Having already written a little bit about the effects of food & how inhibiting drug-metabolizing enzymes can increase bioavailability, what remains is to discuss some more uncommon methods which might increase the bioavailability of orally-administered compounds. Of these, three are especially interesting:
1. Intestinal Permeation Enhancers.
I have written many times about chemical penetration enhancement for transdermal systems... But I may have neglected to mention that the same principles can also be applied to oral drug delivery. The mechanism of action is basically identical: Use chemicals to modulate intestinal cellular membranes and/or loosen/liquefy the tight junctures between intestinal epithelial cells. The former approach is better-suited to lipophilic drugs, whereas the latter appears to be preferable for hydrophilic drugs and small peptides, which are only rarely absorbed into cells.
Sodium caprate, a C10 fatty acid which can be isolated from coconut oil, is perhaps the best-known and most frequently studied intestinal permeation enhancer. It operates via both the transcellular and the paracellular routes, and has been shown to increase the bioavailability of compounds as wildly diverse as berberine (
ref), norfloaxin (
ref), the small polymer ardeparin (
ref), the anti-sense nucleotide
ISIS 104838 (
ref), and a plant polysacharride weighing ~3500da (
ref), among others. A short review can be found
here.
Despite its seemingly broad utility, sodium caprate is not very frequently used in commercial preparations. Like most compounds which modulate cell membranes, it compromises cell viability to some degree & may lead to cell death and gastrointestinal damage after extended periods of use.
There are many other intestinal permeation enhancers -- most of the effective ones are either sodium salts of medium-chain fatty acids (like s. caprate) or zwitterionic surfactants. Both 'flavors' are associated with some degree of gastrointestinal toxicity.
Interestingly (to me, anyway,) there are some claims that chemicals routinely used as transdermal permeation enhancers may also be effective as intestinal penetration enhancers. The manufacturer of "NexACT-88", an ages-old transdermal penetration enhancer, recently started making
claims that it is also useful for increasing oral drug bioavailability. They don't elucidate much, but it makes sense... Though toxicity may still be a major concern....
2. Nanoparticles.
In materials science, a 'nanoparticle' is any particle with a size of 1000nm or less. Pharmaceutical nanoparticles are drug particles with sizes in the 100-1000nm range -- but most typically between 200-600nm. Their large-scale production was invented in the mid 90's & is now used to process four currently-available FDA-approved drugs. (Rapamine, Emend, TriCor, and Megace ES.)
Nanoparticle formulation improves oral bioavailability by a very simple mechanism: Increased solubility & faster dissolution rate. The Ostwald–Freundlich/Kelvin equation essentially states that smaller particles are exposed to greater dissolution pressures in liquid media due to increased surface curvature; the Noyes–Whitney equation states that dissolution velocity rises with surface area. (One hundred 200nm particles has 10x more total surface area than ten 2microM particles, which itself has 10x more surface area than a single 20microM particle.) Improving solubility and dissolution time should greatly increase bioavailability --- and this certainly seems to be the case with nanoparticle drug formulations, which exhibit much better total bioavailability than their micronized counterparts. (Typically around +150-200%.) Tmax also plummets due to increased dissolution velocities & faster absorption.
Megace (Megestrol Acetate) is an especially interesting case. Check out
this study.
...When taken with food, both the nanoparticle and the micronized suspensions are fairly comparable. (The nanoparticle formulation was a little bit more effective, roughly around 50%.) But when taken on an empty stomach, the micronized suspension was effectively useless, whereas the nanoparticle suspension was still extremely effective. We can draw some conclusions from this re: increased aqueous solubility.
Another interesting thing: The nanoparticle suspension was used at 125mg/ml, whereas the micronized suspension was only at 40mg/ml... and yet the nanoparticle suspension was much less viscous, at 10 centipoise vs. 163 centipoise. The properties of nanoparticles in liquids are really incredible.
There are two methods of making nanoparticles, and this applies to metals and semiconductors as well as carbon-based drugs: "Top-down" & "bottom up." The top-down approach involves taking large particles and breaking them down with a mill or a piston; the bottom-up approach involves building nanoparticles from their constituent atoms --- where drugs are concerned, this tends to involve re-crystallizing them from a solution in very particular and painstaking ways. There are standardized, and patented, pharmaceutical approaches for both methods: NanoMorph®, IDD-P™, Dissocubes®, Nanopure®, NANOEDGE®, and others.
Though extremely useful, I think that nanoparticle formulations would be difficult for any supplement company to manufacture. Most of the effective and easy methods are patented; the milling machines required generate lots of heat, & they are also typically very large, expensive, and difficult to maintain/clean properly; lastly, all nano-milling processes are extremely time-consuming, as nanoparticles tend to agglomerate into larger particles as you mill them.
...Still interesting, though.
3. Cyclodextrin complexing.
This is a very popular method. Cyclodextins have been used in more drugs and household products than I care to mention. (Though usually under trade-names such as "Clenzaire".) A very capable expert by the name of Thorsteinn Loftsson has already summarized their properties and pharmaceutical uses
here and
here. Worth a read.
Where steroids, triterpenes, and other very lipophilic small molecules are concerned, there are essentially no drawbacks associated with cyclodextrin complexing. It's an excellent and highly useful method for their oral delivery, sublingual delivery, intranasal delivery, and for their transdermal delivery in aqueous systems... And while it can be expensive, it's still a lot cheaper than buying a nano-mill & safer than using intestinal permeation enhancers.
In a study which compared three different forms of the synthetic androgen Danazol -- nanocrystalline, danazol-
hydroxypropyl-β-cyclodextrin complex, and a regular micronized suspension -- the cyclodextrin complex was the most efficacious, with an absolute bioavailability of 106.7 ± 12.3%. The nanoparticles were a little bit less effective, at 82.3 ± 10.1%. The micronized suspension was no good at all, with only 5.1 ± 1.9% total bioavailability. Read the abstract
here... Then keep in mind that the dogs were
fasted, so these values would certainly be very different in 'fed' dogs. The micronized suspension would do much better, the nanoparticles would also be a bit more effective, and the cyclodextrin complex's bioavailability would probably remain unchanged.
Other studies abound.
Other methods:
--"Self-microemulsifying drug delivery systems" (SMEDDS) are 'wet' solvent/surfactant/oil-based systems for liquid orals or gelcaps. They are designed to emulsify completely upon contact with aqueous media, especially under conditions of heat and pressure. The fact that they tend to contain high concentrations of surfactants can be a problem -- for example, the Cremophor in Taxol® is known to cause allergic reactions. Systemic toxicity is a drawback also associated with the oral use of cosolvents such as propylene glycol... Then, furthermore, one must consider that chemical stability tends to be pretty low with these systems, that batch variation can be high, that shelf-life may be very short, and that they are also expensive to produce...
...Bioavailability doesn't seem to improve by enough to make it worth the trouble. All in all, microemulsions are a pretty ham-handed approach to improving drug bioavailability.
--Drugs can be loaded into mesoporous silicon particles -- nano-scale silicon honeycombs which are very stable and which can be filled with drug or nutrient molecules. This cyclodextrin-like method can presumably be applied to increase the oral bioavailability of large molecules such as peptides. A review of this method -- which is still in early/experimental stages -- can be found
here.
That's all that I know enough to write about. If anybody knows of any additional ways to increase the oral bioavailability of drugs and nutrients, I'd love to hear of 'em...!
Contact: info[at]antaeuslabs.com
-Jake
