1.Rate of dissolution of capsule. Since we know roughly how long it takes before the capsule enters our gut, we can calculate how thick the capsule has to be.
a. Time capsule spend in the mouth is ??? //swallowing takes say 5secs???
b. Capsule will take 5-8secs to travel through the oesophagus
c. Capsule will be in the stomach for 3-4hours
d. When capsule is in the gut, this is when we hope the capsule has completely degraded
2. Obviously we also need to consider the pH.
a. Saliva, which is pH 7.4. The capsule will be subjected to digestion by the slightly alkaline saliva. Also present in the saliva are amylases, which will start digesting any starch.
b. This goes on in the oesophagus.
c. stomach acids, which is around pH 2 will start digesting our capsule. The capsule depending on the material, will either be degraded by the acid, or digestive enzymes in the stomach. Gelatinase will be present, and this degrades gelatine
d. finally, the capsule will reach the intestines. The proximal small intestine is around 6.6 whereas pH in the terminal ileum is around 7.5. The gut has pH 7 on average.
3. Points 1 and 2 allow us to calculate how thick the capsule has to be such that it can survive the initial part of digestion.
4. We must also ensure bacteria can survive in the capsule long enough for it to produce the target drug.
a. Conditions in the capsule in order to keep the bacteria alive must be considered.
b. Technique of freeze drying such that maximal survival rate is ensured. (or perhaps we would like the bacteria dead anyway)
5. Storage problems
6. Rate of release of targeted drug
a. We would like to minimise the initial burst, and try to achieve a slow release of drug
b. Initial burst is caused by heterogeneous drug distribution. This is caused by proteins that are either loosely associated with the surface or embedded in the surface layer
c. Microparticles produced at lower temperatures will be more porous due to delayed solidification and diffusion of aqueous phase into dispersed phase. Research has show that for PLGA matrix, 33c is the best temperature
7. Porosity and density must be considered, as they are related to rate of degradation of capsule
Killing the bacteria
1. pH -> pH in the gut might be high enough to dissolve the capsule. Stomach acid might be enough to kill the bacteria. But then again, this depends on whether we want the bacteria to still be alive when it goes into our gut, or not.
2. Might be a good idea to have a timer that is inducible by heat (will look into it), such that upon contact with the beginnings of our intestinal tract, it will be activated and kill the bacteria in 1hr.
3. We can also incorporate something like a timer to kill the bacteria after it has finished producing the targeted drug. (look into killing mechanisms)
4. Cell life/shelf life?