By: Lara Zibners, MD, MMEd, MBA

Women are:

• 51% of the population
• The majority of prescription drug users (QuickStats, MMWR, 2023)
• Almost always the medical decision maker for the family (US Dept of Labor)
• And, biologically speaking, the source of all men on the planet

However, women’s health has historically received less research and development investment relative to disease burden and healthcare utilization. A 2021 analysis of NIH funding patterns demonstrated that diseases affecting primarily women receive disproportionately less funding compared to those that affect primarily men. In fact, when funding is compared to disease burden, ma

le-dominated conditions get more while female-dominated ones receive less. (Mirin, 2021)

There is hope. Women’s health is having a “moment” and the number of startups, innovation pipelines and research dollars seem to be picking up pace. However, drug delivery specific to women remains a largely untapped space. Vaginal drug delivery is biologically rational but historically neglected, not because of any logical reason but because of societal taboos and a serious lack of imagination.

As the co-founder of a women’s healthcare company that has developed the proprietary Callavid® vaginal drug delivery platform, I believe it’s time to let our imaginations start running wild.

The Unmet Needs in Women’s Therapeutics

Before we dig into improved delivery methods, we need to acknowledge a more basic issue: women need more therapeutics in the first place. Persistent gaps exist across conditions that uniquely or disproportionally affect women. Gynecologic infections, endometriosis, the vaginal microbiome. Menopause, contraception, oncology. What exists today is a tangled web of a lack of R&D in novel therapeutics coupled with delivery challenges that hinder innovation.

Consider danazol, a drug that is extremely effective for endometriosis. When taken orally, however, androgenic side effects limit its utility. (Selak et al., 2000) Vaginal delivery is effective without those same side effects. But where is the incentive to invest in a new delivery mechanism of a generic medication? One has to wonder if the next generation of therapies for endometriosis has stalled not because of science, but because of economics.

The Oral Default Problem

Which brings us to a key issue in therapeutic innovation: the oral default.

When a new therapeutic emerges, the first question is almost always: oral or injectable? In reality, our pharmaceutical toolkit is much broader than that: intramuscular, subcutaneous, transdermal, nasal, buccal and more. The route matters. It influences pharmacokinetics, safety, efficacy and patient adherence.

Still, oral delivery remains the assumed standard. Patient surveys consistently show that people prefer pills to injections…even if the injection is less frequent. (Myers et al., 2024) Developers then make an understandable leap: patient preference translates into better adherence and real-world effectiveness. Those assumptions shape early drug development. (Stewart et al., 2016)

However, if oral drug delivery were really the optimal route always, drug delivery science would have ended decades ago. One milestone often cited in pharmaceutical history is the introduction of the tablet matrix system in the 1950’s, allowing for active pharmaceutical ingredients to be embedded within for controlled release.  (Banker & Anderson, 1958) That innovation transformed oral pharmacokinetics and spawned a generation of drugs well suited to oral delivery.

That was 1958.

It’s 2026. Time to expand our thinking.

Oral administration faces several well-known challenges. Hepatic first pass metabolism. GI transit variability. Enzymatic degradation. And, of course, systemic exposure for conditions that might benefit from local treated. Doses may need to increase to compensate for metabolic loss and that might mean more side effects. Meaning that dosage frequency and side effects may undermine the adherence benefits the oral drug was assumed to provide.

The Vaginal Route: Pharmacologically Elegant, Historically Neglected

Now let’s consider a different route.

The vagina is part of the mucosal immune system. It has a richly vascularized epithelium capable of absorbing many therapeutic agents. Importantly, the hepatic first-pass is avoided, improving bioavailability for certain compounds. (Hussain & Ahsan, 2005)

The vasculature of the vagina results in a “uterine” first-pass effect, whereby drugs preferentially distribute to uterine tissues before entering the systemic circulation. (de Ziegler et al., 1997) This phenomenon makes vaginal delivery particularly useful for conditions localized to reproductive organs.

That said, vaginal drug delivery is not limited to reproductive indications. Case reports have demonstrated effective systemic vaginal delivery of opioids and other drugs when oral delivery was not feasible. (Alexander et al., 2004) Evidence also suggests that steroid hormones may show improved metabolic stability due to avoidance of the hepatic first pass when given vaginally rather than orally. (Hussein & Ahsan, 2005)

Put together, the vaginal route offers several pharmacological advantages:

• avoidance of hepatic first-pass metabolism
• potential for lower-effective doses
• reduction of systemic side effects
• rapid mucosal absorption similar to nasal or buccal delivery

Research has also been done on vaginal administration of antiretroviral agents for both HIV prevention and treatment. Results indicate that both local tissue exposure and systemic absorption is possible. (Malcolm RK, 2014)

So why isn’t everyone pushing for vaginal delivery as topline? I’ll give you a hint: it’s not the pharmacology. Cultural stigma surrounding vaginal health remains surprisingly persistent, even in a scientific context. Investment in formulation science has historically been limited, leaving drug developers reliant on outdated delivery technologies with inconsistent PK profiles.

Legacy Formulations as a Barrier to Future Innovation

Traditional methods of vaginal drug delivery struggle due to inherent flaws. Gels, creams and suppositories commonly cause leakage. Formulations using a mucoadhesive to improve residence time have resulted in patient reports of an unpleasant residue. Leakage and uncertainty cause patient concern and affects acceptability. And as we’ve seen above, the perception of patient adherence has a strong effect at the very start of the innovation process. The uncertainty in dosage and exposure complicates clinical trial design as high variability complicates clear clinical endpoints.

Alternative methods such as rings and intrauterine devices are interesting developments but not appropriate for all drugs or indications. An intrauterine device to deliver progesterone is ideal for patients desiring contraception, not for those trying to conceive. Attempts to reach doses necessary for luteal phase support using a ring have failed to overcome regulatory and manufacturing hurdles. One example is the progesterone ring for luteal phase support, Milprosa, which ultimately faced challenges in approval and commercialization.

The lesson for our industry is that these failures reflect limitations in formulations, not any inherent flaw of the vaginal route of drug administration.

What a Modern Vaginal Drug Delivery Platform Needs to Get Right

If I could design a better way of delivering drugs vaginally, where would we begin? Funny you should ask. As co-founder of a company doing just that, we start by putting the patient front and center. Acceptability and adherence are critical determinants of real-world effectiveness of any therapeutic. A formulation that is effective but also non-messy, discreet and does not disrupt a woman’s daily life is not a “nice-to-have.” It should be the first consideration. Could you imagine if nasal fluticasone required patients to lie down for 30-60 minutes and even then, provided a continuous stream of discharge for hours after every dose? Not to be funny, but actually: yes, I’m being funny. It would be a non-starter. Why aren’t we demanding the same from vaginal therapeutics?

After patient usability, what else would we be looking for? Controlled and sustained release with predictable pharmacokinetics is one. Prolonged contact with the correct mucosa is another. The lower and upper portions of the vaginal canal differ in vascular supply and tissue characteristics, meaning precise localization can influence absorption and efficacy.

Finally, we need to be able to actually make the device. The ability to scale and commercially manufacture a technology requires consistency in order to meet regulatory requirements. Consistency translates directly into patient safety.

Right drug. Right dose. Right place. No mess. No anxiety. No wildly inconsistent pharmacokinetics. The ability to not just talk about it but to make it. None of those seem like such high hurdles to overcome. Ah ha, wait for it.

Innovating for a Solution

The concept for our Callavid® device seems simple and straightforward: a tampon scaffold that is adapted to the individual therapeutic so that drug is released consistently and only inactive ingredients are absorbed. The tampon is connected to a medical-grade sheath that protects the patient from contact with drug or vaginal mucosa. And finally, a small liner is connected to the other end of the sheath and remains external to the body. The liner not only absorbs any leakage that escapes the absorbent portion of the tampon but also provides a nice little “gift wrap” for the used device upon removal.

What sounds simple has taken years of development. Our Callavid® device is not a syringe or applicator. The tampon scaffold is adapted to every therapeutic in a bespoke manner. Device stability. Shelf stability. In vitro testing. Patient engagement. This isn’t a case of “whack some progesterone on a tampon and call it a day.” This is science with patients in mind.

Implications for Drug Developers: Strategic, Clinical, and Commercial

We don’t develop drugs; we “just” deliver them. For the drug developers out there, I would ask you to start considering the benefits to vaginal delivery of your products, both old and new. There is a clear clinical regulatory upside to medications that can be given at lower doses than necessary to overcome hepatic first-pass metabolism. This means an improved benefit-risk profile. Which, in turn, could mean smaller and faster clinical programs.

From a strategic perspective, there are currently thousands of pharmaceutical companies in the world, competing in increasingly competitive spaces. How can a company set themselves apart commercially? Consider delivery-enabled reformulation as a viable innovation strategy. Altering route and dose may mean a better patient experience and extended product life cycles. This strategy as a means of intellectual property extension is not without controversy, but from a pure business standpoint, it makes sense.

Vaginal drug delivery is a smart entry point into women’s health. Compared with brand new molecules, reformulation strategies offer reduced development timelines and lower capital risk. In addition, companies need to set themselves apart with clear, patient-centric value propositions.

Conclusion: the Vaginal Route is Ready. The Industry Just Needs to Catch Up

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?

Both traditional and novel therapeutics for women require delivery strategies that align with biology, not historical precedence. The vaginal route offers a rare combination of targeted local therapy, systemic potential and patient-centered administration. The team of scientists and engineers that I work with have toiled laboriously for the last several years to create a product that is scalable, predictable and commercially viable. Big Pharma is catching on, as we recently announced our first strategic collaboration with Merck KGaA. The industry credibility that came with that announcement didn’t change what the team is doing. It just confirmed the value proposition that we had already recognized. About to start our first in-woman trials for our progesterone product, the road ahead of us remains long but the direction is clear.

The science on vaginal drug delivery has been settled for years. What has shifted is that the push for better care for women has created a wind of change. With that wind, companies such as ours have a chance to provide a delivery technology that can finally catch up with the science.

References

Alexander NJ, et al. Why consider vaginal drug administration? Fertility & Sterility. 2004

Banker GS, Anderson NR. Tablets. In: Lachman L, Lieberman HA, Kanig JL (eds). The Theory and Practice of Industrial Pharmacy. 1958.

de Ziegler D, Bulletti C, De Monstier B, Jaaskelainen AS. The first uterine pass effect. Ann NY Acad Sci. 1997.

Hussain A, Ahsan F. The vagina as a route for systemic drug delivery. J Control Release. 2005.

Malcolm RK et al. Advances in microbicide vaginal rings. Antiviral Res. 2010.

Mirin AA. Gender disparities in the Funding of Diseases by the U.S. National Institutes of Health. J Women’s Health. 2021.

Myers JA et al. Preference for a Novel Oral Alternative to Parenterally Administered Medications. Patient Prefer Adherence. 2024.

Selak V et al. Danazol for pelvic pain associated with endometriosis. Cochrane Database Syst Rev. 2000.

Stewart KD et al. Preference for pharmaceutical formulation and treatment process attributes. Patient Prefer Adherence. 2016.

QuickStats: Percentage of adults using prescription drugs by sex. MMWR. 2023.

U.S. Department of Labor. Fact Sheet: General Facts about Women and Job Based Health. https://www.dol.gov/sites/dolgov/files/ebsa/about-ebsa/our-activities/resource-center/fact-sheets/women-health-care-jobs-fact-sheet.pdf (Accessed 16 March 2026)

Dr. Lara Zibners, MD, MMEd, MBA, is co-founder and Chairman of Calla Lily Clinical Care, a British women’s healthcare company transforming drug delivery for women. She is a board certified pediatric emergency medicine specialist, the national educator for ATLS-UK at the Royal College of Surgeons-England, as well as adjunct faculty at The Ohio State College of Medicine teaching an advanced competency in entrepreneurship in women’s health.