(M1430-02-13) Preparation of Ketoprofen Polymer Based Solid SEDDS Using Twin Screw Melt Granulation to Improve the Solubility and Permeability

Purpose: Hot melt extrusion (HME) has been widely employed and investigated as a single-step continuous manufacturing process for twin-screw melt-granulation (TSMG) [1]. The present study is intended to develop ketoprofen (KTM) polymer-based solid self-emulsifying drug delivery system (S-SEDDS) by employing the TSMG process to enhance the solubility and dissolution rate. using for a poorly water-soluble drug substance, i.e., ketoprofen (KTP). KTP, a non-steroidal anti-inflammatory drug (NSAID) belonging to BCS class II, is selected as a model drug that has a water solubility of 0.016 mcg/mL and pKa of 3.98 [2].

Methods: The solubility of drug substance in various lipid excipients and polymeric surfactants were studied, among which Gelucire^Ò 44/14, Gelucire^Ò 50/13, and Kolliphor^Ò P 407 were selected as oil, surfactant, and co-surfactant. Formulations of liquid SEDDS (L-SEDDS) with varied concentrations of oil (10-30 %w/w) and surfactant to co-surfactant ratios (2:1, 3:1, and 4:1) were developed and characterized for stability, globule size, polydispersity index (PDI) and emulsification time. The stable formulations of L-SEDDS were developed into S-SEDDS by employing Kollidon^Ò VA 64 as a polymeric carrier by the twin screw melt granulation (TSMG) approach. A detailed description of formulation compositions of L-SEEDS and S-SEEDS were shown in Table 1 and 2

Results: The traditional laboratory melt-mixing approach successfully developed the formulations of L-SEDDS. The robust formulation was selected by subjecting the formulations of L-SEDDS to various characterizations such as emulsification time, globule size, PDI, thermodynamic stability, and cloud point. The stable formulations of L-SEDDS were successfully transformed into S-SEDDS by employing KollidonÒ VA 64 as a polymeric carrier, favoring the TSMG process. The characteristics of L-SEDDS were preserved within the granules of S-SEDDS formulations. The emulsification time was delayed for S-SEDDS formulations due to the polymeric carrier’s slower dissolution. The concentration of oil components within the formulations influenced the size of the globules. The formulations of S-SEDDS have demonstrated superior drug release profiles and improved permeation compared to the pure drug. The formulations were stable following three months of storage at accelerated conditions. Figure 1 explains the in-vitro dissolution profiles of S-SEDDS formulations (G1 and G2) and pure drug in (A) water (B) 0.1N HCl (C) pH 7.4 phosphate buffer (D) In-vitro diffusion profiles of pure drug and S-SEDDS formulations. Figure 2 explains the surface morphology of the milled granules of S-SEDDS formulations (A) G1 formulation and (B) G2 formulation.

Conclusion: From the above results, the present study proved that the development of polymer-based S-SEDDS can improve the solubility of drug substances by TSMG as a single-step continuous manufacturing process.

References: 1. Santiago-Villarreal O, Rojas-González L, Bernad-Bernad MJ, Miranda-Calderón JE. Self-emulsifying Drug Delivery System for Praziquantel with Enhanced Ex Vivo Permeation. J Pharm Innov. 2022;1–13.
2. Beliatskaya A v., Krasnyuk II, Krasnyuk II, Stepanova OI, Abgaryan ZA, Kudinova TP, et al. Study on the Solubility of Ketoprofen From Solid Dispersions with Polyvinylpyrrolidone. Moscow University Chemistry Bulletin. 2019;74:93–9.

A detailed description of L-SEDDS formulations and A detailed description of S-SEDDS formulation composition developed by the TSMG approach

In vitro dissolution profiles of S-SEDDS formulations (G1 and G2) and pure drug
in (A) water (B) 0.1N HCl (C) pH 7.4 phosphate buffer (D) In vitro diffusion profiles of
pure drug and S-SEDDS formulations.

Surface morphology of the milled granules of S-SEDDS formulations (A) G1 formulation (B) G2 formulation.