Stability Enhancement of Drug Layered Pellets in a Fixed Dose Combination Tablet
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The purpose of this research was to develop a stable fixed dose combination tablet for a model DPP-IV inhibitor and metformin hydrochloride. The dipeptidyl peptidase IV (DPP-IV) inhibitor was particularly challenging to formulate due to its significant chemical instability and moisture sensitivity. Various formulation strategies were investigated and placed on accelerated stability to determine the lead approach and critical quality attributes. The lead formulation investigated was a drug layered pellet containing the DPP-IV inhibitor, which was further coated with various seal coats and moisture barriers, then compressed into a tablet with compression aids and granulated metformin hydrochloride. The investigations revealed that the drug layered pellets compressed into a fixed dose combination tablet yielded a unique stability enhancement. The stability was highly dependent on the final tablet water content and could be further improved by the addition of moisture barrier coatings. A fundamental understanding of the key critical quality attributes for the fixed dose combination product containing a DPP-IV inhibitor and metformin hydrochloride as an oral solid dosage form were established. This research identified a formulation approach to enable a successful commercial product to be developed.
KEY WORDSDPP-IV drug layered pellets hydrolysis moisture barrier stability
Aqueous moisture barrier
Dipeptidyl peptidase IV
Partially hydrolyzed polyvinyl alcohol
The authors would like to greatly acknowledge the following people for their ideas, dedication, and hard work that supported this project: Joel Sutton, David Tainsh, Robin Currie, Faith Van Horn, Dustin Melton, Karen Crews, Kaitlin Fague, Ken Ackerman, and Bettina Cremer.
- 4.Schlesselman LS. Vildagliptin: adipeptidyl peptidase-IV inhibitor for the treatment of type 2 diabetes. Formulary. 2006;41:494–500.Google Scholar
- 5.Haffner CD, McDougald DL, Reister SM, Thompson BD, Conlee C, Fang J, Bass J, Lenhard JM, Croom D, Secosky-Chang MB, Tomaszek T, McConn D, Wells-Knecht K, Johnson PR. 2-Cyano-4-fluoro-1-thivalylpyrrolidine analogues as potent inhibitors of DPP-IV. Bioorg Med Chem Lett. 2005;15:5257–61.CrossRefPubMedGoogle Scholar
- 12.Opadry II product information brochure (Pib_opadryII_v2_10.2009) 2009. http://www.colorcon.com/literature/marketing/fc/Opadry%20II/pib_opadryII.pdf. Accessed 06 Nov 2012.
- 13.Opadry AMB product information brochure (Pib_opadryam_v2_10.2009) 2009. http://www.colorcon.com/literature/marketing/fc/Opadry%20amb/pib_opadry_amb.pdf. Accessed 06 Nov 2012.
- 14.Okhamafe AO, Iwebor HU. Moisture permeability mechanisms of some aqueous-based tablet film coatings containing soluble additives. Die Pharm. 1987;42:611–3.Google Scholar