Sublingual Rapamycin

#1

I’ve just joined and wanted to say Hi!

I’ve been a big fan of this website for a long time and (whilst lurking) have learnt such a lot here.

Now I feel it is only right for me to come forward and hopefully make a useful contribution.

I’ve been ‘playing around’ with a sublingual rapamycin formulation.

I wanted access to rapamycin powder that I know is authentic and is relatively free of excipients. Unfortunately since my redundancy/retirement I no longer have access to my HPLC-MS & GLC machines so am unable to do the analysis. So I have decided to extract it from a couple of tablets.

Using the table below I decided to use acetone as an extraction solvent since rapamycin is highly soluble in it (20mg/ml) and most excipients are not.

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These are the steps I used to extract rapamycin

Grind up 2x 1mg tabs using agate mortar and pestle

Transfer powder to 1.5ml eppendorf tube along with 10x 2mm zirconia grinding beads

Add 1ml acetone (AR grade)

Vortex mix for 30 seconds

Centrifuge for 5 mins

Extract supernatent and decant to second eppendorf which is then placed on a dry heating block (~40C) with an air current blowing across it to aid evaporation

Add 1ml acetone to pellet in first eppendorf and resuspend using vortex mixer.

Centrifuge and decant supernatent into the eppendorf that has been on the hot block.

In total I did a total of 4 extractions (probably overkill) and ended up with a pale yellow pellet.

For the formulation, I made a Transcutol, propylene glycol, 37% ethanol solution at a ratio of 2:3:5

I added 250ul of this stock to the eppendorf and placed it in a 37C water bath for 2 hours with frequent vortex mixing to ensure solubilisation.

I then added 5ul of green food colouring (optional) so I could judge if the dosing solution was pooling at the base of the tongue, which would mean I’m adding it too fast.

To dose you touch your tongue against the roof of your mouth and with your head slightly back add rapamycin solution drop-wise on either side of frenulum where sublingual veins show. Alternate drops on either side of frenulum and allow time for drops to be absorbed

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VO2max: A Significant Increase via Sublingual Rapamycin?
#2

Great post - thanks for the detailed information. Have you done any blood/sirolimus testing to see how well its getting into your system? How to get a Rapamycin (sirolimus) Blood Level Test

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#3

I haven’t, unfortunately I live in the UK and we don’t have the blood testing opportunities that you have in the States.
The only evidence I have is anecdotal
I have been dosing 2-3 rapamycin tablets with grapefruit juice once a week without side effect.
My first attempt with sublingual rapamycin solution was with 3mg tablet extraction and I developed a mouth ulcer, and I never have mouth ulcers.
Hence I’ve scaled down my dose to 2mgs, I may try 3mgs again to see if I develop a mouth ulcer again

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#4

John,

Can I ask what your background is? It seems given your expertise in creating the sublingual rapamycin that you may be a chemist (i.e. and by that I mean training in Chemistry, not pharmacy). Is that correct?

#5

I’ve been in the pharmaceutical business for over 30 years, I’m retired now after being made redundant, the company I worked for moved its R&D down south.
Although I’ve been in the same job, I’ve dabbled in pretty much everything, computer programming, formulation, bio analysis (HPLC, GLC, mass spec, ELISA, simple chemistry, enzyme preparation etc.
I’ve worked primarily on diabetes and cholesterol. Towards the end of my career I’ve been proposing new drug targets and novel technologies.

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#6

John, it seems you have a great background for the type of things you are doing with rapamycin. I’m curious why you decided to try to make a sublingual version of rapamycin. What are the benefits of this delivery mechanism, from your point of view?

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#7

I have for years been taking rapamycin tablets with grapefruit juice but am unsure if the grapefruit juice is even working.

As I’m not able to get my blood sirolimus levels measured, I wanted to try and stack the odds in my favour in terms of getting good blood levels.

As a bit of a Gedankenexperiment I ran through a number of scenarios in my head. Sometimes answers just come to me which makes it hard to describe my process.

I thought what’s the best route of administration - i.v. but that didn’t appeal to me, but I knew I wanted a way of bypassing the GI tract with its many issues.

Then I learned about transcutol (on this forum) which was the key :key:

The sublingual veins interested me, as you can see how close to the surface they run, also I think it lacks a stratum corneum layer (can’t remember where I’ve read that ) which is the greatest barrier to transdermal transport.

However when you crush up a rapamycin tablet ready for dissolution your hit with the reality of how much of the pill is made up of excipient. Hence the extraction, which also allows me to make the dose volume really small (currently using 125ul) but I’m thinking of reducing that further still to get better absorption.

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#8

Oh - when you look at the tablet size and know that only 1mg is rapamycin, yes its pretty obvious that 99%+ is filler. But its cheap (from India) so I haven’t been concerned about the dosing of upwards of 12 tablets at once (I’ve also tried the grapefruit approach).

Did you consider either intramuscular or intra-nasal? Intramuscular (IM) + Intranasal (IN) Rapamycin - A new paradigm for human longevity translation

#9

I did briefly consider them, but must admit I’m biased towards oral and i.v with i.p a close third.

, it’s just that sublingual vein is so tempting. Personally I think it may be the closest thing to i.v dosing there is, given the use of small dose volumes, good penetration (don’t know what I would do without Transcutol)

People at work used to say you’ve spent too long in the job if your having a conversation with someone and your thinking ‘you’ve got really nice veins, I bet I could get a really nice blood sample out of you’. :man_vampire:

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