameters evolution was monitored before applying the gels, and 5 min, 15 min, 1 h, and 2 h after application. (A) TEWL of PRA-NLC-Car (g/h × m²); (B) PRA-NLC-Sep (g/h × m²); (C) SCH of PRA-NLC-Car (arbitrary units); (D) SCH of PRA-NLC-Sep (arbitrary units). Significant statistical differences: **** p < 0.0001, *** p < 0.001, ** p < 0.01, * p < 0.05, ns = non-significant.

Figure 13

Extensibility device.