FWIW
I have used it topical, orally and by IV on more than one occasion.
Review;
“Dimethyl Sulfoxide (DMSO) in Trauma and Disease” by Stanley W. Jacob
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@rapadmin Thanks for the reference.
@Joseph Thank you for the DSMO study and being an oral/IV DSMO guinea pig.
“Intranasal delivery means rapid, noninvasive access to the brain enabling numerous
novel therapies. However, this is not a panacea, and careful optimization will be needed
for any of these new treatments to reach patients. A major factor will be the formulations
and devices described in this article.”
ok expected that
Some “engineering” parameters to consider.
“Hydrophobic and charged hydrophilic molecules have been shown to diffuse poorly through mucus, whereas uncharged hydrophilic molecules are able to diffuse rapidly through the mesh of mucins nearly the speed of water for smaller molecules. Drugs larger than 500 Da in size will be especially prone to poor mucus diffusion and becoming stuck, though most drugs will be smaller than 500 Da in size, thus it is not an important issue. Optimizing a formulation to maximize crossing into the lamina propria will be crucial for any therapy. This size limit is not entirely inhibiting though, as molecules as large as wheat germ agglutinin–horseradish peroxidase (80 kDa) and even whole stem cells have been transported to some degree. Nonpolar compounds are thought to be transported poorly to the CNS intranasally, though there is a growly body of evidence that the proper microemulsion formulation can greatly increase the intranasal brain area under curve (AUC) compared to IV administration of the compound. Indeed, there is evidence that with some drugs increasing the hydrophobicity can increase delivery to the CNS. It is known that hydrophobic compounds cross biological membranes such as the nasal epithelia, blood vessels, or BBB well. This shows that not only are hydrophobic drugs capable of being administered intranasally with the correct formulation, but this may be an advantage. Often, researchers are administering doses as low as 25 µL but usually closer to 200 µL in size in these experiments; a size selected because this is the maximum volume of the nasal cavity in the model rodents. In humans, the nasal cavity is 6–7 mL in volume, which is impractical at best. Furthermore, 50% of the rodent nasal cavity is covered in olfactory epithelia, compared to <5% in humans. This limitation in area will make delivery to the CNS less efficient and adds emphasis on making sure administered drugs reach the correct region of the nasal cavity. Intranasal administration devices are another compelling strategy that will find a role in the clinical use of intranasal drugs. Recall that the olfactory region is <10% of the entire nasal cavity and located on the superior aspect as well as the rapid mucus clearance in the motile respiratory regions. Traditional spray pumps tend to only reach the anterior and lateral aspects of the nasal cavity, with <3% of the dose reaching the olfactory region.”
Rapamycin is both hydrophobic and a HUGE molecule…26,000 Da. But clearly in the study, no problem getting into the brain. Intranasal bypasses the entire gastric pathway, degradation loss, the massive system dose (and unwanted peripheral side effects) needed for therapeutic brain Rapamycin levels.
In the study, they used “InRapa” by Pfizer. I could not find “InRapa”, is this the same as their oral solution?
https://www.pfizermedicalinformation.com/en-us/rapamune/principal-display
“The treatment was conducted 3 times per week, with a dose of 0.1 μg/μl of rapamycin solution or vehicle in 10 μl (1 μg/mouse) for 90 days total”. 6 mice were treated by single intranasal delivery of rapamycin, with the dose of 1 μg/mouse (0.05 mg/Kg/mouse)"
Based on the 1 ug/ul reference, this is the same as 1mg/ml oral Rapamycin solution, so I am assuming same.
That’s a super lower dose intransal to get large brain Rapamycin levels! Consider in some of the mice longevity studies, oral dose 2.25 mg/kg to 8 mg/kg. "To note, InRapa dose is about 50-times lower than i.p injection dose"
“Collectively, our data demonstrate that rapamycin delivered by intranasal route reached a therapeutic brain concentration comparable to that obtained by i.p. injection but with an extremely lower distribution at plasma level. Therefore, these results, coupled with the analysis by WB of mTOR inhibition in liver and heart tissue, which showed no changes between Ts65Dn rapamycin and vehicle treated groups”
“Overall, our data show that intranasal delivery of the mTOR inhibitor rapamycin was able to target and modulate mTOR kinase activity in the hippocampus. Our analysis of mTORC2 activity, indexed by phosphorylation of mTOR at Ser2481, show no alteration between Eu and Ts65Dn mice either with or without InRapa administration (supporting the low sensitivity of mTORC2 to rapamycin treatment”
Notice the 0.2 ug/uLdid not reduce pMTOR more than the 0.1 ug/uL.
Converting 0.05 mg/kg mouse to HED = 0.29mg @ 70 kg human (if oral or ip is equivalent to intranasal)
I think I won’t reinvent the wheel, make up a DSMO/water/Rapamycin powder solution and find a good intranasal device to deliver where it needs to go.
Now the black hole…qty, dose, and what the heck am I measuring as response?
Maybe will circle back and review some of those online tools…do some baselining, then re-test.
My solution/mix
DMSO
Rapamycin
Saline
Final solution
1% DMSO,
Rapamycin at 1mg per ml,
each spray delivers 1mg of the solution = to 1mg of rapamycin
1mg in each nostril
@joseph You posted this elsewhere
"Dissolve the rapamycin in the DMSO first, then reduce to 50 to 70% {this is the best absorption % through the skin] Higher % of DMSO on skin is not absorbed well and on most people will burn/irritate are. Rapamycin dissolves in DMSO at 200g per ml. The solubility of rapamycin in 50/50 DMSO/water, as used in osmotic pumps, is about 0.5 mg/mL at ambient temperature.”
Re saline, off the shelf saline? I could buy some bulk saline, and then a fancy smaller saline spray to hijack the sprayer, or look for a more highly engineered sprayer.
Dilute the rapamycin/DSMO bulk mix down to 1% DSMO using saline to get 1mg Rapamycin/ml solution?
I think you asked me where I got the powder?
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MAC:
Re: The Rapamycin Store:
They are now pushing transdermal cream. Their prices seem very reasonable.
Paying by Bitcoin is a bit sketchy right now. I do have a Coinbase account.
Have you ordered anything recently?
Re: nasal spray:
Do you really think the saline is necessary?
Does it actually add anything over distilled water?
Not recently but I think they are legit.
Don’t know, for hermetic reasons since I might be making 1-2 months worth, keep it bacterial safe? I could make my own saline with distilled. Probably not materially important for this endeavour.
Mac
I am sorry, I was just lazy and thought maybe there was something you knew so that I wouldn’t have to look it up.
Apparently, a saline solution has no anti-bacterial properties. DMSO in concentrations over 15% is anti-microbial. Additionally, distilled water has less surface tension than salt water. So, in brief, I won’t be using anything but DMSO, distilled water, and rapamycin, unless someone can point out the benefit of using a saline solution.
“A study has been made of the antimicrobial activity of dimethyl sulfoxide (DMSO) against three organisms, Escherichia coli, Pseudomonas aeruginosa, and Bacillus megaterium. Growth was inhibited by increasing DMSO levels and was virtually eliminated for each of the species at approximately 15% DMSO.”
Antimicrobial Activity of Dimethyl Sulfoxide Against Escherichia coli, Pseudomonas aeruginosa, and Bacillus megaterium - ScienceDirect.
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The study referenced saline in the vehicle, so just telegraphed. Thanks for this information.
Wow, DSMO is regulated in Canada, need a script? Ordered through my Amazon US account, ships to Canada, back door. Will go with distilled water as well.
@desertshores are you good with putting some of this DSMO into the brain??
Will keep you posted.
Saline, 0.9 % standard IV saline
I recommend you download the PDF copy of the book I posted, and review.
Dimethyl Sulfoxide (DMSO) in Trauma and Disease” by Stanley W. Jacob
See link in post above.
This is a medical book not a consumer book.
Medical metered spray bottles are commercial available, supplies from a compounding pharmacy.
There are forum members here who are pharmacist, mybe could add to this thread.
I would mix as follows
Assayed grade rapamycin to Pharmaclocigal grad DMSO till totally dissolved.
As a reference 200mg of rapamycin will dissolve in 1ml of DMSO
Then dilute to 1% using standard saline 0.9%
You have to calculate the dose of rapamycin you want per ml deliver sprayer.
In my view I would use 1mg per ml of raperymicin in a 1% DMSO from a nasal sprayer that would deliver 1ml per squeeze.
You get 1mg of rapamycin per ml from each squeeze, 1 squeeze up each nostril would be 2mg of rapamycin.
The laboratory supply company mentioned by RapAdim several times sells Rapamycin, >99% with Certificate of Analysis. They do not sell to individual as RapAdim has stated.
We have a Skunk Works!
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I read briefly through the book mostly looking for toxicology/safety.
Will investigate spray/misters some more.
How much volume of liquid do you think should be sprayed per pump into a nostril? Want to cover the key uptake cells but not have any spillover/dripping?
Or do full headstand or tilt head back 90 degrees after application to allow for diffusion!
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Yes, squirting DMSO up your nose would certainly be scary at this time and I wouldn’t recommend it.
Most of you are not old enough to remember the DMSO craze of the hippy era. Everybody was using it for arthritic pain etc. Then the government temporarily banned it and all kinds of conspiracy theories evolved.
However, I have found the following mentions:
“It also has a calming effect on the central nervous system and it reaches all areas of the body, when absorbed through the skin, including the brain”
So, I don’t think you have to squirt it up your nose to get into your brain.
I have changed my mind and don’t personally plan to do it.
“If you have dirt or anything else on your hands and /or skin, DMSO will take it down to your deep tissue, as far as to the seventh layer into the dermis”
“The clinical use of pharmaceutical-grade DMSO as a penetration enhancer is supported by the robust data that have accumulated over the past 3 decades demonstrating the favorable safety and tolerability profile. Dimethyl sulfoxide is a safe and effective mechanism for facilitating the transdermal delivery of both hydrophilic and lipophilic medications to provide localized drug delivery.”
A number of other compounds have been identified as enhancers.
Dimethylsulfoxide (DMSO), the archetypical enhancer, exemplifies the
effects that can be achieved ( Fig. 124.6 ). As with ethanol and propylene
glycol, both C v and K m are affected. Because DMSO is a superb solvent,
higher drug concentrations can be achieved than with other solvents,
but it also expands the stratum corneum barrier, permitting increased
drug uptake and possibly an increased rate of diffusion ( D) through the
barrier. However, the use of powerful enhancers such as DMSO is
constrained by excessive skin irritation or toxicity 41.
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Transcutol us the most common absorptive chemical used for dermatology i think…
Would that work here? I have links to the papers in the skin and hair thread.
Even a solution at 1% DSMO?
Better solubilizer that can absorb Rapamycin and dissolve in water? @rapadmin mentioned transcutol?
Seems safe, used as food additive.
From manufacturer web site;
“Soluble in DMSO at 200 mg/mL; soluble in ethanol at 50 mg/mL; very poorly soluble in water; maximum solubility in plain water is estimated to be about 5-20 µM; buffers, serum, or other additives may increase or decrease the aqueous solubility.”
Ok, looks like it’s either DSMO/water or Transcutol (Diethylene glycol monoethyl ether). Both appear to have good toxicology re system absorption, and Transcutol is a food additive.
For Transcutol, water is a very poor cosolvent with Rapamycin, so would be used at 100%.
@joseph votes DSMO 1%/water and @desertshores A no for DSMO, but what about 1% DSMO in water?
Anyone else?
Solubilization of rapamycin
https://sci-hub.se/10.1016/s0378-5173(00)00617-7
In the mice study, nasal dose is 50X lower than ip injection dose. So assuming 2mg nasal full absorption, that could be a massive oral equivalency dose.
I would have to do some more dosing equivalency (look at ip injection vs oral mice) and calibrate the mister, titrate from low and work up.
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Thanks for the info.
At this point, I think I will wait for further developments. I have no relatives, living or dead, that I know of, that suffer or have suffered from dementia or Alzheimer’s, so putting rapamycin up my nose is not a high priority at this time.
Unfortunately, DMSO is a two-edged sword.
I consider it relatively safe as it is being used as a carrier for some medications.
And, I like it because, unlike most other solvents, it will carry rapamycin beyond the first layers of skin.
Having said that, it may also carry contaminants that are on your skin or in the medication you are using.
I have not been able to obtain pure rapamycin powder at this time so I don’t know what additives or contaminants are in the pills that I am crushing to get the powder. Zydus and Rapacon both contain titanium dioxide and some other fillers.
I have used a mixture of 50/50 DMSO and water mixed with 20mg. of rapamycin on my skin. I am going to discontinue doing this for the time being.
This has been debated before so I don’t want to debate it again, but I believe high doses of rapamycin, 10 - 20 mg, with grapefruit juice pass the blood-brain barrier.
So, I will continue with this as an alternative to spraying rapamycin up my nose.
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Thank you for your experienced comments, duly noted.
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