Rapamycin and NanoCrystal Formulations

[RapAdmin]

I’ve been doing a little research on the whole issue of formulations of sirolimus / rapamycin using Elan pharmaceutical’s nanocrystal technology.

Here is what I’ve found:

NanoCrystals particles consist entirely of drug, thinly coated with a surface modifier to impart physical stability. NanoCrystals provide manufacturing and clinical performance advantages by eliminating the formulation problems usually associated with physical changes in drugs during micronization and formulation, thereby eliminating problems associated with loading and releasing drugs from delivery devices.

According to Elan, NanoCrystals benefit any drug formulation. Advantages include quicker onset of action, increased dose uniformity, fewer side effects, enhanced bioavailability, improved dose proportionality, elimination of food effects, more predictable therapeutic response, targeted delivery, improved safety, and greater efficacy.

So - what does the science say?

This study suggests:

Rapamune® (Wyeth) is a nanocrystalline-based formulation of the macrocyclic immunosuppressive drug sirolimus (rapamycin). It was the first nanocrystalline product to reach the market and is available in two formulations: oral suspension and tablets [10]. The product was developed using Elan’s NanoCrystal® technology in order to eliminate limitations related to the first commercially available formulation of sirolimus, which is a viscous oral solution of the drug in Phosal 50 PG and polysorbate 80. The lipid-based liquid solution needs to be refrigerated and protected from light upon storage, it is unpalatable and its dispensing protocol is complicated [66]. Rapamune® tablets, on the other hand, exhibited a 27% increase in the bioavailability of the drug compared to the lipid-based solution and their ease of administration contributes to enhanced patient adherence to medication [67].

[Note - this says above that they see a 27% increase in bioavailability compared to the liquid-based solution. No comment comparing it to other tablet based products like the generics from Zydus, Biocon, Dr. Reddy’s etc.]

They reference (for this above quote) this paper:
Merisko-Liversidge E. Nanosizing: ``End-to-End’’ Formulation Strategy for Poorly Water-Soluble Molecules. In: Templeton AC, Byrn SR, Haskell RJ, Prisinzano TE, editors. Discovery and Developing Molecules with Optimal Drug-Like Properties, New York, NY: Springer New York; 2015, p. 437–67. doi:10.1007/978-1-4939-1399-2_13.

where they state:

The biopharmaceutical performance value that particle size reduction can impart on a product is best illustrated by reference to the NanoCrystal products in the marketplace. The first NanoCrystal product that was launched was Rapamune, an immunosuppressive medication in tablet form, indicated for renal transplant patients (Shen and Wu 2007). The active ingredient, rapamycin (sirolimus), is a poorly watersoluble fermentation product (MW.914.17 g/mol). In accordance with the Biopharmaceutical Classification System (BCS) (Benet 2013), Rapamycin is a Class IV molecule, i.e., poorly soluble and poorly permeable. The product was initially launched as a liquid-lipid solution containing phosphatidylcholine, propylene glycol, monoglycerides, ethanol, soy fatty acids, ascorbyl palmitate and polysorbate 80, i.e., Phosal ®50® PS. This solution is stored refrigerated and has a rather elaborate procedure for dispensing and dosing. Conventional tableting approaches proved to be problematic and incompatible with the chemical stability of the molecule. However, with wet-media milling, rapamycin is fractured as a crystalline solid. Maintaining the molecule in a crystalline solid state during processing, improved chemical stability (Liversidge and Wei 2007) and provided opportunity for the product, by launching a tablet after liquid solution. In addition, the nanocrystalline tablet formulation prepared from a nanosuspension of rapamycin exhibited a 27 % improvement in bioavailability (Shen and Wu 2007). Although improved bioavailability was not a goal for the project, it was interesting to observe that when formulated using NanoCrystal technology, the nanosized formulation out-performed the liquid-lipid solution in terms of bioavailability, stability, and ease of administration.

I have yet to study all the papers - but it looks like a moderate improvement in bioavailability - but about the same level of improvement as taking rapamycin with a fatty meal, 20% to 30%. So - not a deal breaker, but interesting.

Given this statement above:

Conventional tableting approaches proved to be problematic and incompatible with the chemical stability of the molecule.

It would seem interesting to know the variations in bioavailability and performance (in terms of raising your blood/sirolimus levels, half life, etc.) of the different generic versions of rapamycin that are available - I wonder if any groups have ever done a head to head comparison.

Given the licensing costs of something like the Elan pharma nanocrystal technology - I’d actually be surprised if any of the generics have anything like it, as the focus in generic medications is always “cost”.

相关阅读：

Progress in the study of drug nanocrystals

Currently marketed pharmaceutical nanosuspension products

From: Emerging role of nanosuspensions in drug delivery systems

Trade name/Company	Drug	Dosage form/Route of administration	Nanosuspension method	Indication
Abraxane®/Abraxia Biosciences	Paclitaxel	Freeze-dried powder for injection/ Parenteral	nab™	Metastatic breast cancer
Cesamet®/Lilly	Nabilone	Capsule/Oral	Coprecipitation	Antiemetic
Emend®/Merck	Aprepiant	Capsule/Oral	Nanocrystal®Elan
Nanosystems	Antiemetic
Giris-PEG®/Novartis	Griseofulvin	Tablet/Oral	Coprecipittation	Antifungal
Invega Sustenna®/ Johnson & Johnson	Palperidone palmitate	Liquid nanosuspension/ Parenteral	High pressure homogenization	Schizophrenia
Megace ES®/Par Pharmaceutical Companies	Megestrol-acetate	Liquid nanosuspension/Oral	Nanocrystal®Elan Nanosystems Media milling	Anti-anorexic
Rapammune®/Wyeth	Sirolimus	Tablet/Oral	Nanocrystal®Elan Nanosystems	Immunosuppressant
Tricor®/Abbott	Fenofibrate	Tablet/Oral	Nanocrystal®Elan Nanosystems	Hypercholesterolemia
Triglide®/First Horizon Pharma	Fenofibrate	Tablet/Oral	IDD-P® Skyepharma	Hypercholesterolemia
Avinza®/King Pharmaceuticals	Morphine sulphate	Tablet/Oral	Nanocrystal®ElanNanosystems	Psychostimulant
Ritalin®/Novartis	Methyl Phenidate HCl	Tablet/Oral	Nanocrystal®ElanNanosystems	Muscle Relaxant
Zanaflex™/Acorda	Tizanidine HCl	Capsules/Oral	Nanocrystal®Elan Nanosystems	Muscle Relaxant
Focalin®XR/Novartis	Dexmethylphenidate hydrochloride	Tablet/Oral	Nanocrystal®ElanNanosystems	CNS Stimulant
Ostim®/Heraseus Kulzer EquivaBone®/Zimmer BiometOsSatura®/IsoTis Orthobiologics NanOss®/Rti Surgical	Hydroxyapatite	Paste/Injection	a	Bone substitute
Vitoss®/Stryker	Calcium phosphate	Foam packs, Foam strips/Injection	a	Bone substitute
Ryanodex®/Eagle Pharmaceuticals	Dantrolene sodium	Freeze-dried powder for injection/intravenous	a	Malignant hypothermia

The first five examples were manufactured using wet bead milling (Elan’s NanoCrystal® technology, now owned by Alkermes), while the last one uses high pressure homogenization (Skye Pharma’s IDD-P technology).

[pollux]

looks like some user reported the effectiveness of different brands.
https://forum.age-reversal.net/profile/q526x5

• [GEdwards]

Van Hi, tried Biocon india and was disappointed. Pfizer Sirolimus and the one Dr. Green sourced out of Kentucky work well! My severe hands arthritis respond to it, but Biocon… It took 12mgs to feel a positive effect that I get from three from pfizer branded. Cycled on and off Biocon… No bueno! Been on this stuff for three 1/2 years… Getting out from a hospital in MX at first then by prescription from Dr Green on early 2018.

• gedwards
• 1 yr ago
  Mark Thimineur Hi, the source of the ‘rapamycin’ I got was Biocon and I found that it did not appear to have the 1mg dose as stated simply from the reaction I get from my arthritis of my hands. To reach the equivalent of 2 1mg doses of Pfizer’s Rapamune obtained from a hospital pharmacy I had to take 6+ Biocon pills. Believe me, I would prefer to pay Biocon prices but I alternated between the two sources and every time got a low-to-no reaction from Biocon.

[RapAdmin]

@pollux

I titrate based on Rapamune via Pfizer and find Biocon to be ~15% the claimed dose!

Interesting - but I find this a hard to believe… would like to see a pre and post test of this using the LifeExtension blood sirolimus test… a subjective feeling of impact seems hard to measure. I don’t think I could do it.

But, from this and the lab testing results it does generally seem that the Biocon product is a little lower quality than some of the other products. Its hard to know how much, without lab testing from multiple batches.

[zmm]

based on all this, i wonder what the taking 6mg or rapamune with a fat source, would compare to taking a generic

[RapAdmin]

So - yes, I think what you meant to say would rapamune = generic + high fat meal, and that would seem to be the case given the details we have above.

I generally eat a can of sardines before I take my sirolimus anyway - so this information doesn’t change anything for me.

[zmm]

I am taking rapamune with a fat source. I am wondering what my dose of 6mg a week compares to when I see other people writing about much higher doses, but using a generic.

For example, Mikhail Blagosklonny is taking 20-22mg every other week. looking at his video, it appears he is taking a generic formulation, and I have no idea if he takes it will a fat source. I am wondering if we switched to rapamune with a fat source, what dose would he take.

[RapAdmin]

Ah - I thought you were on generic sirolimus. It seems that all things being equal that the rapamune with nanocrystal technology might be 20% to 30% better bioavailability - so adjust accordingly.

But - there is a lot of individual variability in terms of bioavailability and I suspect that may be a bigger effect than the nanocrystal technology, or fat / meal difference.

I’ve seen Blagosklonny’s posts and I think he usually takes rapamune, but he has commented at least once that his prescription was replaced with a generic.

Incidentally, if you look at the rapamycin clinical studies in healthy people page, there is a research paper at the bottom of the post that has the dose response / blood level of sirolimus in different people in the trial - as you can see, there is a huge variation in the blood levels of different people at the same dosing… so we need to optimize for our own biology, and not get too caught up in what other people are taking in terms of dose, though the higher doses may be a general indicator of tolerability.

Here is the graph:

[zmm]

he is clearly using generic

and this is rapamune

[pollux]

He was taking Rapamune in this video

Mikhail Blagosklonny

[zmm]

good catch

I just came across this publication after reading a comment that says that cbd increase rapamycin levels.
not sure how to interpret this for us

Cannabidiol Elevates Mechanistic Target of Rapamycin Inhibitor Levels in...

[RapAdmin]

Yes - this has been mentioned. I need to summarize this and create a list of the more common substances that can impact rapamycin use:

Supplement interactions w/ Rapamycin

Another one to add to the list, and one that’s proven to increase levels of rapamycin in human patients. CBD (cannibidiol):

The Key issue of Dosing Levels and Intervals for Best Rapamycin Outcomes

I’ve been taking 30mg of CBD for the past year and started rapamycin last month increasing now to 6 mg/week. Some research has been published showing that CBD increases the blood level of rapa similar to grapefruit–to the extent of 200% or more. But they don’t talk of how much CBD does this. Does anyone have any input on how much CBD is needed to have this effect? I’m a patient of Dr Green & he thinks 30mg of CBD is not a problem but he didn’t have any direct knowledge of the issue. Any feedback would be appreciated as I’d like to keep taking CBD but don’t want to overdose on rapa. Thanks Jim

and related info:

Can cannabis/weed be good for insulin sensitivity?

I don’t really like the cognitive effects [most of the time], but I microdose from time to time and use Kiva sleeping formulations to sleep. I also only use edibles.

[Ray]

Peter Attia’s podcast with Dr. Richard Miller (Interventions Testing Program) mentioned an issue with absorption of Rapamycin in mice. They had added Rapamycin to the mouse chow, but discovered that 97% of the drug was absorbed by the stomach acid. A coating was added to the medication so that it could be absorbed in the small intestine. Something as simple as different coatings on the pills could affect correct dosage. I’ve obtained Rapamycin capsules from a US based compounding pharmacy, Pfizer Rapamune tablets, and generic Rapa from a local pharmacy. I have not noticed a huge difference in the way each variation performs, but the only indications I have when on Rapa are the occasional mouth ulcer, and the acne pimples.

[zmm]

technically this question could be answered quickly. someone could take rapamune followed by a blood test, and then take a generic the following week and check again

[Dr_Spin]

Yes, you are very right! Has anyone done it?

Many thanks,
Dr. Spin