(M0930-09-49) Formulation Development of Simvastatin Self-Emulsifying Drug Delivery System Using Hot Melt Extrusion

Purpose: The study aims to enhance the dissolution rate of simvastatin, a poorly water-soluble drug used to lower cholesterol levels and prevent cardiovascular events, by developing self-emulsifying drug delivery systems (SEDDS). Gelucire® 48/16 (oil), Gelucire 44/14 (surfactant), and Cremophor RH40 (co-surfactant) are evaluated as potential excipients for SEDDS formulation. The study employs SEDDS formulations, with optimization based on in-vitro drug release studies. To transform the lead SEDDS formulation which is in liquid form into granules of by adsorbing the drug-lipid mixture onto solid carriers (Neusilin®️ US2, TRI-CAFOS 500, and a mixture of MCC and Ludiflash®️) using the Twin Screw Granulation (TSG) approach. The formation of self-emulsifying drug delivery systems (SEDDS) and their subsequent adsorption onto solid carriers occur within the framework of Twin Screw Granulation (TSG).

Methods: This study involved screening of various lipids and their combinations to assess their impact on the drug release. Followed by screening of carriers to assess their impact on the properties of granules produced using TSG. Initial SEDDS formulations are prepared using a method developed by Gattefossé, based on the solubility of simvastatin in solid lipid excipients. Optimization of these formulations is carried out using in-vitro drug release studies. Lead formulations are then transformed into granules of using the Twin Screw Granulation (TSG) approach, with temperature extrusion shown to improve drug release in dissolution studies. The lead formulations of both SEDDS (Before adsorption) and SEDDS (After adsorption on to the carrier) are evaluated for emulsification time, globule size, and polydispersity index (PDI). Additionally, the solid-state properties of the formulations are analyzed using differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR) confirms drug-excipient compatibility and the absence of interactions. Flow properties of the extruded granules are also analyzed to assess their suitability for drug delivery applications.

Results: The study successfully develops SEDDS formulations that enhance the drug release of simvastatin. Better drug release of simvastatin was observed in a 1:9.75, Drug: combination of lipid (Gelucire® 48/16), surfactant (Gelucire 44/14) and co-surfactant (Cremophor RH40). Lead SEDDS formulation was adsorbed on to different solid carriers, but combination Ludiflash and MCC show improved drug release properties, with temperature-extruded granules exhibiting enhanced dissolution rates. Emulsification time, globule size, and PDI of the formulations are evaluated, and solid-state properties analysis confirms the presence of simvastatin in an amorphous state. FTIR analysis demonstrates drug-excipient compatibility, and flow properties analysis confirms the suitability of the extruded granules for drug delivery applications.

Conclusion: The initial development of SEDDS involved varying concentrations of lipid and surfactant, (60 mg, 120 mg and 180 mg). Among those with 180 mg has shown better drug release with the addition of cremophor RH40. The lead formulation, F7, was successfully converted into granules by adsorbing it onto a solid carrier (Neusilin®️ US2, TRI-CAFOS 500, and a mixture of MCC and Ludiflash®️) using twin screw granulation. The in-vitro drug release order among carriers was found to be (MCC and Ludiflash®️) > TRI-CAFOS 500 > Neusilin®️ US2. Despite Neusilin®️ US2 with less quantity exhibiting better flow properties, but it did not yield satisfactory drug release results. In contrast, Ludiflash®️ demonstrated better release, possibly due to its water-soluble nature. Also, it exhibits fair flow when extruded as granules. The lead formulations exhibited the desired polydispersity index (PDI), globule size, and emulsification properties. In conclusion, developed SEDDS formulation could be an effective oral delivery platform for simvastatin, potentially leading to better therapeutic outcomes due to enhanced dissolution rate of the poorly water-soluble drug.

References: Nyavanandi D, Mandati P, Narala S, Alzahrani A, Kolimi P, Vemula SK, et al. Twin Screw Melt Granulation: A Single Step Approach for Developing Self-Emulsifying Drug Delivery System for Lipophilic Drugs. Pharmaceutics. 2023 Sep 1;15(9):2267.
Vithani K, Jannin V, Pouton CW, Boyd BJ. Colloidal aspects of dispersion and digestion of self-dispersing lipid-based formulations for poorly water-soluble drugs. Adv Drug Deliv Rev. 2019 Mar 1;142:16–34.
Eedara BB, Nyavanandi D, Narala S, Veerareddy PR, Bandari S. Improved Dissolution Rate and Intestinal Absorption of Fexofenadine Hydrochloride by the Preparation of Solid Dispersions: In Vitro and In Situ Evaluation. Pharmaceutics. 2021 Feb 27;13(3):310.

In-Vitro Drug release from SEDDS

Fig 3: DSC thermograms of simvastatin, physical mixture, Ludiflash, Microcrystalline cellulose, Gelucire® 48/16, Gelucire 44/14, S-5&S-6 (Optimized SEDDS after adsorption on to carrier)

FTIR spectra of Simvastatin, Microcrystalline cellulose, Ludiflash, Gelucire® 48/16, Gelucire 44/14, S-5& S-6 (Optimized TSG-SEDDS), physical mixture.