Development of transmucosal patch loaded with anesthetic and analgesic for dental procedures and in vivo evaluation

Abstract

Most of the dental surgeries require preoperative anesthetic and postoperative analgesic for painless procedures. A multidrug transmucosal drug delivery system loaded with lignocaine (Lig) base for immediate release and solid lipid nanoparticles (SLNs) of diclofenac (Dic) diethylamine for prolonged release was developed. SLNs were prepared by solvent emulsion-evaporation method with Precirol ATO 5 and Geleol as lipids and Pluronic F 68 as surfactant and optimized with Box-Behnken design for particle size and entrapment efficiency. SLNs were incorporated into the transmucosal patch (TP) prepared with hydroxypropyl cellulose-LF (HPC-LF) and with a backing layer of ethyl cellulose. Optimized SLNs and TP were characterized for Fourier transform infrared spectrophotometry, differential scanning calorimetry, scanning electron microscopy, X-ray diffraction, in vitro release, ex vivo permeation through porcine buccal mucosa, Caco-2 permeability, and residual solvent analysis by gas chromatography. The TP was also evaluated for swelling index, in vitro residence time, tensile strength, and mucoadhesive strength. Preclinical pharmacokinetic, pharmacodynamic, and histopathological studies by application of TP on the gingiva of New Zealand rabbits were carried out. Particle size and entrapment efficiency of the optimized SLN "S8" were determined as 98.23 nm and 84.36%, respectively. The gingival crevicular fluid and tissue concentrations were greater than plasma concentrations with increase in C max and area under the curve (AUC) of Lig and Dic when compared to the control group. Pain perception by needle prick showed prolonged combined anesthetic and analgesic effect. The developed TP loaded with Lig base and Dic diethylamine-SLNs exhibited immediate and complete permeation with tissue accumulation of Lig followed by controlled prolonged release and tissue accumulation of Dic at the site of application. Thus, it could be anticipated from the in vivo studies that the developed TP provides immediate initial anesthetic effect, and the analgesic effect would be prolonged for 24 hours, since optimal gingival crevicular fluid and tissue levels of analgesic would be achieved, while the tissue remains anesthetized.

Keywords: Box–Behnken design; Caco-2 permeability; histopathology; pharmacokinetics and pharmacodynamics; solid lipid nanoparticle; transmucosal patch.

Figure 1

Physicochemical characterization of DDEA-SLN, TP, physical mixtures and excipients. Notes: (A) DSC thermograms of (a) DDEA; (b) Compritol ATO 888; (c) Precirol ATO 5; (d) Geleol; (e) PA; (f) SA; (g) melted Compritol with DDEA; (h) melted Precirol with DDEA; (i) melted Geleol with DDEA; (j) melted PA with DDEA; (k) melted SA containing DDEA; (l) melted mixture of Precirol and Geleol containing DDEA; (m) DDEA-SLN; (n) LB; (o) physical mixture of LB and DDEA and HPC-LF; (p) TP. (B) FTIR spectrum of (a) DDEA; (b) Precirol ATO 5; (c) Geleol; (d) melted mixture of Precirol and Geleol containing DDEA; (e) DDEA-SLN; (f) LB; (g) physical mixture of LB, DDEA, and HPC-LF; (h) TP. (C) XRD diffractograms of (a) DDEA; (b) Precirol ATO 5; (c) Geleol; (d) SLN; (e) LB; (f) physical mixture of LB, DDEA, and HPC-LF; (g) TP. Abbreviations: DDEA, diclofenac diethylamine; DSC, differential scanning calorimetry; FTIR, Fourier transform infrared spectrophotometry; HPC, hydroxypropyl cellulose; LB, lignocaine base; PA, palmitic acid; SLN, solid lipid nanoparticle; TP, transmucosal patch; XRD, X-ray diffraction; SA, stearic acid.

Figure 2

ANOVA results of PS and EE as responses. Notes: 3D plots showing the effect of independent variables on responses Y₁ (A–C) and Y₂ (D–F). (G and H) Linear correlation plot between actual and predicted values for response Y₁ and Y₂. (I and J) Corresponding residual plot for response Y₁ and Y₂. PS (Y₁) =Particle size and EE (Y₂) =Entrapment efficiency. Abbreviations: AP, aqueous phase; 3D, three dimensional.

Figure 2

ANOVA results of PS and EE as responses. Notes: 3D plots showing the effect of independent variables on responses Y₁ (A–C) and Y₂ (D–F). (G and H) Linear correlation plot between actual and predicted values for response Y₁ and Y₂. (I and J) Corresponding residual plot for response Y₁ and Y₂. PS (Y₁) =Particle size and EE (Y₂) =Entrapment efficiency. Abbreviations: AP, aqueous phase; 3D, three dimensional.

Figure 3

Drug diffusion patterns from DDEA-SLN and TP. Notes: (A) In vitro release study of the batch DDEA-SLN and TP and (B) ex vivo permeation study of DDEA-SLN and TP. Abbreviations: DDEA, diclofenac diethylamine; LB, lignocaine base; SLN, solid lipid nanoparticle; TP, transmucosal patch.

Figure 4

SEM images of (A) DDEA; (B) Precirol ATO 5; (C) Geleol; (D) SLN; (E) LB; (F) placebo patch of HPC-LF; (G) patch with DDEA-SLN only; (H) TP. Note: The green (^*) is the diameter of the SLN. Abbreviations: DDEA, diclofenac diethylamine; HPC, hydroxypropyl cellulose; LB, lignocaine base; SEM, scanning electron microscopy; SLN, solid lipid nanoparticle; TP, transmucosal patch.

Figure 5

P_app ×10⁻⁶ of LB, DDEA, DDEA-SLN, and TP drugs from Caco-2 mono culture. Notes: All values are expressed as mean ± SEM (^*P<0.05, ^**P<0.005, ^***P<0.0005). P_app represents the apparent permeability. Abbreviations: DDEA, diclofenac diethylamine; LB, lignocaine base; SLN, solid lipid nanoparticle; SEM, standard error of the mean; TP, transmucosal patch; ex, extracted.

Figure 6

In vivo evaluation of TP. Notes: (A) GCF and (B) plasma concentration–time profile of LB and DDEA after application of TP (group 1) and of the control (group 2) (n=6). Abbreviations: DDEA, diclofenac diethylamine; Dic, diclofenac; GCF, gingival crevicular fluid; LB, lignocaine base; Lig, lignocaine; TP, transmucosal patch.

Figure 7

Gingival tissue morphology immediately after in vivo studies. Notes: (A) Positive control, (B) group 1, and (C) control group. The magnification power is 100×.

Figure 8

Pain score on categorical scale (mean value, n=6).