Vaginal Drug Delivery Beyond Gynecology: Let’s Think Outside “The Box”
Pun totally intended. Absolutely, 100% But go with me here. When you hear “vaginal drug delivery,” I’m guessing you think “reproductive medicine.” But there is increasing evidence that the vaginal route offers unique anatomical, physiological, and pharmacokinetic advantages that can be leveraged for systemic treatment of non-gynecological conditions. What’s that, you ask? Could women have secret weapon when it comes to their overall health? You betcha!
Why route matters
How you take a medication matters. The route can affect the efficacy, safety and patient compliance with any medication. Most of us just assume that oral (by mouth) drugs are best but that’s not necessarily true. Most common, yes. Best? The gastrointestinal tract, for all its popularity, is not always the most reliable collaborator—particularly for drugs that dislike enzymes, acids, or being metabolized before they’ve had a chance to do anything useful.
Drugs given orally risk being degraded in the GI tract, are subject to something called “the hepatic first-pass” effect and also depend on individual factors such as gut motility. For a breakdown on how GLP-1’s can affect how your body absorbs progesterone orally, see this article on “Ozempic babies and Menopause.”
Mucosal surfaces are often used as an alternative to oral delivery. Think allergy spray in your nose. Nitroglycerin spray under the tongue. And now think vaginal drug delivery. Traditionally, this route has been confined to gynecologic conditions. However, I’m going to argue that the relative scarcity of non-gynecological vaginal therapies appears to reflect a lack of imagination rather than a lack of feasibility.
Why the vagina
The vagina is not just an escape hatch for babies. It’s a highly vascularized (lots of blood flow) organ with a much larger surface area than your nostril and excellent at absorbing certain molecules. Any drug that is absorbed via a mucosal route avoids the dreaded hepatic first-pass, where the liver has a chance to break down a significant portion of many drugs before they get where they are trying to go. That means potentially better bioavailability at lower doses.
The vagina is a complex organ that has its very own microbiome and is also a very active immune center for the body. Full of immune cells, the vagina is part of the mucosal immune system which is different (yet complementary) from the systemic immune system. The gut is another example. It’s well established that “priming” the mucosal immune system of the gut can reduce food allergies by teaching the body not to react when it encounters an allergen via another route, such as on the skin.
Vaginal absorption can improve the performance of drugs that are poorly absorbed orally. Lower doses mean fewer side effects. Some drug delivery systems, such as rings, can avoid the need for daily dosing. In patients who have trouble swallowing, are prone to GI side effects or are on multiple medications, the vaginal route offers an alternative to popping piles of pills or dealing with nausea and vomiting. Add to that patient autonomy and privacy and it seems to be that the vagina has been way underestimated as a route for delivering many more therapeutics than many of us realize. It’s got great blood flow and is way more cooperative than the GI tract when it’s having a bad day.
There are some amazing graphs in Alexander et al (2004) showing the difference in blood levels of ethinyl estradiol when given orally, transdermally and vaginally. The oral formulation spikes up and down daily, the transdermal patch dips and rises with weekly patch changes and the vaginal route (via ring) just chugs along all merrily.
Now consider the possibilities
- Hormones & Endocrine therapies: evidence exists showing reliable systemic absorption and better metabolic stability of steroid hormones when delivered vaginally as opposed to orally. Yes, we are talking local estrogen replacement, progesterone delivery for pregnancy support and the like. But what about conditions like adrenal insufficiency or systemic menopausal replacement therapy? Even insulin has been shown to be absorbed through the vagina!
- Infectious Disease: the administration of antiretrovirals vaginally (to prevent HIV transmission) has been studied and the research shows the potential for systemic absorption. The added bonus is that you get local resistance as well.
- Pain management and neurological conditions: research has shown that the vaginal delivery of some analgesics is not only effective but may show a benefit when given vaginally because they exhibit a steadier systemic concentration. The added bonus is that when your migraine makes you nauseous, you don’t have to try and keep down an oral medication.
- Vaccines and immunotherapy: lots of research has gone into the mucosal administration of vaccines (think Flumist) which provide not only the same immune response systemically as an injection but a mucosal one as well, giving you added protection at the point of entry.
The Challenge Within
Probably the biggest barrier to convincing regulators, clinicians and patients alike that the vaginal route is a superior alternative for some drugs is not a scientific challenge, it’s a collective failure of the imagination. There has been a quiet assumption that this route if “niche” by default. No one thinks twice about spraying a medication up the nose or placing it under the tongue. But vaginally?
That’s not to say this route isn’t without inherent challenges. Individual variability, the role of the microbiome, love making in the afternoon and the menstrual cycle are all potential sources of variability in systemic absorption. One of the biggest challenges may be in how we actually get the drugs up there. That’s the one that the team at @calla is trying to tackle. A hygienic, leak-free platform for vaginal drug delivery. For just about anything.
References
https://www.sciencedirect.com/science/article/abs/pii/S0168365904006297?via%3Dihub
https://www.fertstert.org/article/S0015-0282(04)00509-6/fulltext
https://pubmed.ncbi.nlm.nih.gov/25335842/
