Hi… Matt Kaeberlein regularly mentions that it is important that rapamycin has enteric coating. For example in his latest video (Youtube ID 0AdYtOvdVk8, time index 1:20:42). I switched brands recently, and my new sirolimus tablets (“SiroBoon”) to my surprise have a clear score line, suggesting it is permissible to split them up to fine-tune dosing. But doesn’t that mean that these pills have no enteric coating? Because splitting them up would supposedly render any coating useless, or doesn’t it? Can someone make sense of this? I had side effects in the area of the mouth after the first two times I took the new pills, so I think they are what they say they are and work. Thanks!
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From a RapAdmin post:
Avoid Siroboon - they are a small company with questionable quality control that has been widely discussed here (do a search on Siroboon on these forums if you want).
Zydus and Biocon are the best India-sourced brands for sirolimus, see these lab tests: Rapamycin / Sirolimus from India, Lab Test Report on Quality / Purity
Generally, see this thread: Generally Good Indian Pharma Companies
I think in general those on here report Siroboon has been problematic in getting into the blood system.
Any Siroboon users… comments?
Never have used… currently using Zydus.
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The generic manufacturing of sirolimus is exceptionally difficult. The original drug uses wet media milling to produce a nanocrystal coating on the tablet core — most people don’t grasp just how challenging that process is. To put it bluntly: even China’s generic sirolimus comes in capsule form instead. India’s Zydus tried to enter the Chinese market with their version and got rejected due to substandard manufacturing. Personally, I’d only recommend Indian generics for topical use. If cost is an issue, taking it with grapefruit juice can help boost bioavailability.
You should really read Bottle of Lies by Katherine Eban. It exposes the dark secrets and crazy truth behind Indian generic drugs. It’s mind-blowing.
Katherine Eban’s Bottle of Lies: The Inside Story of the Generic Drug Boom is a chilling recount of real-life events surrounding the rise of the generic drug industry. Split into seven multi-chapter parts, complete with a prologue and epilogue, the book follows Dinesh S. Thakur, an ex-Ranbaxy employee who became an infamous whistleblower uncovering the unsatisfactory manufacturing and operating standards of Indian generic drug companies. What started out as a great public health endeavor to increase equity for patients through affordable generic versions of brand name drugs quickly devolved into an opportunity for companies to maximize profits by providing lower quality drugs to the poorest patients.
During his employment at Ranbaxy, an Indian generic drug company, Dinesh Thakur witnessed pervasive deception and fraud; drugs went untested, data were falsified, and products that did not meet the quality standards of one country were shipped to less rigorous markets. Not only were resulting generics less efficacious than their brand name counterparts, but there were also differences between generics themselves. Furthermore, the FDA’s bioequivalence standard only considers the comparisons of peak drug concentrations and does not take into consideration the differences in release rates over time. In the US, physicians and patients were noticing that when patients who had previously been stable switched from brand name to certain generic drugs, their symptoms reappeared or worsened.
After leaving Ranbaxy, Thakur took it upon himself to reveal what he had become privy to during his time in India. The resulting litigation case spanned several years and faced countless hurdles. The FDA was under pressure to approve more generic drug applications and the Justice Department simply did not seem to prioritize the case. In the midst of this, Ranbaxy was approved to launch the highly sought-after atorvastatin, the first generic version of the cholesterol lowering drug Lipitor. As the best-selling prescription drug in world history, any delays in generic production would have been costly to the US government. Eventually, the Ranbaxy case concluded with a $500 million settlement, the largest settlement to date with a generic drug manufacturer. However, even today, there remains significant difficulty in regulating the quality of international drug markets.
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We’ve discussed that book many times on this site, and are well aware of these issues (which have also been discussed extensively by others, such as Peter Attia).
Re: using generic sirolimus out of India - let’s not lose perspective here. The first big concern is whether the sirolimus pill is correctly dosed with the active ingredient.
And as luck would have it, we can put the guns down - fortunately, that’s something you don’t have to guess at - you measure blood levels, duh. That is something you should do as a matter of course regardless of the origin of the pill. You must understand your levels so you can adjust your dose. That’s what I, for example, have been doing with both the generic sirolimus brands I purchased from India (Biocon and Zydus) from the moment I started taking it. I took multiple tests of both over a prolonged period of time and with a variety of dosages and timing. I still do tests every time I add any drug or adjust my stack. So I can see clearly (at least so far) that there is no issue with the presence of the active ingredient. The second issue is what else may be included in the pill as a result of manufacturing (impurities/contaminants) or constituent formulation (inactive ingredients). Both issues were discussed extensively here, including lab tests (that’s how the Siroboon sirolimus brand was found wanting).
The other point is that the original manufacturer of sirolimus in the US (Pfizer), stopped manufacturing their sirolimus brand. Since then, the sirolimus that is still being used in medical practice in the US, is actually an Indian generic (ref. Dr. Reddy) - and there have been no problems reported to the FDA or complaints - and used in trials/studies from compounding pharmacies. Given this track record, and my own tests, I have no hesitation in using rapamycin from the Indian manufacturer/marketer Biocon/Eris.
Finally, as Pfizer is no longer involved, you have no choice but to use a generic from India (if in the US) unless you want to inform all users in the US, including transplant patients, that they should no longer use their physician prescribed and FDA overseen Indian generic sirolimus except as a topical. As always, YMMV.
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Damn… makes me glad to be using prescription rapamycin. My Labcorp 4 month testing always comes off on target for dose 1 mg dose equals 3 ng/mL. My weekly dose 6mg is 18 ng/mL At 2 hours post dosing.
I mistakenly purchased Siroboon at one point as well. I was able to get blood test results comparable to 6mg of Zydus (based on reporting from others here, not my own bloodwork) by placing 15mg of Siroboon in enteric capsules.
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Thanks for your responses and references to other discussions. I really believe I had positive effects with SiroBoon on my tennis ellbow once (that was a 9 mg dose) and on pain/inflammation/arthritis from a previously broken toe (that was a 6 mg dose). And as I said I had side effects around the mouth twice, so I think I must have absorbed a proper dose.
My takeaway:
- SiroBoon is theoretically great because it’s cheap and available in higher doses per pill so that shipments from India or pills in travel baggage (with much fewer pills needed) still look like for personal consumption and not like you want to sell this stuff commercially.
- SiroBoon’s actually delivered dose can vary and for many users seems to be on the very low side, perhaps because the pills are not properly coated (the package says “film coated”), perhaps because of potency and/or quality issues.
I guess I will finish my SiroBoon enclosed in enteric capsules as well and then look elsewhere. ; (
What enteric capsules are you using?
I found some from an eBay shop that sells all kinds of empty capsules. Not sure if there are better sources. I tested them with my daily tadalafil and noticed the effect delayed by about five hours compared to no capsule.
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It does help to have a predictable dose from any particular supplier. I use a mix of Zydus and Biocon. Plus a standard red grapefruit.
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There are some unresolved issues here. Banded Rapamune is not enteric-coated. The FDA and DailyMed labels describe it as a film-coated tablet, and the excipient list is a sugar/film-coat system. There is no gastro-resistant enteric polymer (no methacrylic-acid copolymer, no cellulose acetate phthalate/HPMCP) anywhere in it. It appears that a score line tells you nothing about enteric status because there’s no enteric coat to disrupt.
Park Pharmaceuticals is not a small company but it is a generalist pharma plant that is not, on the face of it, equipped to manufacture the nanocrystal formulation standard for rapa. This might produce the erratic, batch-dependent bioavailability some are reporting here. Does anyone have any recent hard lab data on its effectiveness in terms of blood levels?
True. The enteric capsules are kind of a hack to get around the fact that Siroboon is made incorrectly. Not a great method, but can get some of the rapamycin effect while you wait for Zydus to arrive after a mistaken purchase.
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I found quite a few empty enteric on Amazon. Did you crush the Siroboon and put in s small capsule? It looks like you can purchase 00, 0, 1 sizes.
Also looks like a distinction between ‘Enteric’ and ‘Delayed Release’ withing the same brand. Any thoughts on which would optimize assimilation?
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I take Rapapro (sirolimus nanoparticles) 50 x 1mg Film coated., PROFOUND PRODUCTS, Made in India. Do you know if this product has been known to have the correct doseage? I’m new to Rapamycin so I’m not familiar with the previous discussions.
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That’s what I took before I switched to SiroBoon. Did you get it from theantiaging.store before they closed, or may I ask what your source is? I would guess that Rapapro is a good product because I got mouth ulcers from it twice when I started.
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I can’t access information to get beyond this but of relevance:
Claude
Sirolimus is the opposite of a conventional molecule: it’s the BCS Class II, effectively-insoluble macrolide whose reference product only works because Wyeth delivers it as an Elan nanocrystal nanodispersion. A general-purpose Baddi third-party manufacturer is precisely the profile least likely to possess wet-media nanomilling or nanodispersion-coating capability. My strong speculative read (flagged as such): Park is almost certainly making SiroBoon as an ordinary micronized-API wet-granulation or direct-compression tablet, with no attempt to reproduce the nanocrystal formulation — which would produce exactly the low, erratic, batch-dependent bioavailability the reviews describe, without the tablet necessarily being underdosed on paper. In other words, the corporate profile independently predicts the H2 (formulation/dissolution) failure mode I sketched last time, and predicts it more confidently than the raw anecdotes did.
Multiple Sources
Separate the API from the formulator. The active ingredient in a large share of Indian (and global) sirolimus is fermentation API from Concord Biotech — a Dholka-based, USFDA/EU-GMP/PMDA-inspected house that is the world’s largest fermentation immunosuppressant API maker, holds a US DMF for sirolimus, and supplies 250+ formulators across 70+ countries. The practical implication is that the molecule going into many different brands is often the same high-grade, regulator-inspected material — so the API is usually not the differentiator, and axis-A purity failures are less common than the community assumes. The variance lives downstream, in who presses it into a tablet and whether they reproduced Rapamune’s nanocrystal dissolution behavior. You are evaluating formulators, not molecules.
Multiple Sources
Zydus holds an actual US FDA-approved sirolimus ANDA (approved January 2014), and Dr. Reddy’s and Glenmark are also currently marketing FDA-approved generic sirolimus in the US. That means those specific formulations had to prove bioequivalence to Rapamune in a human PK study — regulator-verified formulation competence, not reputation. I was unable to find another India manufacturer that holds these certifications.
Several formulas I reviewed suggested that one (the average person?) might assimilate the same mount of active ingredient with 2-3x the dose of simple compressed tablets.
I may use some of my Park SiroBoon tablets but will order Zydus soon.
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FWIW, I have taken both Zydus and Biocon/Eris. As I regularly get blood tests for various reasons, I always include a sirolimus test. Consistently, after 6mg dose 50 hours later, the Biocon/Eris levels are substantially higher than the Zydus (5.6ng vs 4.5ng) - all measured by the same lab. This well over a one year period of time. I always take my rapamycin the same way (first thing in the morning, empty stomach, no food for 90+ minutes etc.) - so same protocol. So, while Zydus may be US FDA-approved, the Biocon/Eris gives me higher blood values. What to make of it? It’s possible that the Biocon/Eris contains more of the active ingredient sirolimus as a kind of safety margin? Or maybe the same protocol (empty stomach) works different with Zydus pills vs Biocon? IDK. And while it’s good that there is the presence of the active ingredient, both too little and too much compared to the stated dose are undesirable as it may indicate QC issues. Regardless, my approach is to go by my blood test results and not just by what it states on the label, that way at least I know what I’m getting. YMMV.
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After wading through several dozen pages on pharma manufacturing – all over my head – is is clear that one should test blood levels at least a few times to ensure that the target is being hit.
This journey into vats and soups also made clear the reasons for which your experience with Biocon has been more positive than with Zydus. It also illuminated the possibility of cramming raw pill pressed rapa into enteric capsules can be more or less effective, depending on other factors – again: blood tests.
The original patented nano formulation, now shared by Zydus and a few others is designed to capture the greatest portion of the aggregate human assimilation curve. The evidence shows that it does that well but not well enough for there to be no outliers, as in your case. It is also possible that Biocon is formulating a nano product, possibly just not certified in the same way as those I mentioned.
The one point that came up from multiple perspectives in that the individual differences in assimilation (NB: we have few here actually confirmed by controlled blood tests) is least likely to be due to product shortage or overage in the pill.
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Source? Please don’t tell me ‘‘Trust me bro’’.
You will definitely want to do your own work @Cole. Following are the websites I drilled down into over the course of 10 days or so. When you see conflicting information, keep cross-checking until you have a sense of preponderance. You will find the family of ANDA documents and, of course, the pharmacological methodologies and their relations to patents, to be especially helpful.
Have fun!
Primary source URLs:
https://www.accessdata.fda.gov/scripts/cder/ob/
https://www.accessdata.fda.gov/scripts/cder/daf/
https://www.accessdata.fda.gov/scripts/cder/psg/
https://www.cder.fda.gov/dissolution/
https://dailymed.nlm.nih.gov/
https://www.accessdata.fda.gov/scripts/cder/ndc/
https://datadashboard.fda.gov/
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters
https://www.accessdata.fda.gov/cms_ia/importalert_189.html
https://eudragmdp.ema.europa.eu/
https://extranet.who.int/prequal/
https://www.accessdata.fda.gov/scripts/cder/dmf/
https://www.edqm.eu/
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