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.

(b)

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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).