(T1030-01-01) Vegetarian Softgels Using SeaGel® Technology for Pharmaceutical Applications

Purpose: The preference for softgel delivery forms is growing as softgels readily encapsulate a variety of liquid and semi-solid formulations and have been used to effectively deliver poorly soluble active ingredients and played a crucial role in enhancing bioavailability. Several grades of gelatin have been developed for use in the pharmaceutical industry to overcome gelatins potential to crosslink with active ingredients, which can lead to reduced solubility of the capsule shell. However, these gelatin grades are still sensitive to temperatures greater than 40 °C, presenting challenges filling API formulations at temperatures greater than 40 °C, as well as storage and shipment of gelatin softgels. There is also a growing consumer preference for non-animal products to suit different dietary needs (vegan, halal, kosher, etc). In this study, the dynamic mechanical spectra of various wet and dry films using either gelatin film formulations or plant-based materials using SeaGel^® technology were investigated. Furthermore, the stability of the softgels was investigated on softgels encapsulated with a model fill formulation of a poorly soluble active pharmaceutical ingredient (API), Ibuprofen (IB), using either gelatin or SeaGel^® as the shell-forming material.

Methods: Gel masses of gelatin or SeaGel^® (carrageenan and modified starch) were prepared on a Ross CDA-4 mixer. The prepared gel masses were then transferred to a rotary die process using a Farmateck FTK55 encapsulator. Capsules were made using size 7.5 oval dies and filled with 400 mg of a 7.3 wt % IB in medium chain triglycerides (MCT). Dynamic mechanical thermal analysis (DMTA) measurements of the wet films were performed using an Anton Paar MCR-702e Rheometer in parallel plate mode. The measurements were performed at a constant frequency of 1 rad/s and sheer strain amplitude of 0.25% in the temperature range of 80 to 20 °C with a cooling rate of 1 °C/min. DMTA measurements of the dry films were also carried out using ARES-G2 Rheometer in tensile mode. The measurements were performed at a constant frequency of 1 rad/s and strain amplitude of 0.09% in the temperature range of -19 to 90 °C with a heating rate of 1 °C/min. Capsule disintegration was tested using disintegration tester (model QC-21, Henson) as described in USP < 701 >. A modified USP I method was used for in vitro dissolution experiments with Agilent 708-DS and spectrophotometer Carey 60. HPLC analyses of IB were also conducted using an Agilent chromatograph consisting of G1311B pump, G1329B autosampler, G1316A oven, and G1314F UV detector. Capsule burst strength, elasticity, and hardness were measured using a texture analyzer with TA-4 probe and 1 mm/s compression speed.

Results: The impact of temperature on the flow behavior of SeaGel^® and gelatin wet films are shown in Figure 1. It was observed all gelatin grades (and formulations) had tan d > 1 when temperatures (T) were > 40 °C. The only exception was the formulation with Gelatin S (which was designed for improved stability)/glycerin where tan d > 1 when T > 45 °C. While SeaGel^® wet films demonstrated tan d < 1 at all temperatures and for all formulations. This means that SeaGel^® wet films behave more like an elastic solid and will be able to enable high temperature fill materials. Additionally, the SeaGel^® softgels showed consistent mechanical stability while gelatin capsules showed decreased hardness over various aging conditions.  Furthermore, SeaGel^® softgels showed slightly delayed disintegration (~ 5 min delay) compared to model gelatin capsules at the time of capsule production, but more consistent disintegration behavior than that of gelatin softgels over accelerated aging conditions. The SeaGel^® softgels also showed approximately equivalent API dissolution behavior as that of model gelatin capsules at the time of capsule production. This is consistent with similar findings of other scientists. ¹

Conclusion: Evaluation of physical and chemical stability of softgels is critical to ensure product quality and consistency during the drug product life cycle. SeaGel^® softgels showed their ability to tolerate high temperature fill and their superior stability against gelatin capsules at various aging conditions up to 12 months of aging time.


Comparison of temperature dependence of tan d for gelatin wet films and SeaGel® CAP201 Prem wet film.