Fabrication and Characterization of Fast-Dissolving Films Containing Escitalopram/Quetiapine for the Treatment of Major Depressive Disorder

Abstract

Major depressive disorder (MMD) is a leading cause of disability worldwide. Approximately one-third of patients with MDD fail to achieve response or remission leading to treatment-resistant depression (TRD). One of the psychopharmacological strategies to overcome TRD is using a combination of an antipsychotic as an augmenting agent with selective serotonin reuptake inhibitors (SSRIs). Among which, an atypical antipsychotic, quetiapine (QUE), and an SSRI, escitalopram (ESC), were formulated as a fixed-dose combination as a fast-dissolving film by coaxial electrospinning. The resultant fiber's morphology was studied. SEM images showed that the drug-loaded fibers were smooth, un-beaded, and non-porous with a fiber diameter of 0.9 ± 0.1 µm, while the TEM images illustrated the distinctive layers of the core and shell, confirming the successful preparation of these fibers. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies confirmed that both drugs were amorphously distributed within the drug-loaded fibers. The drug-loaded fibers exhibited a disintegration time of 2 s, which accelerated the release of both drugs (50% after 5 min) making it an attractive formulation for oral mucosal delivery. The ex vivo permeability study demonstrated that QUE was permeated through the buccal membrane, but not ESC that might be hindered by the buccal epithelium and the intercellular lipids. Overall, the developed coaxial fibers could be a potential buccal dosage form that could be attributed to higher acceptability and adherence among vulnerable patients, particularly mentally ill patients.

Keywords: coaxial fibers; electrospinning; escitalopram; fast-dissolving films; major depressive disorder; quetiapine; treatment-resistant depression.

Figure 1

SEM images of (a) blank fibers, (b) drug-loaded fibers, (c) blank fibers size distribution, (d) drug-loaded fibers size distribution. The blank and drug-loaded fibers were smooth, un-beaded, and non-porous with a fiber diameter of 1 ± 0.2 and 0.9 ± 0.1 µm, respectively.

Figure 2

TEM image of drug-loaded coaxial fiber, showing the distinctive fiber layers of the core and shell.

Figure 3

DSC data for ESC, QUE, PVP, physical mixture (PM), drug-loaded fibers (DL), and blank fibers (BF), indicating the melting temperatures of ESC and QUE at 154.3 and 176.8 °C, respectively. DL fibers exhibited no drug endothermic peaks that indicated the molecular dispersion transformation of the drugs within these fibers.

Figure 4

XRD diffraction patterns of ESC, QUE, PVP, physical mixture (PM), blank fibers (BF), and drug-loaded fibers (DL), showing that both drugs have distinctive peaks, indicating that they are in the crystalline form, while the polymer is in the amorphous form represented by broad halos. There are distinctive peaks in the PM representing both drugs which lacked in the BF and DL coaxial fibers (broad halos), indicating the molecular dispersion of both drugs in the DL.

Figure 5

(a) FTIR spectra of ESC, QUE, PVP, PM (physical mixture), BF (blank fibers), and DL (drug-loaded fibers), showing each material’s distinctive peaks. Chemical structures of (b) ESC, (c) QUE, and (d) PVP were drawn by chem-space.com.

Figure 6

Photos of the disintegration of (a) blank fibers, and (b) drug-loaded fibers, showing that both fibrous systems have a disintegration time of 2 s.

Figure 7

In vitro dissolution profile of the drug-loaded fibers, showing the release of more than 50% of ESC and QUE in the first 5 min and a full release of both drugs after 120 min.

Figure 8

Ex vivo permeation data of QUE in bovine buccal mucosa showing the mean % of applied dose with respect to time. QUE in the fibers had an enhanced permeation starting from 60 min, up to 240 min; however, it was not significantly different (p > 0.05).

Figure 9

XRD pattern (a) and DSC thermogram (b) of the drug-loaded fibers (DL), showing a broad halo and lack of drug endothermic peaks, respectively. This indicates the amorphous nature of the DL fibers after 4 month storage period at ambient conditions (20–25 °C and relative humidity 30–45%), which suggests good stability.