noteablequotable
GLP-1 Specialist
This is literally the paper I was posting direct quotes from above....did you read through any of my previous posts at all?
Reconstituting agent for Cagrilintide
- Thread starter Christine S
- Start date
This is literally the paper I was posting direct quotes from above....did you read through any of my previous posts at all?
TooBigtoFail
GLP-1 Novice
Here is my contribution on the pH:
Pramlintide put Novo on the track for Cagrilintide, very stable at pH4.
Read this paper "Kinetics of pramlintide degradation in aqueous solution as a function of temperature and pH"
https://pmc.ncbi.nlm.nih.gov/articles/PMC2784819/
It provides info on Pram pH@4.0, temperature and stability of a peptide improved on, to create Cagri. Now read this article on Cmpd C, a new peptide better that Cagri. See how bad Cagri does at pH7.4 on a standard thermal test to evaluate stability (this is used to figure out its survivability during poor transport conditions) .
"789-P: Discovery of a Novel, Long-Acting Amylin Receptor Agonist for Body Weight Control"
https://diabetesjournals.org/diabet...789-P-Discovery-of-a-Novel-Long-Acting-Amylin
My plan is to target a ph4.0 for my Cagri recon, to retain a decent potency for 28 days or more. I am days away to get all my supply in, for my first recon of Cagri and can't wait to correct my Tirz stall with Cagri.
Based on a few tests, I need to add between 2cc to 6cc of AA@0.6% to get down to pH4.0, unless QSC 's lyophilized vials have the correct buffer already mixed in. One simple option is that if I blindly add 2cc of AA on an already buffered QSC vial, and get a pH3.5, Cagri patent say it is fine at pH3.5. It may string (and I will have to add bac to my next syringe before I poke) but will have to do, until I find a way to accurately measure recon pH. I really do not want to open and waste a Cagri recon just to use my electronic test probe.
Pramlintide put Novo on the track for Cagrilintide, very stable at pH4.
Read this paper "Kinetics of pramlintide degradation in aqueous solution as a function of temperature and pH"
https://pmc.ncbi.nlm.nih.gov/articles/PMC2784819/
It provides info on Pram pH@4.0, temperature and stability of a peptide improved on, to create Cagri. Now read this article on Cmpd C, a new peptide better that Cagri. See how bad Cagri does at pH7.4 on a standard thermal test to evaluate stability (this is used to figure out its survivability during poor transport conditions) .
"789-P: Discovery of a Novel, Long-Acting Amylin Receptor Agonist for Body Weight Control"
https://diabetesjournals.org/diabet...789-P-Discovery-of-a-Novel-Long-Acting-Amylin
My plan is to target a ph4.0 for my Cagri recon, to retain a decent potency for 28 days or more. I am days away to get all my supply in, for my first recon of Cagri and can't wait to correct my Tirz stall with Cagri.
Based on a few tests, I need to add between 2cc to 6cc of AA@0.6% to get down to pH4.0, unless QSC 's lyophilized vials have the correct buffer already mixed in. One simple option is that if I blindly add 2cc of AA on an already buffered QSC vial, and get a pH3.5, Cagri patent say it is fine at pH3.5. It may string (and I will have to add bac to my next syringe before I poke) but will have to do, until I find a way to accurately measure recon pH. I really do not want to open and waste a Cagri recon just to use my electronic test probe.
I don’t know about the most recent stuff but I checked ph on my qsc cagri purchased about 4 months ago and it was around 7. So, no buffer.
FreeSpectator8
GLP-1 Member
The only thing that whole long meaningless facebook post says is that in manufacturing the drug needs to be at PH 4 and no higher. It has nothing to do with storage after formation.
FreeSpectator8
GLP-1 Member
No they clearly didn't. And they clearly don't understand the research they are quoting and are spreading misinformation and fearmongering.
They are testing for fibrils on the manufactured material in it's post-buffered state in both the patent and in the paper quoted. They even assess it over multiple weeks in the patent. This is not just during the manufacturing process, this is in it's post-buffer, post-constitution state.
There are reasonable arguments about whether or not any of this matters (and indeed, NN is testing a single-chamber pen for cagrisema now), but you are incorrect in this statement.
JohnnyGobbs
GLP-1 Novice
I tested my nexa cagri with Amazon bac, ph was approx 6. I then added acetic acid and got it down to approx 4.5-4.0.
FreeSpectator8
GLP-1 Member
Can you share roughly the amount of each liquid you used? Also if you dont mind linking the products you used?
I'm curious about this for Cagri as well. My plan is to start with BAC to test ph, then lightly add AA if needed. However, it would be interesting to see others recon trials if they have to adjust PH for Cagri and the amount consensus of each. I also contemplated using Hospira BAC w/ AA mix, but that may make ph more difficult to tweak, if tweaking is needed.
FreeSpectator8
GLP-1 Member
First of all, I was not talking to you. I was directly responding to a user who claimed that NN had admitted that the current Cagri compound will create fibrils.
That however is not what that hogwash of a facebook post says, it only talks about the chemicals that were tried in the process of developing Cagri.
Now addressing you, you seem to be completely misunderstanding the entire point of the research paper you keep referencing. The research was *not* conducted in such a way as to find out if chemical 23 (Cagrilintide) is dangerous, it is the culmination of all the different research they did before deciding that Cagrilintide is the safest and most effective choice for human use.
That means Novo went and paid probably millions of dollars trying to develop this drug, and they decided that Cagrilintide was the safest and best choice to move forward with for testing, OK? That means after spending all that money, they decided to move foward with this drug for trials, knowing that if they get approved and it later ends up being unsafe they will be paying out the ass in lawsuits.
Now, does that mean we dont have to buffer cagri? I cannot say, but the solubility of 23 (Cagri) is fully soluble and stable all the way up to a PH of 8. Additionally, compound 1 still fibrilated in high dosages despite being in a 4 PH solution, they theorize that is because compound 1 was not soluble at higher PH and after injection the chemical is mixed with the human bodies fluids which are by and large a very constant 7.4-ish PH, no amount of buffering will change this, and you dont want it to because if you did it would fuck you up. It is theorized at low doses compound 1 was kept soluble by albumin, a chemical in human serum fluid, so in higher dosages, as the compound binds and uses up all local albumin, it allows the chemical to fibrilate, and the fibrils do not necessarily redisolve once the albumin returns to the area because the compound is not soluble above PH 5.
What this very clearly shows is that the solubility of the chemical is leaps and bounds more important than the PH of the fluid. YES in storage a ph of 4 is probably better, but when the chemical gets in your blood it is going to be in a 7.4ph solution until it is fully removed from your body.
Cagrilintide (Compound 23) solves this issue by being soluble up to a ph of 8.
It is in my opinion that with the information blatantly available, Cagri is most likely perfectly safe in the short term after reconstitution whether you buffer it to PH 4 or not. As you have said they are already mixing the to in CagriSema.
As far as your concerns about their testing showing that high heat and wear and tear on the chemical can cause fibrils, I would just remind you that these medications are stored in a form that is not reconstituted, and once reconstituted are nowhere near those conditions.
FreeSpectator8
GLP-1 Member
One thing to keep in mind is your body is PH7.4... so really worrying about the PH of the recon really only matters for the short term storage while you use the vial.
Research wise and scientifically, there was only fibrilation of cagri with high temperature and physical stress, which cagri will not (or atleast shouldnt lol) experience sitting in your fridge.
FreeSpectator8
GLP-1 Member
The thing i would be much more concerned about is if the Chinese labs are manufacturing the peptides at 4 PH before lyophilization. which we have no way of knowing really.
I should have clarified... the duration of the shelf stability once reconned is actually my focus of the proper PH. I do know I don't plan on shaking it around like a martini though.
FreeSpectator8
GLP-1 Member
Someone probably (or a group finance kind of deal) need to get a few bottles of cagri, recon some with BAC and some with AA to a PH of 4 and let both sit in a fridge for like 6 months or a year and then have them tested against some unrecon'd bottles of the same batch.
Though in my trials, I would/do not use anything reconned more than 6-8 weeks, ( Cagri no more than 1 month), your idea would certainly be an interesting research project.
I have posted this info elsewhere, but I think it could be partly useful to answer OP: I also wanted to target a lower pH for reconstituted cagri, so I used Hospira Bacteriostatic 0.9% Sodium Chloride. Specifically, the monograph reads "Each milliliter (mL) contains sodium chloride 9 mg and 0.9% (9 mg/mL) benzyl alcohol added as a bacteriostatic preservative. May contain hydrochloric acid for pH adjustment . . . . The pH is 5.0." When I reconstituted cagri with this, I got a solution with a pH of about 5.0 to 5.25. I tested the refrigerated solution's pH over the course for a few weeks and it stayed in that range and the stuff kept working on RS. I'm presently on hiatus from cagri due to a case of sluggish oligomerphobia, but I have an acetic acid vial on hand to someday attempt to lower such a cagri solution to 4.0. This is just my narrow experience and I have precious little clue what I'm up to, so take it for what it is worth.
[Presently, I take no position on how any of this relates to cagri oligomerpyleing, fibriliferating, or manifesting an intermediate Cascade-like sheeting action on the way to slimming your brain, pancreas, or waistband.]
[Presently, I take no position on how any of this relates to cagri oligomerpyleing, fibriliferating, or manifesting an intermediate Cascade-like sheeting action on the way to slimming your brain, pancreas, or waistband.]
JohnnyGobbs
GLP-1 Novice
Need to hear @hexagonal rebuttal to freespectators points. Hex talking points about cagri is what got my layman brain concerned in the first place to tweak the PH lol
JohnnyGobbs
GLP-1 Novice
Yea this is basically my scenario too. Took 5mg vial of cagri, 1ml of bac (amazon) that was about 5.5-6 PH. Then Added .4ml of AA (Amazon) and it dropped to 4-4.5 PH. I stopped at 4-4.5 and Pinned and it worked fine (Another .1ml-.2ml of AA would prob get it into the 3’s). I’m also a total amateur and scared of fibrils and oligomers lol.
TooBigtoFail
GLP-1 Novice
I buy StatLab bac 2ml vials (actually has ~3.1-3.5ml) on Amazon. I had one vial half empty (1.6ml) so I added AA 0.6% (from Quality Research Chemical 10 ml on Amazon). After adding 1.4ml of AA, I got pH4.5. No sting, so for next Cagri recon I will do 75% AA to get ~pH4.0. Looks like pure AA should be pH2.8 @ 0.6%. (0.1Mole). My AA was about pH3.5. Was it mixed with water? not really 0.6% ? Is AA alone a good enough peptide preservative for 30 days? Works for pickling ! USP standard allows a lot of variance for the pH of bac water: Hospira bac pH5.7 can be between pH4.5 to 7.0. The mannitol filler is pH6.3. Conclusion: need to test the pH of the bac/AA, and also the final recon pH.
JohnnyGobbs
GLP-1 Novice
This basically. I also used stat labs and quality research brands. Great minds… 🍻
FreeSpectator8
GLP-1 Member
I got lambda water BAC water, and Quality Research Chemicals AA, we will see how it goes. Bought PH test strips to see if they can work instead of having to buy a 50+ dollar PH tester.
JohnnyGobbs
GLP-1 Novice
Yea I used the strips. They worked fine.
As I am more concerned with stability after recon, I read this a couple times to absorb this..... it makes sense. Thanks for adding your experience.
NN is explicit that fibrils do form in cagrilintide, in both that research paper and in the patent. I have quoted those sections extensively across these threads. In the research paper, yes, they use a test that puts it in relatively extreme conditions vs. what is going to be seen after it is reconstituted by most people here, but we don't know what it looks like on the manufacturing side, how roughly it is treated there, how it is stored, etc. The patent filing uses a significantly less torturous test, but we still see fibril formation in the longer term with that test as well.
Part of the testing in the paper is to determine if fibrils are formed. I have never claimed this makes it dangerous - I have explicitly said I do not understand enough about the science to know if these fibrils truly are dangerous. What I will say is that in the testing conditions in the paper and the patent filing, they do find that cagrilintide produces fibrils.
You're writing a whole lot that doesn't actually say anything one way or other about the concern. No one is arguing that the PH remains low in your body.
No one has produced details on what PH is being used for the single chamber pen - we seem to be assuming it is a higher PH, and I wouldn't be surprised if that is the case, but they might also be going with a lower pH for the entire solution, unless someone has evidence that semaglutide is harmed at the lower pH.
Again, the patent involves a significantly more gentle test, at temperatures below 100F and just doing 100 end-over-end inversions of the vial on the liquid form of cagrilintide + buffering agent each day.
I've also been quite explicit my primary point is we have no idea what is happening with the manufacturing before the lyophilization. How long was it in the pre-lyophilized state? What pH was it manufactured at and stored at in between? What were the conditions during that time period? If I thought that just reconstituting it at a lower pH solved all ills, I would be using cagrilintide myself - I'm certainly confident in my ability to lower the pH of a solution. All I've said about it in reconstituted form is that if I had decided to press on and use it regardless of the rest, I would filter it and reconstitute at a lower pH to do what I could to prevent further fibril formation.
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No one should be taking anything I say as anything beyond my own layperson interpretation of the paper and patent filing, lol. I'm certainly no expert.
Appreciate your humble and thoughtful approach to all this. I think one of the reasons these conversation get ugly is that team fibril has several vocal members (leaders?) who are… ummmm… less measured in their tone and less lucid in their language. Your interpretation was helpful.
Thanks!
My biggest worry in engaging on all of this is people assuming I'm some sort of professional and taking my opinion as anything more than a nerd reading papers and interpreting them to the best of his ability.
TooBigtoFail
GLP-1 Novice
Great discussions. Google AI results say it may be over the course of 10-20 years of accumulation before plaque forms. Specific conditions. Is there enough material in Cagri 2.5mg weekly, taken for 6 months to be a concern? These are all relatively young GPL medication. In a study, to create fibrils, they had to keep the temperature near 37celcius for days and then use a 0.22um filter to count them(fibrils measure 10nm) Am I to conclude that using a .22um filter would remove them? Should I be filtering my grey market peps anyway as I expect to stay on maintenance for 1 or 2 years after I reach my goal? A survey on filtering?
.22um is 220nm, so individual fibrils would still pass through.
My understanding is fibrils do tend to clump so you could potentially filter out any large enough clumps, which is why I would personally filter if I were to decide to use cagri.
JohnnyGobbs
GLP-1 Novice
I know but your rebuttals and skepticism are pretty solid. Debate is healthy.
