It’s a great read but is this really the history of oral peptides?

abainbridge 3 hours ago | parent | next [-]

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."

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pstuart 2 hours ago | parent [-]

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.

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CGMthrowaway an hour ago | parent | next [-]

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.

	▲	cassepipe 19 minutes ago \| parent [-]
		> BUT, low (<1%) bioavailability does not necessarily mean useless. Can you say more about that point ?

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rodarmor an hour ago | parent | prev [-]

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

	▲	39 minutes ago \| parent \| next [-]
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	▲	pstuart 33 minutes ago \| parent \| prev [-]
		Insufflation for medicinal purposes if it works and doesn't cause harm seem like a win. Less needles == more use.

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Nevermark 24 minutes ago | parent | prev [-]

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.