(295a) Preparation of Enteric Capsules Using a Fugitive Salt

Preparation
of Enteric Capsules Using a Fugitive Salt

Jin Zhao¹, Roland Adden²,
Robert Schmitt¹, Wes Spaulding¹, Uma Shrestha¹,
Debbie Holbrook¹, Josh Imperial¹,
Shrikant Khot¹

(1) Pharmaceutical
Excipients R&D, Dow
Pharma & Food Solutions, Midland, MI 48674

(2)
Food
& Nutrition R&D, Dow Pharma & Food Solutions, Bomlitz,
ND 29699, Germany

To protect acid sensitive
active pharmaceutical ingredients (API), current technology typically involves
coating multi-particulates, capsules or tablets with a known enteric
polymer.  Such coating processes usually
involve organic solvents that are flammable, toxic, and explosive, or involve
aqueous dispersions that are hard to handle, tend to block coating nozzles and
have poor stability(1-3).  To
overcome these drawbacks, films and capsules were directly prepared using aqueous
enteric solutions based on a fugitive salt.

Films
and capsule shells were prepared using aqueous hypromellose
acetate succinate (HPMCAS) solutions based on a model fugitive salt, ammonium
bicarbonate.  The rheology of such
aqueous solutions was adjusted to fit manufacturing requirements by varying the
polymer concentration and the addition of triethyl
citrate. The resulting films demonstrated comparable mechanical strength to
films made from organic solutions.  The
API diffusion across the film also demonstrated acid
resistance that satisfied USP enteric requirement.

HPMCAS capsules were
produced by a dipping process where the aqueous solution with model fugitive
salt enhanced the dipping and drying process (Figure 1a).  The residual by-product of the neutralization
reaction such as H₂CO₃ can act as plasticizer via association
with the succinic groups ? C(O) ? R ? COOH.  When the aqueous composition is dried on the
molding pin, the residual ammonium bicarbonate,
decomposes at the drying temperature. Accordingly, the evaporation of NH₃,
CO₂ and H₂O facilitates gelation of the polymer on the
mold pin resulting in a homogeneous film. The resulting dried capsule does not
comprise substantial amounts of residual alkaline material. Even though the gel
strength of the aqueous HPMCAS solution is significantly lower than that of
HPMC solutions, the low gelation temperature and quick formation of the HPMCAS film
leads to a  straightforward
capsule manufacture technique advantaged over the current state of the art (4). The
dissolution of the enteric capsules and subsequent API release also demonstrated
the necessary acid resistance to satisfy USP enteric requirements (Figure 1b).

The findings from this
research can help pharmaceutical scientists utilize truly enteric capsules as
opposed to enteric coated conventional capsules. This can protect APIs from
degradation in the acidic gastric environment, prevent irritation of the gastric
mucosa that often leads to ulceration, and achieve delayed and targeted release
in the small intestine.

Figure 1.
Enteric capsules made from HPMCAS aqueous solutions (a) and demonstrated
enteric performance by acetaminophen loaded capsules (b).

Acknowledgements

The authors wish to thank Shrikant Khot for
his insights and suggestions throughout this research.

References

1.            M. A. Osman, R. B. Patel, D. S.
Irwin, P. G. Welling, Absorption of theophylline from enteric coated and
sustained release formulations in fasted and non-fasted subjects. Biopharmaceutics & drug disposition 4, 63-72 (1983).

2.            M. A. Osman, R. B. Patel, D. S.
Irwin, P. G. Welling, Absorption of theophylline from enteric coated and
sustained release formulations in fasted and non-fasted subjects. Biopharmaceutics & drug disposition 4, 63-72 (1983)

3.            P. Mura, F. Maestrelli, M. Cirri, M.
L. Gonzalez Rodriguez, A. M. Rabasco Alvarez, Development of enteric-coated
pectin-based matrix tablets for colonic delivery of theophylline. Journal of drug targeting 11, 365-371 (2003).

4.            D. Cade, H. straub. (Capsugel France
SAS, WO2013/164121).