Time Release Systems - Subcutaneous and Oral
So, I can see a number of applications for subcutaneous time release systems for various molecules. NGF is one example. There are a number of drugs that are administered this way so I've been looking into how the "time release" function is achieved. Examples include:
Olanzapine Pamoate has very poor water solubility and thus can be injected every few weeks. It simply goes into solution very slowly due to its structure.
Another method is esterification of a parent drug to a long chain fatty acid. An example of this is Haloperidol Decanoate. Decanoic acid is bound to haloperidol which limits the rate of release to the speed of hydrolization splitting the molecules apart.
Microsphere Polymers are sometimes used. The drug is contained between the microspheres, which limits the release of the drug based on the speed of diffusion through the structure formed. An example of a drug using this system is Eligard which treats prostate cancer.
Finally, there are suspensions. These seem to consist of a lipid, non-lipid, and an acid. Examples include depo shots and the like.
Unfortunately, none of these methods are really available to us except in specific cases where something has already been developed as a drug. So for my example substance, NGF, I wouldn't be willing to try to put it into suspension or bind it to a lipid chain because I may break down the relatively delicate compound.. or have it release all at once... etc. A microsphere polymer system is a possibility but any that has been developed specifical for such a purpose is locked down as proprietary and second we'd still need to work out and test the diffusion rates and release. This is something that someone may want to make a project out of at some point.
I've set my objective rather lower than achieving a multi-week all-purpose subcutaneous time release system. If we can find a safe and dependable method of time release that lasts even as little as 24 to 72 hours, we'd still be able to add excipient materials to implants that serve functions like increasing healing rate, limiting inflammation, anti-biotic function, and enhancing things like neurogenesis.
I've been looking at methods used in oral time release systems for this. Often, oral meds are released over a time as long as 12 hours. The main limitation is after a certain period of time, the unit moves out of the absorbing portions of the GI system. If injected subcutaneously, this limitation wouldn't matter. The absorption would be far quicker than the methods described above but I think that I could hit the 72 hour mark.
So, one way oral medicaions are made into time release formulatons is with Cellulose or cellulose derivatives such as methyl cellulose or carboxymethyl cellulose. Another additive used at times is Xanthan Gum. A pretty good paper on making metoprolol time release using these substances is here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663665/
Another good paper to take a look at: http://www.ncbi.nlm.nih.gov/pubmed/23627242
The calculations don't really apply here though seeing as though we are comparing subcutaneous and oral. Ok, so the cool part about finding these papers is that we can take nearly any nootropic or the like and make it time release. Many of the racetams have very short durations of action so this could be rather valuable. In fact, I almost think we that we could monetize on this if anyone wants to make a line of time release yaddah yaddah (hit me up. :))
Beyond this though, these substances are for the most part safe and should be viable either injectable or usable as a coating.... I think. Ok, so I haven't yet been able to get: Tissue biocompatibility of cellulose and its derivatives,(Takeaki ). I'll have it tommorow or so.
http://onlinelibrary.wiley.com/doi/10.1002/jbm.a.30570/abstract?deniedAccessCustomisedMessage=&userIsAuthenticated=falseIn vivo biocompatibility of bacterial cellulose. This makes it seem just fine though.
http://www.sciencedirect.com/science/article/pii/S0142961201001521 As does this one, with some other rather interesting factors that warrant attention in other possible projects.
Here are my concerns: If administered subcutaneously, the cellulose compound may simply remain rather inert and not significantly release a compound at all or breakdown rapidly enough... or perhaps release it faster than breakdown through diffusion through the material. Another concern is accidental IV administration.. it's important to note that while I'm researching subcutaneous safety... my ideas here can't be generalized to include IM or IV. Both of these have had research contraindicating administration... hemolysis and necrosis are bad stuff.
I'm going to try a few different recipes I've found and play with texure/viscocity etc. Im going to play with dehydration and rehydration of these compounds. I'm going to use color indicators to determine how quickly the release occurs in 0.9% saline... and then I'm going to inject a few cc's and see how it works out. Any comments? Ideas? Concerns?
Comments
the oral time release...think something like this would work for short durations? http://www.wikihow.com/Make-Jawbreakers
http://en.m.wikipedia.org/wiki/Nexplanon
Replicating this with a nootropic is something I've wanted to do for a while.