(T1330-11-71) Development of Hot-Melt Extruded Solid Self-Nanoemulsifying Drug Delivery System for Improved Oral Delivery of Poorly Water-Soluble Drug Using Central Composite Design

Purpose: Lipid-based formulations such as the self-nanoemulsifying drug delivery systems (SNEDDS) offer several benefits when administered orally, including increased drug apparent solubility, improved permeability, and decreased pre-systemic metabolism (1). SNEDDS are multicomponent systems that include an oil or lipid, surfactant(s), and co-solvent(s). When SNEDDS encounter digestive fluids along with gastrointestinal motility, they spontaneously convert into nano emulsions that can solubilize the formulated drug (2). Commercially, SNEDDS are available as liquids in capsules and have limitations such as high production costs, poor stability and mobility, and drug precipitation during storage (3). Hence, novel solid dosage forms that retain the benefits of the liquid SNEDDS formulation while minimizing its drawbacks are required. Solid- SNEDDS can be produced from liquid SNEDDS using numerous methods (1), although hot melt extrusion (HME) is the most promising because the process does not require solvents and is easily scalable for continuous manufacturing (4). This research focuses on the continuous manufacturing of solid-SNEDDS using HME technology. The effect of the formulation variables on the performance of the developed solid-SNEDDS was investigated using Central Composite Design (CCD). Quetiapine fumarate (QTF), an atypical antipsychotic drug used for bipolar disorder and schizophrenia, was utilized as the model drug for the investigation.

Methods: QTF solubility was screened in various lipids and surfactants by adding 20 mg QTF to 300 mg of the excipient in glass vials at a temperature of 70±2°C with 1000 rpm magnetic stirring, examined visually for any presence or absence precipitated drug particles and chosen for saturation solubility. Various FDA approved polymers – Soluplus®, HPC, Neusilin US2®, MCC were screened for their suitability of solid carriers. Response surface methodology in the form of Central Composite Design (CCD) was utilized with 3 independent variables (oil concentration, surfactanct:co-surfactant, surfactant type) to figure the optimal levels for the mean globule size (GS, nm, Y₁) and emulsification time (ET, min, Y₂) at 2 levels assigned. The CCD was generated by the Design-Expert^® software (StatEase^®, version 13.0) with a total of 22 runs with 18 different formulations (Table 1), including 8 factorial points (levels, ±1), 8 axial points (levels, ±α), and 6 replicates at the central point for pure error estimation. The physical mixtures of all 18 formulations fed into twin screw extruder (feeding rate - 0.4g/min, extruder barrel temperature -125ᵒC, screw speed - 50 rpm) and the extrudates were collected from 2 mm die. All extrudates were investigated for self-emulsification test, globule size, PDI, assay and content uniformity. The optimized formulation was evaluated for in vitro release, dug-excipient incompatibility (FTIR), solid-state characterization (DSC, PXRD) and stability studies (25±2ᵒC/60±5% RH and 40±2ᵒC/75±5% RH for 3 months).

Results: Screening of suitable excipients and solid carriers is important for the formulation development of solid-SNEDDS. Screening investigations identified Capmul MCM® as oil, Gelucire (48/16, 44/14) as surfactant, and propylene glycol as co-surfactant, and HPC and Soluplus as solid carriers. All the formulations suggested by CCD were tested for GS (87.1–256.7 nm) and ET (3.4–59.6 mins). The statistical analysis of the CCD concluded that all tested independent variables affected globule size and emulsification time (Fig. 1). To achieve the desired responses with 95% confidence intervals (CI), the software suggested one solution with the following composition; QTF (10% w/w), Capmul MCM (10% w/w), Gelucire 48/16 (32% w/w), propylene glycol (8 %w/w), and Soluplus: HPC (20% w/w, 1:1). To check the validity of the selected quadratic model, a fresh SEDDS formulation (n = 3) was prepared to compare the observed/experimental GS and ET values against the software predicted values. The mean of experimental PS and ET values was found to be within a 95% CI of the software values. The optimized formulations showed GS, PDI, ZP, and ET of 91.2 nm, 0.24, -10.2 mV and 3.8 mins emulsification respectively. The optimized formulation showed no melting peaks while evaluated for DSC (Fig.2), and P-XRD (Fig.2), demonstrated no characteristic peaks of QTF within the optimized formulation, indicating the amorphous nature of QTF. Furthermore, FTIR (fig.2) results showed no incompatibilities between drug and the excipients.

Conclusion: Hot melt extruded QTF S-SNEDDS were successfully prepared with solvent-free, easily scalable, continuous process with relatively high throughput rates, and economical technology. CCD was applied to optimize the solid-SNEDDS with a small GS and fast ET. The optimized formulation was stable at room temperature and accelerated storage conditions for 3 months, with no significant change observed in drug content, release profile, and solid-state characteristics. Therefore, the optimized solid-SNEDDS could increase the oral bioavailability and improve therapeutic outcomes compared to conventional commercial dosage forms.

References: 1. Silva, L. A. D., Almeida, S. L., Alonso, E. C., Rocha, P. B., Martins, F. T., Freitas, L. A., Taveira, S. F., Cunha-Filho, M. S., & Marreto, R. N. (2018, April). Preparation of a solid self-microemulsifying drug delivery system by hot-melt extrusion. International Journal of Pharmaceutics, 541(1–2), 1–10. https://doi.org/10.1016/j.ijpharm.2018.02.020
2. Schmied, F. P., Bernhardt, A., & Klein, S. (2022, September 11). Preparation of Solid Self-Nanoemulsifying Drug Delivery Systems (S-SNEDDS) by Co-Extrusion of Liquid SNEDDS and Polymeric Carriers—A New and Promising Formulation Approach to Improve the Solubility of Poorly Water-Soluble Drugs. Pharmaceuticals, 15(9), 1135. https://doi.org/10.3390/ph15091135
3. Maji, I., Mahajan, S., Sriram, A., Medtiya, P., Vasave, R., Khatri, D. K., Kumar, R., Singh, S. B., Madan, J., & Singh, P. K. (2021, September). Solid self emulsifying drug delivery system: Superior mode for oral delivery of hydrophobic cargos. Journal of Controlled Release, 337, 646–660. https://doi.org/10.1016/j.jconrel.2021.08.013
4. Tan, D., Maniruzzaman, M., & Nokhodchi, A. (2018, October 24). Advanced Pharmaceutical Applications of Hot-Melt Extrusion Coupled with Fused Deposition Modelling (FDM) 3D Printing for Personalised Drug Delivery. Pharmaceutics, 10(4), 203. https://doi.org/10.3390/pharmaceutics10040203

Response surface 3D plots showing the effect of oil concentration and surfactant: co-surfactant on (A) Globule size and (B) Emulsification time of QTF Solid-SEDDS..

A. PXRD for pure QTF , excipients and optimized formulation(S-SEDDS)
b. FTIR for pure QTF , excipients and optimized formulation(S-SEDDS)
C. DSC for pure QTF , excipients and optimized formulation(S-SEDDS)

Globule size and Emulsification time for the formulations suggested by Central Composite Design(CCD).