Theoretical and Experimental Aspects of Sodium Diclofenac Salt Release from Chitosan-Based Hydrogels and Possible Applications

Abstract

Two formulations based on diclofenac sodium salt encapsulated into a chitosan hydrogel were designed and prepared, and their drug release was investigated by combining in vitro results with mathematical modeling. To understand how the pattern of drug encapsulation impacted its release, the formulations were supramolecularly and morphologically characterized by scanning electron microscopy and polarized light microscopy, respectively. The mechanism of diclofenac release was assessed by using a mathematical model based on the multifractal theory of motion. Various drug-delivery mechanisms, such as Fickian- and non-Fickian-type diffusion, were shown to be fundamental mechanisms. More precisely, in a case of multifractal one-dimensional drug diffusion in a controlled-release polymer-drug system (i.e., in the form of a plane with a certain thickness), a solution that allowed the model's validation through the obtained experimental data was established. The present research reveals possible new perspectives, for example in the prevention of intrauterine adhesions occurring through endometrial inflammation and other pathologies with an inflammatory mechanism background, such as periodontal diseases, and also therapeutic potential beyond the anti-inflammatory action of diclofenac as an anticancer agent, with a role in cell cycle regulation and apoptosis, using this type of drug-delivery system.

Keywords: cancer; chitosan; drug-delivery systems; endometrial damage; intrauterine adhesions; multifractality; nanomedicines; periodontal disease; sodium diclofenac salt.

Figure A1

(a,b) Drug-release functional modes at differentiable scale resolution plot of $Re\left[h\left(\Omega ,t\right)\right]$ with $\Phi =2.35$: (a) 3D and (b) 2D.

Figure A2

(a,b) Drug-release functional modes at non-differentiable scale resolution plot of $Im\left[h\left(\Omega ,t\right)\right]$ with $\Phi =2.35$: (a) 3D and (b) 2D.

Figure A3

(a,b) 2D polymer–drug release dynamics at various scale resolution; plot of (a) $Re\left(h\right)$ and (b) $Im\left(h\right)$ for $\left(\Omega =0-140, t=0-200\right) \mathrm{a}\mathrm{n}\mathrm{d} \Phi =2.35$.

Figure A4

(a,b) 2D polymer–drug release dynamics at various scale resolution; plot of (a) $Re\left(h\right)$ and (b) $Im\left(h\right)$ for $\left(\Omega =0-275, t=0-400\right) \mathrm{a}\mathrm{n}\mathrm{d} \Phi =2.35$.

Figure 1

The FTIR spectra of the studied formulations and DCF.

Figure 2

(a–e) Hydrogel state of the formulations proved by (a) the dependence of G’ and G’’ on the oscillatory frequency (black: G’; red: G’’; triangle: D1.5; circle: D2) and (b,c) inverted tube test; representative image of D1.5 hydrogel, (d) before and (e) after swelling in water.

Figure 3

POM microphotographs (crossed polarizers): (a) D1.5 and (b) D2 formulations (magnification: 400×).

Figure 4

SEM images of the (a) D1.5 and (b) D2 formulations (magnification: 5000×; scale bar: 20 μm).

Figure 5

(a,b) Curves of the in vitro release of DCF from the chitosan-based matrix: (a) time (hours)–cumulative drug release (%); (b) cumulative drug release (%)–time (hours).

Figure 6

Fractal fit of the in vitro release of diclofenac sodium salt from the chitosan hydrogel matrix. The release curve for the D1.5 formulation corresponds to a fractal degree of 1.3, whereas the release curve for the D2 formulation corresponds to a fractal degree of 1.7, implying the fact that the drug-release processes take place on two resolution scales.

Figure 7

3D representation of drug-release correlative and non-correlative modes at global scale resolution (simultaneously differentiable and non-differentiable scale resolution) plotted in dimensionless coordinates through $\left|h\left(\Omega ,t\right)\right|$ with $\Phi \equiv 2.35$. Such a representation encompasses various types of drug-release processes.

Figure 8

(a–c) 3D representations of drug-release correlative and non-correlative modes at global scale resolution (simultaneously differentiable and non-differentiable scale resolution) plotted in dimensionless coordinates through $\left|h\left(\Omega ,t\right)\right|$ with $\Phi \equiv 2.35$: (a) cellular-type structures ($\Omega =0-40, t=0-60$); (b) channel-type structures ($\Omega =0-150, t=0-200$); (c) mixed cellular-channel-type structures ($\Omega =0-300, t=0-400$).

Figure 9

Graphical representation of compositions of the formulations and their codes.