Preparation and In Vivo Evaluation of a Lidocaine Self-Nanoemulsifying Ointment with Glycerol Monostearate for Local Delivery

Abstract

Lidocaine, a commonly used local anesthetic, has recently been developed into a number of ointment products to treat hemorrhoids. This study examined its efficient delivery to the dermis through the pharmaceutical improvement of hemorrhoid treatment ointments. We attempted to increase the amount of skin deposition of lidocaine by forming a nanoemulsion through the self-nanoemulsifying effect that occurs when glycerol monostearate (GMS) is saturated with water. Using Raman mapping, the depth of penetration of lidocaine was visualized and confirmed, and the local anesthetic effect was evaluated via an in vivo tail-flick test. Evaluation of the physicochemical properties confirmed that lidocaine was amorphous and evenly dispersed in the ointment. The in vitro dissolution test confirmed that the nanoemulsifying effect of GMS accelerated the release of the drug from the ointment. At a specific concentration of GMS, lidocaine penetrated deeper into the dermis; the in vitro permeation test showed similar results. When compared with reference product A in the tail-flick test, the L5 and L6 compounds containing GMS had a significantly higher anesthetic effect. Altogether, the self-nanoemulsifying effect of GMS accelerated the release of lidocaine from the ointment. The compound with 5% GMS, the lowest concentration that saturated the dermis, was deemed most appropriate.

Keywords: glycerol monostearate; hemorrhoids; lidocaine; local anesthetic ointment; self-nanoemulsification.

Figure 1

DSC thermograms of raw materials and prepared lidocaine ointments. MCT, medium-chain triglyceride.

Figure 2

X-ray diffraction patterns of the raw materials and prepared lidocaine ointments. MCT, medium-chain triglyceride.

Figure 3

Examination of compounds by Raman spectra. (A) Raman spectra of the raw materials, and prepared lidocaine ointments; (B) Raman spectra of lidocaine base, L1 ointment, SD-rat skin, and L1 ointment treated SD-rat skin (red line: Raman peak of lidocaine base at 1670 cm⁻¹). SD: Sprague-Dawley.

Figure 4

TEM images of diluted lidocaine ointments (magnification: ×20,000, scale bar: 400 nm). TEM: transmission electron microscope.

Figure 5

In vitro dissolution tests of lidocaine ointment. (A) Dissolution profile of prepared lidocaine ointments; (B) Correlation between kinetic constant (k) and GMS ratio (%) (mean ± standard deviation, n = 4). GMS: glycerol monostearate.

Figure 6

Raman mapping of the stratum corneum and other skin layers at different depths after ex vivo skin permeation test using lidocaine ointment.

Figure 7

Deposited amount of lidocaine in the stratum corneum and other skin layers with SD-rat skin (mean ± standard error, n = 4). SD: Sprague-Dawley.

Figure 8

Permeation tests of L4, L5, L6 ointments. (A) Permeation profile of prepared lidocaine ointments and reference product A with cadaver skin; (B) Permeated amount of lidocaine at 6 h; (C) Correlation between flux and GMS ratio (%) (mean ± standard deviation, n = 4). GMS: glycerol monostearate. § ANOVA, LSD, p-value < 0.05 compared with L5 group. ** ANOVA, LSD, p-value < 0.005 compared with Ref. A group. ## ANOVA, LSD, p-value < 0.005 compared with L4 group.

Figure 9

Latency profile of in vivo tail-flick test (mean ± standard error, n = 4).

Figure 10

In vivo tail flick latency vs. time passed; comparison by concentration. The latency of in vivo tail-flick test at (A) 30, (B) 90 and, (C) 105 min; (D) Correlation between area under the curve (AUC) and glycerol monostearate (GMS) ratio (%) (mean ± standard error, n = 4). * ANOVA, LSD, p < 0.05, compared with the normal saline group. # ANOVA, LSD, p-value < 0.05, compared with Ref. A group. § ANOVA, LSD, p-value < 0.05 compared with L4 group. ** ANOVA, LSD, p-value < 0.005 compared with Normal saline group. ## ANOVA, LSD, p-value < 0.005 compared with Ref. A group. §§ ANOVA, LSD, p-value < 0.005 compared with L4 group.