Sublingual Drug Usage And Inactive Ingredients

When you have the option of taking a drug sublingually, does taking it in that fashion in any way dissolve away or lessen the impact of the inactive ingredients, rendering the intended drug effects more equal between brands?

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I'd also like to add whether the bioavailability of the drug between two brands becomes more identical when the drug is administered sublingually as opposed to swallowed.

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Hello Schleprock,

All routes of administration of the same dosage of a drug regardless of brand are required by the FDA to meet a standardized number of the active ingredient entering your blood stream. For example all generic versions of 100mg tylenol (acetaminophen), regardless of administration route, are required by the FDA to have +/- 20% of amount of acetaminophen in your blood stream as the tylenol brand does. The reason that generics offer a variety of administration options is for people who are unable to use a particular method.

This means that regardless of the administration or inactive ingredients there is still a FDA requirement that the same amount of the drug get into your blood stream as the brand name. So in a perfect world all brands/generics would be equal but where this falls short if that some people's body reacts better to certain inactive ingredients which understandably results in them forming opinions of which brand is the best. Some brands are touted as the best but really they only have the most tolerated ingredients among the general masses.

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Re: Kevin (# 2)

tl;dr; There are so many factors that go into the performance and therapeutic profile of a drug that there is no way to know for sure since each generic has its own separate and distinct ingredients. Even inactive ingredients have their own effects profile and can enhance or hinder the active ingredient, and have their own side effects. So it may reduce GI issues sublingually taken, but lessoning the impact of an inactive ingredient that aids the active one in crossing the blood brain barrier would only hinder therapeutics. Depends on which impact in particular. I have yet to come across a general rule of thumb that is true in most cases. Best guess is bioavailability would not change much, they were already within less than 5% difference (see more below) You probably mean bioequivalence: maybe yes/ maybe no. Or specifically therapeutic equivalence: hopefully, some generics suck. But by doing so hope that doesn't include making the name brand less effective for the generic to catch up.

@ Kevin - The +/- 20% blood concentration you mention isn't quite right. It's based on the Area Under the Curve (AUC) of the blood concentration of Active Pharmaceutical Ingredient (API) taken at set intervals. Then the ratio of the geometric mean of the AUC for the generic to the brand is calculated and that has to be +/- 20%. Also, the 90% Confidence Interval (CI) is calculated and the entire CI has to also be within +/-20%. What it actually comes down to is active ingredient blood concentration have been shown to almost always be between 2.5 and 5%. There is also Cmax which is the max API concentration and Tmax which is the time to Cmax which helps control the difference in AUC curves. A ton mor stats are calculated but those tend to be the most important.

I haven't seen it mentioned that the FDA requires bioequivalence regardless of administrative options. Quite the opposite actually. 2022 working guidelines stress following the manufacturer's instructions closely for comparison. Tylenol may have instructions for multiple administration options so then it may be required that different routs of administration be within the therapeutic range. But i don't see how you could expect the same formulary designed for a specific route to work the exact same for a different one. I suspect maybe the idea is tylenol pill, capsule, injection, oral solution etc. if they all stated 500mg as the basis would have therapeutically equivalent pk scores. If the bioavailability of the oral solution is 90% and the tablet 65%, to have the same blood concentration profiles the oral solution would need significantly less API. But may still be called 500mg solution because it's therapeutic equivalence. But, those 2 drug variations are considered different drugs and are treated as such when it comes to generic versions and bioequivalence testing.

@Schleprock and @Kevin The inactive ingredients (excipients) can have several functions. Some just bind stuff together so the pill doesn't fall apart. Others assist the med by changing gastrointestinal or urine ph to aid in absorption and reabsorption. Or help it through the first pass of the liver. Others may assist it through the blood brain barrier. Others lubricate things.

Also, excipients often have their own actual effects and side effects that may help and at times hinder the active ingredient. Or have completely unrelated side effects. Some excipients may also be stimulating themselves, compounding the stimulation of 1 generic over another. Many many many excipients to choose from with their own distinct and combinatory profiles.

FDA bioequivalence does not say anything for actual therapeutic equivalence, they just assume that it is. Blood concentration of 2 generics or brand name may be identical, but if 1, 90% gets through the blood brain barrier and the other 20%, that is a huge difference (made up example, don't have any actual stats for specific manufactures)

So excipients do have their function. Ones that affect gastrointestinal absorption or first pass through the liver may be rendered useless by under the tongue administration. If one that helps the active ingredients through the blood brain barrier for some reason doesn't get absorbed or gets transformed, then it would decrease the effectiveness.

So after all that, to answer Schleprock's 2 questions, the answer is unfortunately that it depends. Different manufacturers, different ingredients, different proportions of same ingredients, it all depends on the actual profile of each drug. I'd say best guess that inactive ingredients that get absorbed the oral route would likely get absorbed under the tongue most of the time (again, best guess). But ingredients that were not absorbed at that time if not spit out would likely be swallowed. Less concentrated than all at once swallowing the pill whole may cause less effects if sensitive to them and be more tolerable. GI side effects I would assume to be less. Therapeutic effects it is too hard to tell.

example, If a company uses cheaper ingredients and the result is a lower % of active ingredients is absorbed (bioavailability), they may have had to add more of the active ingredients to meet the bioequivalent profile. Higher % of API is absorbed sublingually and skips the first pass of the liver may mean that a drug that was lower in bioequivalence and/or bioavailability is now higher due to these factors. So, again it all depends on the individual and combined factors of each formulary ingredient as well as external factors of the individual taking the drug.

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Re: Kevin (# 2)

This is fascinating because this isn’t happening. The FDA isn’t even monitoring these generics to make sure that they are even within 20% of the strength of the name brand.

This isn’t happening anymore if it ever really did. I think it’s super cute that you think the FDA actually cares if our medication works. They don’t anymore.

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Re: Optimistic (# 4)

Part of the problem with the FDA is that they are underfunded and no way to monitor that much without proper funding. Even with better funding, they are not likely to be able to monitor everything. The FDA fact sheet would put that into perspective. over 272,000 FDA registered facilities around the world. Over 20,000 approved prescription drug products, Not even getting into non prescription products. They monitor 78% of the U.S. food supply and much much more.... https://www.fda.gov/about-fda/fda-basics/fact-sheet-fda-glance.

Plus, Republicans hate government and regulation. So they have limited what the FDA can actually do. Some things you would expect the FDA to do, they actually can't and are restricted. Like when Shire caused an adderall shortage many years ago by making more Vyvanse instead of giving the quota of amphetamines they were supposed to, to generic makes of Adderall. Forcing desperate people to switch to other drugs including their name brand Vyvanse, and name brand Adderall, the FDA couldn't do anything but complain publicly and watch them rake in the money while they blamed the DEA for not upping the quota of amphetamines they redirected.

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