A small Italian pharmaceutical company that is now part of a larger European entity sought Aptuit's assistance in the development of a drug product treating inflammatory and auto immune diseases. Because of the low solubility of the API, the client was looking to identify a formulation with improved bioavailability. The decision to work with Aptuit was enhanced by the comprehensive strategy that Aptuit was prepared to implement. The strategy focused on using three different formulation development approaches for the drug product and the corresponding placebo formulations. The processes that were evaluated were wet granulation, hot melt granulation and semi-solid in capsule development.

An Aptuit Project Manager was assigned to coordinate the project and initiate and facilitate the team in ongoing evaluations throughout the processes. All three processes resulted in the packaging of the product in amber glass bottles. After the comprehensive evaluation was completed, the hot melt granulation formulation was selected since it demonstrated the best pharmacokinetic results.

The Challenge

Aptuit was required to identify which of the three formulations resulted in the best bioavailability. While all three of the formulations yielded good physical and analytical results, pharmacokinetic studies were required to select the best prototype formulation.

The Aptuit Solution

Work flow charts for wet granulation, hot melt granulation and semi-solid capsule processes guided the path to packaging granules in amber bottles.

 

 

Prototype formulations included two granules for reconstitution, one via a wet granulation process using a cyclodextrin solution and Diosna high shear granulator equipment (Figure 2).

In the alternative hot melt granulation process, Gelucire 44/14 was melted at Impellor and Chopper Speeds to allow the powder agglomeration into granules. Once again the Diosna equipment (Figure 3) was used in the development of this second formulation.

The same processes were used to prepare corresponding placebo formulations. The particle size of the granules were determined by sieve analysis. The results (Figure 4) showed that the same distribution was obtained for active and placebo granules and therefore in both granulation processes, the granule agglomeration proved independent from the presence of API.

 

A third developed prototype was a semi-solid formulation in a hard gelatin capsule form. Self Emulsifying Drug Delivery System technology was used to form capsules such as those shown in Figure 5.

All of the prototype formulations were assessed for in-vitro dissolution (Figure 6) and pharmacokinetic animal studies.

 

Conclusion

Each of the active and placebo formulations were successfully manufactured with suitable physical and chemical results. However, the hot melt granulation process was selected since it demonstrated the fastest in-vitro dissolution performance (Figure 6) and the best pharmacokinetic results (not shown). The client reported that ongoing communications through Aptuit's Project Management ensured confidence in the progress of the formulation development. They were impressed with the span of Aptuit services that allowed them to reach their goals from a single source. At Aptuit, it's all about the science.