Application Note

Unlock Oral Delivery Potential For Macromolecules With A Parallel Screening Approach

Source: Catalent
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Executive Summary
Salmon Calcitonin is a peptide with poor oral bioavailability. To assess its potential for oral delivery, Catalent conducted a parallel screening with 2 different technologies targeting duodenal and sublingual biological barriers respectively. Lipid formulations and lyophilized tablet formulations were developed in parallel. Subsequently, based on the animal PK study data, the optimal formulation and dose form was identified which shows the oral bioavailability of Salmon Calcitonin was increased by more than 20 times.

The Challenges
Salmon Calcitonin (C145H240N44O48S2) is a well-known peptide with molecular weight of 3431.85Da. It is currently delivered via injection to treat osteoporosis in postmenopausal women. An oral dose form is not available because of its poor oral bioavailability. Although Salmon Calcitonin is water soluble, it has poor permeability through tight junctions and limited transcellular pathways due to its molecular size, geometry, and flexibility.

The Catalent Solution
Catalent’s scientists applied OptiForm® Solution Suite Bio with OptiGel™ Bio and Zydis® Bio technologies to overcome duodenal and sublingual biological barriers.

The first step was to assess the stability of Salmon Calcitonin with a variety of excipients to ensure good compatibility with both lipid and solid excipients. To test permeability against duodenal and sublingual barriers with simple candidate formulations, Salmon Calcitonin in solution with the permeation enhancer sodium caprate and in non-optimized lyophilisates were prepared and dosed in a PK study performed in dogs. Both formulations showed enhanced bioavailability compared with Salmon Calcitonin dosed orally alone as reference (figure 1.1 and figure 1.2).

In the second step, scientists developed two lipid formulations in the softgel dose form using OptiGel™ Bio technology and one optimized lyophilized tablet using Zydis® Bio technology. The animal PK study showed that the Zydis® Bio tablet enhanced the bioavailability by 4 times, equivalent to the bioavailability with the solution of permeation enhancer which was developed in step 1. The first lipid formulation did not reproduce the bioavailability in step 1 and thus was not selected for further optimization. The second lipid formulation reached higher bioavailability and was therefore selected for further development. (figure 2.1 and figure 2.2).

In the third step, the selected lipid formulation (Lipid Formulation 2) was further developed using OptiGel™ Bio technology. The optimized formulation enhanced its bioavailability by more than 50 times when compared to Salmon Calcitonin oral dose (Reference). With this optimized lipid formulation (Lipid Formulation 3), Salmon Calcitonin showed great potential for oral dose development. (figure 3.1 and figure 3.2)

Conclusion
Catalent’s OptiForm® Solution Suite Bio incorporates OptiGel™ Bio and Zydis® Bio technologies to screen the potential of peptides and macromolecules for oral delivery against two biological barriers simultaneously: the duodenal and sublingual barriers. The animal PK data in each phase was used to select the promising formulations for further development to achieve the optimal oral bioavailability. Your macromolecule has oral delivery potential; our passion is to help unlock it.