Purpose: The use of lipid-based drug delivery systems (LBDDS) for oral delivery of poorly water soluble compounds is of growing interest. Although softgel is an ideal dosage form for LBDDS, few information is available about the impact of lipid-based excipients on softgel performance. The purpose of this study was to understand the potential interactions between typical lipid-based excipients and the two most common types of softgel shells: glycerol-based and sorbitol-based formulas.
Methods: Gel masses consisting of a mixture of limed bone gelatin, purified water, and a plasticizer (glycerol or sorbitol partially dehydrated) were manufactured in gel reactors using a cold melt process. Gel ribbons were cast in a rotary-die encapsulation machine and used to encapsulate single LBDSS excipients. A range of oils, solvents, co-solvents, and surfactants with different molecular weights, polarities and, where appropriate, different HLB's were selected (Table 1). Although not a lipid, Transcutol® HP was included in the study as it is a powerful solubilizer often used in LBDDS. Softgels were dried in drying tunnels until they reached target hardness. The elasticity of the softgels was tested with a Bareiss Hardness Tester, expressed as the force required to indent capsules by 2 mm. The robustness and flexibility of the softgels was tested using the Pharmatron® 6D(SG) Soft Gel Capsule Tester, the samples were compressed till breakage occurs and the force (N) required to burst was recorded or till a maximum force of 400 N. The disintegration test was performed according to EP method <2.9.1. Disintegration of tablets and capsules> with apparatus A in purified water. To pass the test all n=6 capsules must have disintegrated. Stability studies were conducted for 9 months at long term (25°C/60% RH) and accelerated (40°C/75% RH) ICH storage conditions.
Results: Softgels were manufactured with two gel masses prepared with the two most common plasticizer types: glycerol (lots G1 to G6) and sorbitol partially dehydrated (lots S1 to S6) (Table 1). Softgels of acceptable quality were obtained, no odd shaped nor leaking capsules were identified.
All lots were tested at t=0 and after 9 months on stability at conditions 25°C/60% RH and 40°C/75% RH. Softgels manufactured with MCT oil, Labrafil® and Labrafac™ performed well on all items assessed independently of the shell formula used. Elasticity (Fig. 1) and robustness (Fig. 2) were comparable at t=0 and after 9 months for long term storages conditions. As expected, at accelerate storage conditions, hardness values decreased and shell flexibility increased because of the capacity of softgels to absorb water in an environment of high temperature and high humid. All lots with the 3 excipients above mentioned passed the EP disintegration test. Capryol® 90, Labrasol®, and Transcutol®, used of as single fill ingredients, had undesirable effects on one or more characteristic(s) of the product. We found that Capryol® 90 induced shell crosslinking in time, as demonstrated by the failure of the softgels to rupture during the EP disintegration test. This happened regardless of the type of plasticizer used in the gel formula, and at both long term and accelerated storage conditions. Similarly, Labrasol® crosslinked the glycerol-based softgel shell when stored at accelerated conditions. In addition, the robustness test revealed that the products with the highest tendency to break (90 to 100% breakage) were Labrasol® when encapsulated into both glycerol and sorbitol-based shells and Transcutol® when encapsulated into glycerol-based shell. Furthermore, the increase by 2-fold of the hardness value of Transcutol® lot (G5) stored at 25°C/60% RH indicates that glycerol and/or moisture migrated from the shell to the fill. This interaction was not observed with the sorbitol-based shell, attesting of its better compatibility with Transcutol®. This increase of hardness correlates with the decrease of elasticity observed (Fig. 1 & 2).
Conclusion: Highly hydrophobic excipients such as MCT oil, Labrafil® and Labrafac™ are well suited for both glycerol and sorbitol-based shells. However, excipients that are more hydrophilic such as Labrasol® and Transcutol® were found be better compatible with sorbitol-based shell. As Capryol® 90, and to some extent Labrasol®, induced shell crosslinking during the stability study, shell development in this case should aim at mitigating this outcome. Since LBDDS are usually a mixture of 2 or more excipients, insightful and efficient shell formulation design should aim at balancing identified adverse effects of different fill component on the shell. Additionally, as lipid excipients are oxidation prone by nature, shells containing sorbitol-only or a sorbitol-glycerol combination have the advantage to be less permeable to moist and oxygen, ensuring a longer product shelf life.