Materials
The author prepared a capsule-in-capsule system for investigation. Model compounds caffeine (Sigma Aldrich, St. Louis, MO)
and nicotinamide (Sigma Aldrich) were chosen. PEG 6000 Ph. Eur. (BASF, Ludwigshafen, Germany), Gelucire 50/13 (Gattefossé, St-Priest France), and Labrafil (Gattefossé) were used as thermosoftening
carriers.
Methods
Figure 4: Dissolution profiles for series 3 doses. The outer Labrafil (Gattefossé, St-Priest, France) capsule contained caffeine
(caff.), and the inner Gelucire 50/13 (Gattefossé) capsule contained nicotinamide (nic.). Results after 0, 2, 3, and 5 months'
storage are shown. (FIGURE IS COURTESY OF THE AUTHOR)
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Trial formulations of model compounds caffeine and nicotinamide were prepared at bench-scale in the selected thermosoftening
carriers, which are suited to liquid-filled hard capsules. Inner clear/clear size 2 gelatin capsules (Capsugel, Peapack, NJ)
were filled manually at 300 mg to provide 5 mg of nicotinamide in PEG 6000 or in Gelucire 50/13. Filled capsules were banded
with gelatine. A proportion of nicotinamide–PEG 6000 capsules was enteric-coated with Eudragit L100-55 (Röhm, Darmstadt, Germany)
at 10 mg/cm2 using a Strea-1 coater (GEA Pharma Systems, Wommelgem, Belgium). These inner size 2 capsules, with or without enteric coat,
were placed into size 0 capsules.
The second formulation was also filled into the size 0 capsules at the required fill weight to provide 5 mg of caffeine in,
Labrafil and the capsules were sealed. Samples comprising nicotinamide–PEG 6000 and caffeine–Labrafil, nicotinamide–PEG 6000
enteric coated and caffeine–Labrafil, and nicotinamide–Gelucire 50/13 and caffeine–Labrafil were designated as series 1, 2,
and 3, respectively.
Dissolution testing was carried out in European Pharmacopoeia Apparatus 2 (i.e., paddles), using 900 mL of dissolution medium, stirring at 100 rpm. Dissolution testing of series 1 and
3 samples used water as the dissolution medium. Testing of series 2 samples used 0.1N HCl for 2 h, followed by adjustment
to pH 7.0 using NaOH. Release of each component was determined by high-performance liquid chromatography at 262 nm. Capsule
integrity and dissolution profiles were monitored at time zero and after two, three, and five months' storage at 25 °C in
glass bottles.
Figures 2, 3, and 4 show in vitro dissolution profiles for all series at 0, two, three, and five months. Series 1 represented a nominal fast–fast release profile.
Series 2 represented a fast–enteric-coated–fast release profile. Series 3 represented a fast–slow release profile. The formulations
were designed to represent differing formats using widely-accepted thermosoftening carriers. Here, PEG 6000 and Labrafil provided
matrices considered suitable for fast release of each model compound. Gelucire 50/13 provided a matrix considered suitable
for the slow release of nicotinamide. The three sample series demonstrated that differing in vitro release profiles could be achieved readily using the approach described here
It is important that the system show the potential for product stability, particularly in terms of consistent integrity of
the double-capsule format and the required release profiles. Each sample series demonstrated continuing capsule integrity
and dissolution stability over the five-month time period. This result was particularly important to the sample in which the
inner capsule was enteric-coated because the formulation contained in the outer capsule could adversely affect the enteric
coat of a coated inner capsule. In this example, Labrafil was compatible with the enteric coat. It is worth noting that another
common liquid-fill carrier (i.e., Labrasol, Gattefosse) was incompatible with the coating agent used in this study.
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