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Oral shipping of systemic monoclonal antibodies, peptides and minute molecules the exercise of gastric auto-injectors

Summary

Oral administration presents a straightforward and non-invasive arrangement for drug shipping. Nonetheless, attributable to glum absorption and swift enzymatic degradation within the gastrointestinal tract, a broad fluctuate of molecules wish to be parenterally injected to attain required doses and pharmacokinetics. Here we contemporary an orally dosed liquid auto-injector able to handing over as much as 4-mg doses of a bioavailable drug with the hasty pharmacokinetics of an injection, reaching an absolute bioavailability of as much as 80% and a maximum plasma drug focus within 30 min after dosing. This vogue improves dosing efficiencies and pharmacokinetics an define of magnitude over our previously designed injector capsules and as much as two orders of magnitude over clinically on hand and preclinical chemical permeation enhancement technologies. We administered the capsules to swine for shipping of clinically relevant doses of four recurrently injected medications, in conjunction with adalimumab, a GLP-1 analog, recombinant human insulin and epinephrine. These multi-day dosing experiments and oral administration in unsleeping animal devices reinforce the translational doable of the system.

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The records dilapidated to generate the figures and numerical statistics in this paper may maybe well moreover be came across as hooked up Excel files within the Supplementary Knowledge. Offer data are supplied with this paper.

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Acknowledgements

We thank J. Haupt, M. Jamiel, C. Cleveland, C. Anker, A. Benfeldt, C. Jensen, H. Toftelund and A. H. Uhrenfeldt for again with in vivo porcine work. We thank the MIT Koch Institute Swanson Biotechnology Center histology and excessive-throughput cores for technical reinforce. We thank U. Stilz, T. Kjeldsen, L. F. Iversen, M. Bielecki and P. B. Nielsen for discussions about SOMA building. We’re grateful to all contributors of Langer and Traverso laboratories and Novo Nordisk for their experience around biologic drug shipping. We thank the team at GTReel Productions, particularly Giancarlo Traverso, for assistance with assembly of the supplementary movies. Work became once funded, in section, by a Novo Nordisk grant (R.L. and G.T.), National Institutes of Health grant no. EB-000244 (R.L. and G.T.), National Science Foundation GRFP fellowship (A.A.), Karl Van Tassel (1925) Occupation Pattern Professorship, Department of Mechanical Engineering, Massachusetts Institute of Skills and Division of Gastroenterology, Brigham and Ladies’s Health center (G.T.) and the Viking Olof Björk scholarship have confidence (N.R.).

Author data

Author notes

  1. Alex Abramson

    Show handle: Department of Chemical Engineering, Stanford University, Stanford, CA, USA

  2. Morten Revsgaard Frederiksen

    Show handle: Orbex Denmark, Copenhagen, Denmark

  3. Xiaoya Lu

    Show handle: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA

  4. Jacob Wainer

    Show handle: Fractyl Health Inc., Lexington, MA, USA

  5. These authors contributed equally: Alex Abramson, Morten Revsgaard Frederiksen, Andreas Vegge.

Affiliations

  1. Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Analysis, Massachusetts Institute of Skills, Cambridge, MA, USA

    Alex Abramson, Xiaoya Lu, Jacob Wainer, Pleasure Collins, Siddartha Tamang, Keiko Ishida, Alison Hayward, Niclas Roxhed, Robert Langer & Giovanni Traverso

  2. Devices and Transport Solutions, Novo Nordisk A/S, Hilleroed, Denmark

    Morten Revsgaard Frederiksen, Brian Jensen, Mette Poulsen, Brian Mouridsen, Mikkel Oliver Jespersen, Jesper Windum, Mikkel Wennemoes Hvitfeld Ley & Peter Herskind

  3. Global Drug Discovery, Novo Nordisk A/S, Maaloev, Denmark

    Andreas Vegge, Rikke Kaae Kirk & Ellen Marie Straarup

  4. Global Analysis Technologies, Novo Nordisk A/S, Maaloev, Denmark

    František Hubálek, Jorrit J. Water, Johannes Fels, Stefán B. Gunnarsson, Adam Bohr, Stephen T. Buckley & Ulrik Rahbek

  5. Division of Gastroenterology, Brigham and Ladies’s Health center, Harvard Clinical College, Boston, MA, USA

    Keiko Ishida, Alison Hayward & Giovanni Traverso

  6. Department of Mechanical Engineering, Massachusetts Institute of Skills, Cambridge, MA, USA

    Alison Hayward & Giovanni Traverso

  7. Department of Micro and Nanosystems, KTH Royal Institute of Skills, Stockholm, Sweden

    Niclas Roxhed

  8. Institute for Clinical Engineering and Science, Massachusetts Institute of Skills, Cambridge, MA, USA

    Robert Langer

  9. Media Lab, Massachusetts Institute of Skills, Cambridge, MA, USA

    Robert Langer

Contributions

A.A., M.R.F., R.L. and G.T. developed the theory. A.A., M.R.F., M.O.J., J. Windum, B.M. and B.J. designed the system. M.W.H.L. and M.P. performed injection characterization reports. A.A., J. Wainer and X.L. performed excessive-velocity video experiments. A.A., A.V., E.M.S., J.C., S.T., K.I. and A.H. performed in vivo experiments. J.J.W. and A.B. developed liquid formulations and dissolving pellets. F.H. performed assignment and stability assays on liquid formulations. J.F., S.B.G. and A.V. performed prognosis on in vivo data. R.K.K. performed histology. U.R., S.T.B., P.H., N.R., R.L. and G.T. had oversight and leadership responsibility for the study assignment planning and execution. A.A., M.R.F., A.V., R.L. and G.T. wrote the manuscript. All authors discussed outcomes and commented on the manuscript.

Corresponding authors

Correspondence to
Ulrik Rahbek or Giovanni Traverso.

Ethics declarations

Competing interests

M.R.F., M.P., A.V., B.M., F.H., J.J.W., J.F., R.K.K., S.B.G., E.M.S., S.T.B., P.H., M.O.J., J. Windum, A.B., E.S. and U.R. are employees of Novo Nordisk. M.W.H.L. and B.J. are employed as consultants for Novo Nordisk. A.A., M.R.F., A.V., M.P., J.J.W., M.W.H.L., B.J., J. Windum, J. Wainer, X.L., N.R., U.R., G.T. and R.L. are co-inventors on patent capabilities describing oral biologic drug shipping. A.A., R.L. and G.T. file receiving consulting fees from Novo Nordisk. A.A. experiences receiving consulting fees from Eli Lilly. Total particulars of all relationships for profit and not for profit for G.T. can came across at the following hyperlink: https://www.dropbox.com/sh/szi7vnr4a2ajb56/AABs5N5i0q9AfT1IqIJAE-T5a?dl=0. For a list of entities with which R.L. is enthusiastic, compensated or uncompensated, understanding https://www.dropbox.com/s/yc3xqb5s8s94v7x/Rev%20Langer%20COI.pdf?dl=0.

More data

Ogle overview data Nature Biotechnology thanks Maria Jose Alonso, David Brayden and the assorted, nameless, reviewer(s) for their contribution to the peer overview of this work.

Publisher’s show Springer Nature remains neutral with regards to jurisdictional claims in printed maps and institutional affiliations.

Extended data

Extended Knowledge Fig. 1 Liquid Formula Balance.

Human Insulin (HI) concentrated to 12.5 mg/mL and a semaglutide (Sema) exploratory formula concentrated to 50 mg/mL were positioned internal of either an L-SOMA or a pitcher vial and were subjected to a 40 °C and 75% relative humidity atmosphere for 2 weeks. (a) Purity loss and (b) excessive molecular weight protein (HMWP) formation were then measured. (Imply ± SD, n = 3 system replicates; Unpaired t take a look at).

Offer data

Extended Knowledge Fig. 2 L-SOMA needle injection photos.

(a) High velocity pictures of an preliminary prototype L-SOMA system with a 21 G needle actuating into 0.3% agarose gel demonstrated that all of the liquid exits through the needle tip and not one amongst the liquid exits through the bottom membrane. (Photography are from one amongst n = 3 technical replicates). (b) No drug is delivered if the needle lacks a facet channel (Photography are from one amongst n = 3 technical replicates). Prototypes dilapidated throughout future ex vivo and in vivo reports employed a 32 G needle rather then a 21 G needle. (n = 3 technical replicates). (c) Hole on high of the L-SOMA system enables salvage admission to to the (d) dissolving pellet, which actuates the needle injection. (eg) Sequential MicroCT photos of a non-retracting L-SOMA handing over distinction dye into ex vivo swine tissue. (Photography are from one amongst n=8 technical replicates). Scales Bars = 5 mm.

Extended Knowledge Fig. 3 Injection take a look at mechanism setup and ex vivo injection force calculations.

(a) (Top) Laptop aided originate of the personalized actuation mechanism dilapidated to insert a needle a controlled distance and inject an true quantity of fluid. (Bottom) Experimental setup of controlled injection reports. The texture analyzer pushes down on the plunger which causes the liquid to inject into the swine abdominal tissue under. (b, c) The force required to inject a depot into ex vivo swine abdominal tissue at a given needle insertion depth. (Imply ± SD; 4 mm: n=11; 4.5 mm: n=9; 5 mm: n=18). (d, e) The force required to inject a depot into ex vivo swine abdominal tissue the exercise of a needle with a 10° backgrind and a backgrind of >50°. (Imply ± SD; 10°: n=20; >50°: n=5; Unpaired t take a look at).

Offer data

Extended Knowledge Fig. 4 Dogs ex vivo histology from L-SOMA injection.

Histology of ex vivo dog abdominal after an L-SOMA insulin injection the exercise of a (a) hematoxylin and eosin stain, (b) an immunohistochemistry stain in opposition to insulin, (c) or an immunohistochemistry stain in opposition to soft muscle actin. These are instance photos from one amongst three replicates. Scale bar = 1 mm.

Extended Knowledge Fig. 5 L-SOMA needle retraction mechanism originate.

The system first actuates after the hub pellet (red) dissolves and enables the latching mechanism at the tip of the capsule to free up. The retraction spring, positioned axially across the needle shaft, compresses after the first stage of actuation attributable to the inherent circulation of the needle throughout injection. The dissolution of the 2nd pellet, which is exposed handiest after the first pellet dissolves, frees the spring to develop and design the needle relief into the capsule.

Extended Knowledge Fig. 7 In vivo swine histology after L-SOMA epinephrine injection.

Hematoxylin and eosin stain histology of swine abdominal hours after L-SOMA injection. L-SOMA devices were injected within the fundus or body of the stomachs. An develop in cellularity is viewed between the retain watch over and the experimental tissues, however this variability is anticipated in tissue locations with unexpectedly dividing cells. Moreover, the well-liked injection of epinephrine within the abdominal throughout endoscopy supports the safety of intermittent administration of this drug in this region. The retain watch over histology is of swine abdominal tissue not dosed with any system. These are instance photos from one amongst three animal replicates.

Extended Knowledge Fig. 8 Pharmacokinetics of gavage dosed epinephrine and adalimumab.

Dissolved (a) adalimumab (4 mg) or (b) epinephrine (0.24 mg) were dosed through an endoscope into the lumen of swine stomachs (n=3 animal replicates).

Offer data

Extended Knowledge Fig. 9 Histology taken from swine dosed a lot of events with L-SOMAs over three days.

(ac) Three samples were easy constant with traditional histopathological procedures representing the (a) cardia, the (b) fundic, and the (c) pyloric space. No therapy linked findings were noticed in these traditional samples in any of the three swine. (d) Histology from a minimal focal lesion from the fundic space of one amongst the three swine. The image exhibits an acute minimal erosion with sloughing of epithelial cells and peripheral acute hemorrhage. This hurt is in all probability a mechanical trauma introduced about by the endoscope when dosing the animal and isn’t very an instantaneous stay of the intended L-SOMA dosing. (e) Zoomed in image of “d”. (a-c: Scale Bar = 500 µm; d: Scale Bar = 1 mm.; e: Scale Bar = 250 µm).

Extended Knowledge Fig. 10 SOMA actuation in dog abdominal after oral dosing in an unsleeping dog.

A radiograph of the SOMA system (a) ahead of and (b) after actuating within the gastric cavity. Show the extension of the spring within the appropriate panel. Scale Bar = 5 mm.

Supplementary data

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Abramson, A., Frederiksen, M.R., Vegge, A. et al. Oral shipping of systemic monoclonal antibodies, peptides and minute molecules the exercise of gastric auto-injectors.
Nat Biotechnol (2021). https://doi.org/10.1038/s41587-021-01024-0

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