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."
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.
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.
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.
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."
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.
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.
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It would be hilarious if people wound up snorting or boofing their GLP-1s (≧▽≦)
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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.
Is this ChatGPT?