Where I Left Off
In the last installment of my symlin saga, I had found that Symlin, Amlyn Pharmaceutical‘s synthetic amylin, helped slow gastric emptying and reduce post-prandial spikes. I also found that Symlin had to be injected subcutaneously, either with the Symlin Pen or from a second pump, and that allegedly, Symlin and insulin cannot be mixed. This segregationist statute comes from the fact that Symlin is manufactured at a pH of 4.0, and insulin runs at a pH of about 7.0 – 7.5. And, insulin being as finicky as it is, lowering the pH of of insulin too close to the isoelectric point drastically increases the risk that the insulin will precipitate and be insoluble, clogging up pumps and failing to absorb into the bloodstream.
Where I’m Going
But: Novolog, Novo Nordisk’s rapid-acting insulin, maintains a high degree of solubility even with a pH in the mid sixes. So the question that’s up next is, can the pH of Symlin be raised sufficiently such that the two solutions can remain soluble and effective while mixed in a single pump chamber?
The pH of Symlin
The first part of determining whether it is safe to alter the pH of Symlin is to determine why it is manufactured with such a low pH to begin with. Most insulins are made with a pH in the 7 range to ensure maximal solubility; is the same true for Symlin in the 4 range?
According to Amylin and research reported in “Kinetics of Pramlintide Degradation in Aqueous Solution as a Function of Temperature and pH,” the standard pH of Symlin has less to do with solubility of the peptide, and more to do with degradation over time. The isoelectric point of Symlin, as I mentioned in the last installment, is above 10.5, so Symlin has a lot of upward mobility before the molecules lose their charge and therefore motility.
However, the Symlin solution naturally degrades and becomes less potent over time, and this degradation happens at a rate that depends heavily on both storage temperature and pH. This particular study found that at a pH of 4.0, Symlin maintains potency for about two years at 5ºC (i.e., in a refrigerator) and for about one month at 25ºC (i.e., at room temperature). In contrast, at a pH of 5.0, the Symlin solution was found to degrade about three times faster. Similar results were published in a patent held by Amylin, in which the pH of 4.0 is selected as the most stable formulation of the solution, as, as the graph to the right shows, the rate of reaction increases rapidly with increasing pH.
But What About Me?
Clearly, for sale and commercialization of Symlin, long shelf life and solution stability is important. But I only need to the Symlin to maintain potency for as long as it lives in my pump plus the small amount of time it takes upon entering my body to be absorbed. So, thirty days at room temperature is probably more than I need. I could do with a week at room temperature, and that would still give me some wiggle room.
So let’s say– let’s say I mixed my Novolog and Symlin in a ratio that would be appropriate for my bolusing needs generally (that, of course, I would have to determine…), and added a weak base to raise the final pH of the solution to somewhere in the 6.5 – 7.0 range. Let’s say. Would I be able to get at least a week of solubility out of the insulin? And a week of potency out of the Symlin?
It certainly seems possible. And the reward if it works– the ability to use Symlin without separate injections or a second pump– is indeed tempting, enough that I will have to run at least a few tests to determine the feasibility of this.
Tests? Like, Human Tests?
Eventually, if everything goes as planned, I will have to try out any resulting mixture on myself, since I’m pretty sure it’s not legal to run ad hoc lab tests on pet store mice. That said, I’m certainly not going to just mix insulin and Symlin, load up my pump, and see what happens; a few test-tube trials are in order first.
My plan is to acquire some Symlin, some sodium acetate trihydrate (the weak base used to buffer and modify the pH of Symlin, according to Amylin’s documentation; fortunately, this is a standard sodium acetate, and even available from Amazon.com), and a pH meter. The pH meter may be a bit tricky, since meters with a decent level of accuracy are at least $100 (perhaps someone I know locally will have one to spare?). After I collect these materials, I will be able to mix and monitor the pH of various combinations and ratios.
I’ll keep my mixtures around for a while, and see if I get any obvious precipitation, clouding, or other corruption. Exact solubility and potency of each solution will be much harder to measure given my lack of lab equipment (anyone have a chromatograph I can borrow?), but… well… I’ll figure that one out when I get there.
Assuming any formulation of my mixture appears to maintain clarity for at least a week, and assuming I don’t get cold feet, I can consider moving on to stage two, where I become my own lab rat.
(Let me pause for a moment here and say: if you are a medical professional, Amylin employee, Novo Nordisk employee, or other knowledgeable party, and have reason to believe I might do some serious harm to myself, please, please, let me know.)
Why Hasn’t Anyone Else Done This Yet?
Now, that plan sounds pretty fun to me, but I must ask: if it’s so easy, why hasn’t someone done this? Why isn’t Amylin or Novo Nordisk all over this, marketing a mixable formulation? I have far too much faith in the power of the free market, human innovation, scientific inquiry, etc. etc. etc. to believe that no one’s thought of selling a mixable formulation!
And indeed, after some research, I found that as I suspected, Amylin and others are indeed all over this problem. On top of the studies mentioned earlier on mixing pramlintide and insulin, and on formulations of Symlin at different pHs, I came across a few patents that reassured me that my home-brew method will likely be made obsolete soon enough. Amylin Pharmaceuticals has a number of patents covering different formulations of pramlintide, one of which speaks specifically about solid formulations for pills, polymerized formulations for nasal or pulmonary delivery, and, most interesting for my purposes, formulations that were mixed with insulin and tested for solubility and potency. According to the tests cited in the patent, pramlintide was mixed with Regular insulin and alsp 70/30 Regular/NPH combinations. The resultant solutions had pHs in the upper-six to seven range, and, according to the cited tests, maintained insulin solubility for up to 33 days at 30[0][C]. Not bad! And, very promising for my upcoming home trials.
The obvious question is, why isn’t this on the market yet? And that I must admit I do not know; I don’t know enough about the pharmaceutical pipeline and FDA regulations to know what it takes for an idea, tests, and a patent to come to the shelves. (Any Amylin employees out there want to weigh in?)
More promising still, Amylin is not the only player in this game. In addition to patent applications for dual-chamber pumps, I came across a very interesting series of applications from Novo Nordisk for their own proprietary amylin agonist, and formulations based upon it. According to the application, their version of the peptide is more stable than Amylin’s version, with a longer action time in the body, and also reduced chance of degradation and fibrillation at higher pH levels. This allows for more easy mising with Novo Nordisk’s own insulins, and thus is a very promising prospect for us diabetics. The applications are from early 2009; so I’ll keep my eye out, but I certainly won’t hold my breath, given that the Patent Office and the FDA are two notoriously slow regulatory agencies standing in the way of any new drug.
To Be Continued
So, clearly, the free market is out there, working to create the next drug I will happily purchase, but until then, it looks like I’m on my own. I admit, part of me isn’t really disappointed; I’m pretty excited about my home-chemistry project. It’s been a while since I’ve gotten to play with pH buffering!
And One Last, Really Interesting but Only Tangentially Related Addendum
In the course of my patent search, I came across one other Amylin patent for Symlin uses that I found particularly notable: “Amylin agonist for treating depression, anxiety disorder and schizophrenia.” Apparently, Amylin Pharmaceuticals has found that
amylin is shown to share properties of anxiolytic, antidepressant, and antipsychotic agents in behavioral testing. Thus, it has now been discovered that amylin and amylin agonists may have the surprising ability to treat psychiatric disorders. Psychiatric disorders that can be treated include mood disorders, anxiety disorders, schizophrenia and other psychotic disorders, substance-related disorders, sleep disorders, somatoform disorders, and eating disorders. These compounds may be particularly effective in treating psychiatric disorders that have elements of metabolic disturbances, e.g., eating disorders, or in treating patients with a psychiatric disorder or those with a psychiatric disorder and who also suffer from a metabolic disturbance.
Allegedly, according to a number of animal tests that Amylin has done, amylin and amylin agonists like Symlin have been shown to reduce anxiety and stress, perhaps by modulating the corticotropin-releasing factor and glucocorticoid pathways. The pathways proposed in the patent are known to play a role in the intricate and delicate interactions of the hormones of the brain and endocrine system, stopping along the way at the hypothalamus and metabolic processing. Plus, unlike other psychiatric drugs out there, pramlintide tends to cause weight loss rather than weight gain, so that would be one less side effect to worry about.
Clearly, this has not been proven effective or commercialized yet, but it’s an interesting idea and an interesting read, especially if you, like me, are fascinated by the interdependencies of metabolism, endocrine hormones, inflammation, and various incarnations of depression and anxiety.
Please note: I am not a doctor, or a medical professional, or even a chemist. The above is intended to be purely informational, and is based on my own research; it has not been independently verified, and is not medical advice.
Fascinating — I have a bruise from a Symlin injection on my stomach, and am very interested to hear what happens with your experimentation.
Novo Nordisk has a habit of patenting many things but never commercializing them. In fact, Novo Nordisk has a patent (U.S. Patent #7317000 to be precise) for a type of “smart” insulin, even though another Massachusetts-based company (SmartCells, Inc., which announced a partnership with the JDRF’s IDDP program last fall for a similar but not identical patent, in this case U.S. Patent application #0040202719), whose patent is dated several years later, but is already further along in business development. My guess is that the company appears to patent even concepts they do not have very science to support with the… Read more »
Karmel, thanks for the very creative thinking around these issues. Hope your experiments are successful. Take good care!