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Yep, I think it is. The point is there's almost no history of oral peptides, other than stomachs destroying them.

FTA: "So to summarize the state of the art in oral peptide delivery: there are exactly two FDA-approved products that use permeation enhancers to get peptides into your bloodstream through your GI tract. Both achieve sub-1% bioavailability. Both required over a decade of development, thousands of clinical trial participants, and hundreds of millions of dollars."

by pstuart4 hours ago|

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Would a sublingual dose be possible/more effective? Research in other (um, yeah, medicinal!) compounds shows that it can be an effective pathway to the bloodstream rather than trying to survive the digestive system.

by CGMthrowaway4 hours ago|

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Sublingual is even harder. The sublingual mucosa is thin but selective. It strongly favors molecules that are small, lipophilic and uncharged. Semaglutide is about 8-10x too big, highly polar and charged.

Injection is really the only method with any substantial bioavailability. BUT, low (<1%) bioavailability does not necessarily mean useless.

by cassepipe3 hours ago|

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> BUT, low (<1%) bioavailability does not necessarily mean useless.

Can you say more about that point ?

by nerdsniper3 hours ago|

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If the drug has a relatively low marginal cost of production, and the stomach just breaks down 99% of it without side effects, you can just manufacture 100x more, give it orally, and eat the cost of the 99% that gets lost along the way.

Injectable Semaglutide/Tirzepatide (>99.8% pure) are currently sold at a profit from China for around $2-3/weekly dose. Rybelsus (oral semaglutide) is sold at roughly the same cost per milligram, even though it's made in FDA-approved facilities (you just need to take >= 40x more milligrams per month, bringing it to $1000/month in the USA)

So manufacturing oral doses 100x higher than injectable seems to be economically viable.

by rodarmor4 hours ago|

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It would be hilarious if people wound up snorting or boofing their GLP-1s (≧▽≦)

by 4 hours ago|

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deleted

by pstuart3 hours ago|

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Insufflation for medicinal purposes if it works and doesn't cause harm seem like a win. Less needles == more use.

by LoganDark2 hours ago|

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Ancedotal but it's really hard for me to do insufflation because of the discomfort. Of course if my life depended on it I could probably do it but otherwise I'd rather not.

by Nevermark3 hours ago|

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Here is a list of ways bioactivity is achieved in 6 cases via 7 mechanisms:

Cyclization + N-methylation — lipophilicity, protease resistance (cyclosporine)

D-amino acid substitution — protease evasion (desmopressin)

Permeation enhancers — transient tight-junction opening or membrane fluidization (semaglutide/SNAC, insulin formulations)

Extreme potency — tolerating <1% bioavailability (desmopressin)

Minimizing size to di/tripeptides — exploiting PepT1 active transport (collagen hydrolysates)

Prodrug masking — protecting reactive groups, intracellular unmasking (S-acetyl-glutathione)

Local buffering — pH microenvironment control (semaglutide)

One I take, PEP19, apparently is unique in being naturally bioactive. Evidence is early stage, but I get noticably better sleep with it (by some non-drowsiness mechanism), taking 6mg, 3x the recommended dosage for sleep, but the higher dose may promote fat burning and fat browning at night (only 1 study). It only has 10 residues which apparently avoid having typical cleavage points, fragments may retain bioactivity, and it has extreme potency in very small doses so any absorption means a lot.

Despite a plethora of peptides, successes are not common.