Purpose: Patient compliance for a high dose active pharmaceutical ingredients (APIs) with a short biological half-life is challenging due to the increased dosage size and frequency required to maintain effective plasma concentrations. These limitations can be addressed by developing modified release dosage forms. We attempted to develop (a) an Extended Release Matrix Tablet and (b) a combination Immediate Release-Delayed Release (IR-DR) capsule to achieve adequate therapeutic endpoint and obtain in vitro-in vivo correlations.
Methods: The ER matrix tablet formulation was developed for 12 hours dissolution profile for twice a day administration. The IR-DR formulation strategy was developed as a two population multi-particulate filled capsule. The first population of particulates were provided an immediate burst release and the second population was enteric coated to deliver at the intestinal region. Both IR and DR particulates were encapsulated. A two-stage in vitro dissolution method consisting of (a) an acid stage and (b) a neutral buffer stage was developed around the pH change in the stomach and small intestine. This dissolution method was used to demonstrate acid resistance of the DR portion of the dosage form.
Both formulations were tested in beagle dogs. The IR-DR formulation was administered to male beagle dogs and pharmacokinetic data was obtained. The in vitro data was correlated to in vivo plasma concentration in beagle dogs and the correlation was compared to other formulations of the molecule available in literature.
Results: When tested in beagle dogs, the ER formulation fell short of the adequate Cmax required for its therapeutic effect, however, the IR-DR formulation was able to achieve the effective plasma concentration. Further, a single IR-DR dose was able to achieve and maintain an effective plasma concentration for a longer period of time when compared to multiple doses of the ER formulation. The in-vitro in-vivo correlation was obtained for both compositions.
Conclusion: A pH based IR-DR formulation strategy addresses the limitations of therapeutic applications for an APIs with a short biological half-life. The establishment of an in vitro and in vivo correlation further lays the ground work for future QbD approaches to optimize and scale up the manufacturing process around the pharmacokinetic data. This work can be expanded to develop controlled release drug formulations for similar APIs with a short biological half-life requiring bi-phasic release.