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Q&A:Breaking Through the Barriers of Oral Biologics

Dr. John Vrettos, Enteris BioPharma

Q: Are all solubility excipients used FDA approved?
A: All excipients used by Enteris are either compendial, GRAS, or have a DMF on file with FDA.

Q: Is LLC interacting with the API protecting it from the protease or binding to the protease inhibiting its action more generally?
A: We have not done mechanistic studies, but I think there are at least three possibilities: (1) surfactant is interacting with API and blocking the action of proteases, (2) the surfactant is inhibiting the proteases by binding to them, or (3) API is sequestering into surfactant (LLC) micelles, thus avoiding proteases.

Q: Does a protein require spray-drying or other type of processing prior to incorporation into this tablet delivery system?
A: No. We have manufactured tablets using lyophilized powders and spray-dried drug substances.

Q: Have you applied your platform to extended release type applications?
A: Yes, we have manufactured extended-release tablet formulations with our enhancing technology.

Q: What type of stability conditions does the tablet formulation achieve?
A: We routinely achieve room-temperature stable finished drug product.

Q: Are there any concerns with use of permeability enhancers for drug interactions?
A: I think you are asking about concomitant dosing of a drug product that contains permeation enhancers with another drug. Many clinical trials have been conducted using Enteris’s permeation enhancing technology, and this concern has never been raised by a sponsor or health authorities. From a practical perspective, it is extremely unlikely that a concomitantly-dosed drug would be subjected to the permeation enhancement effect of our technology. For this to happen, the second drug would have to be released in the same location of intestine and at the same time as the drug product containing permeation enhancers. This is highly unlikely to happen.

Q: I am interested in Oral delivery of Bio-Logics and could partner if you have any potential technique. Can you please share any technique for Oral delivery of Biologics ?
A: If you are interested in conducting a feasibility study with Enteris, please contact us and we would be glad to discuss working with you!

Q: How did you overcome challenges in protein stability due to heat generated during tableting and coating?
A: In our experience, all the peptide APIs we have worked with were stable throughout the manufacturing process. I attribute this to the short duration of time for tablet compression, which limits the time spent at elevated temperature. In the case of film coating, heat is drawn away from the tablet bed as the solvent evaporates, so the internal temperature of the tablet core likely does not rise by much.

Q: How do you manufacture the protein or peptides into a solid form? Have you tried any amorphous forms?
A: The peptide or protein drug substance is typically a lyophilized or spray-dried amorphous powder. The drug substance is blended with the other tablet excipients and then pressed into a tablet.

Q: Was LLC used in the original sCT clinical trials with this type of formulation? The literature is confused on this.
A: No, the formulation for oral sCT (currently being developed by R-Pharm) does not, and never did, contain LLC.

Q: Very interesting presentation sir! 1.Do you recommend any in-vitro permeability assay for screening of permeation enhancers?
A: Enteris has not had success with in-vitro assays, in that we have not found them to be predictive of permeation enhancement in-vivo. I think there are at least two reasons why this is so. First, in-vitro cell-based assays do not secrete mucus, which is an important barrier to diffusion. Second, it is difficult to translate the dissolution of a tablet in the intestines into a liquid formulation that mimics the event; for example, what volume of water (and hence, concentration of excipients) should be assumed? However, in-vitro assays may be useful for rank-ordering permeation enhancers relative to each other.

Q: Is there any major challenges for biologics’ stability in comparison to small molecules?
A: During manufacturing, prolonged exposure to high temperatures can accelerate degradation of biologics to a much greater extent than most small molecules. As far as stability of the finished drug product, Enteris routinely achieves room temperature storage conditions.

Q: Can we measure bioavailability by testing elimination rate of urine?
A: I am not familiar with this approach, but I suppose for a drug with primarily renal clearance this might work.

Q: Didn’t see Monkey in your list of animal model. How does monkey compare to rat, dog, and minipig, in the evaluation of biologics?
A: The choice of an animal model should be done carefully, taking into consideration the purpose of the experiment and the limiting physiology of a particular species. In the case of cyno monkeys, we have had mixed results. In one study, we saw high variability and a longer-than-usual delay in the PK; we attributed this to difficulty passing the enteric-coated tablet through the pyloric sphincter of a small animal. Smaller tablets gave less variability.

Q: Are you aware of electrostatic spray drying at RT?
A: I can see how electrostatic spray drying at room temperature could be a useful process for peptide APIs that are heat sensitive.

Q: How many oral Peptide and Protein products are on the market?
A: There are 4 oral peptide products that are systemically absorbed, that I am aware of: cyclosporin A, desmopressin, taltirelin and glutathione.

Q: What is highest bioavailability reported for a biologic in dog or monkey or human?
A: A small, cyclic, protease-resistant RGD peptide was reported to have an oral bioavailability of 35-40% in monkeys.

Q: What is the best in vitro model to mimic the epithelium for studying paracellular uptake of peptides?
A: The best model would have both functional tight junctions and secretion of mucus, so, a co-culture mixture of enterocytes and goblet cells.

Q: Page 11. was PEG used as the macromolecule model? Most PEG are linear molecules so in one dimension it will be smaller than the pore size?
A: While one possible conformation of PEG is a linear arrangement, all of the single bonds in the molecule can rotate. Thus, there are many more conformations consisting of a more collapsed, compact structure. The hydrodynamic radius of the average, more compact structure is the “effective” size of the PEG.

Q: What is your opinion on the potential of ionic liquids for oral delivery of biologics?
A: I think this is a formulation space that needs to be explored more. Having a liquid dosage form means there is no delay in solubilizing the composition, and all components are in solution simultaneously. The components of ionic liquids may promote permeation and protection from proteases.

Q: When discussing Pathway 2 (proteases) you mentioned that reducing the pH can be a way to overcome it. Wouldn’t it also affect the stability of the peptide?
A: This would be a concern for peptides that are particularly acid-sensitive. In practice, it has been Enteris’s experience that most peptides are kinetically stable to the low pH environment created by our dosage form.

Q: What’s the best in vitro assay for screening the cell permeability of peptides? I’ve encountered many varied opinions in the field on the accuracy/translation of classic assays like PAMPA. I’d love to hear your opinion.
A: The best model would have both functional tight junctions and secretion of mucus, so, a co-culture mixture of enterocytes and goblet cells. Here is a reference, for example: Béduneau A, Tempesta C, Fimbel S, et al. A tunable Caco-2/HT29-MTX co-culture model mimicking variable permeabilities of the human intestine obtained by an original seeding procedure. Eur J Pharm Biopharm. 2014;87(2):290-298.

Q: Is there any major challenges for biologics’ stability in comparison to small molecules?
A: During manufacturing, prolonged exposure to high temperatures can accelerate degradation of biologics to a much greater extent than most small molecules. As far as stability of the finished drug product, Enteris routinely achieves room temperature storage conditions.