4 ms·

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

abainbridge 8mo ago
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."
- pstuart 8mo ago
  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.
  - rodarmor 8mo ago
    It would be hilarious if people wound up snorting or boofing their GLP-1s (≧▽≦)
    - deleted 8mo ago
      [deleted]
    - pstuart 8mo ago
      Insufflation for medicinal purposes if it works and doesn't cause harm seem like a win. Less needles == more use.
      - LoganDark 8mo ago
        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.
  - CGMthrowaway 8mo ago
    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 8mo ago
      > BUT, low (<1%) bioavailability does not necessarily mean useless. Can you say more about that point ?
      - nerdsniper 8mo ago
        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.
Nevermark 8mo ago
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.
- JumpCrisscross 8mo ago
  Is this ChatGPT?

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."

pstuart 8mo ago
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.
- rodarmor 8mo ago
  It would be hilarious if people wound up snorting or boofing their GLP-1s (≧▽≦)
  - deleted 8mo ago
    [deleted]
  - pstuart 8mo ago
    Insufflation for medicinal purposes if it works and doesn't cause harm seem like a win. Less needles == more use.
    - LoganDark 8mo ago
      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.
- CGMthrowaway 8mo ago
  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 8mo ago
    > BUT, low (<1%) bioavailability does not necessarily mean useless. Can you say more about that point ?
    - nerdsniper 8mo ago
      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.

Nevermark 8mo ago

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.

JumpCrisscross 8mo ago
Is this ChatGPT?