(W1230-11-72) Formulation Development of Programmable Drug Delivery Multi-Unit Systems for the Delayed and Extended Release of Fixed Dose Combination Drugs

Purpose: The aim of this study is to develop a formulation for fixed dose combination (FDC) of N1 and N2 mini tablets / multi-unit dosage forms intended for delivery in the duodenum and small intestine respectively in a programmed manner for the treatment of cancer.

Methods: N1 is a new chemical entity intended for withstanding the acidic environment and delayed release in the duodenum and enhancing the bioavailability of a low dose drug N2 which has an absorption window in the lower part of the intestine. Both actives are highly sensitive to moisture and thermal degradation hence, it is very difficult to formulate using conventional palletization technique. N2 is a BCS Class IV molecule with poorly bioavailability of less than 5% by oral route. Different mini tablets of N1 & N2 were developed using wet granulation and dry granulation technologies respectively, compressed into mini tablets and coated with various pH independent and dependent polymers using custom designed automatic tablet coating machine and filled in a single capsule based on count of tablets. The release of N2 from the mini tablets was programmed in such a way that it is resistant to acid environment of stomach, delayed for a period of about 1 to 1.5 hours after release of N1 followed by extended release in lower intestinal pH for about 2 hours. The most challenging part of the formulation development was to select and optimize the combination of polymers, solvent systems and percentage of weight buildup on mini tablets.

Results: All the factors studied, like the combination of pH dependent and independent polymers, solvent system and % weight build up were impacting the programmed drug release of both the actives. As the % of polymers increased there was a significant impact on the release profile of N1 and N2. A suitable combination of solvent system was optimized to solubilize the polymers and plasticizers to attain a uniform and flexible coating. Also, a critical range of percentage weight build up was identified to achieve the desired programmed release of N1 and N2 from the mini tablets. Moreover, the formulation was successfully scaled up to the manufacturing location.

Conclusion: The desired programmed drug release of N1 & N2 has been successfully achieved by optimizing the ratio of pH dependent polymers, solvent system and percentage weight build up. As mini tablet technology has been developed for each active, flexibility in dosing can be achieved by changing the number of mini tablets and hence useful in dose ranging studies. Moreover, the formulation was successfully scaled up to the manufacturing location and the FDC was found to be stable for 6 months as per the ICH stability requirements.

Drug release profile of N1 and N2

Assay and Total impurities of N1 and N2 on stability

Minitablets and capsule intended for Programmed release of FDC