Scientists have created a reversible contraceptive microneedle patch that is able to slowly release the hormone levonorgestrel, through the skin. The study was published November 6, 2019, in Science Advances.
Levonorgestrel is a synthetic progestogen used in contraception and hormone therapy. It was initially granted US approval by the Food and Drug Administration (FDA) in 1982. Globally, it is the most commonly used emergency contraceptive. In addition to its above use, it is also used as a hormonal contraceptive released from an IUD and can be used as part of a combination contraceptives. [LM1]
Unlike most microneedle patches, which are designed for fast drug release, this patch was required to release the hormonal contraceptive over a longer duration – presenting the team with two challenges.
Firstly, the microneedles would need to be designed to use a non-water-soluble formulation, to prevent fast release, and ensure enough drug would last the required duration (long-acting). Secondly, to avoid the user having to wear the patch over the duration of drug release, the microneedles would need to be biodegradable and have the ability to separate from the backing once embedded in the skin.
Designing and applying the patch
The patch includes a novel effervescent or “fizzy” backing and an array of microneedles. The biodegradable polymer used to create the microneedles is called poly(lactic-co-glycolic) acid or “PLGA” was chosen due to its excellent safety profile and recognized use in many pharmaceutical and medical products.
By manually applying pressure to the patch on the surface of the skin, the microneedles can (painlessly) penetrate and release the hormone into the upper layers of the skin.
Once placed on the skin the backing separates from the microneedles – leaving them to biodegrade as they release the contraceptive hormone underneath the skin over the course of one month. The backing separation is achieved through its contact with interstitial fluid (ISF) in the skin. Sodium bicarbonate and citric acid present within the patch backing react to form carbon dioxide bubbles that weaken the microneedle–backing “bond”, resulting in separation within one minute.
Testing the patch
To investigate the pharmacokinetics of levonorgestrel the team administered a levonorgestrel-loaded microneedle patch to rodents. The hormone’s plasma concentration gradually decreased, but remained above the human therapeutic threshold level (0.2 ng/ml) for more than 30 days.
Observation of the rodents revealed no erythema, edema, or other signs of irritation during the 60-day study. In addition, histological analysis of the skin treated with the patch did not indicate any changes in skin or tissue damage.
Needle discomfort, patch tolerability and backing separation were then tested in human participants, more specifically women of reproductive age. The patches used in the human study were placebo-loaded and contained no levonorgestrel. In addition, the microneedles were designed using water-soluble excipients (i.e., PVA and sucrose) rather than PGLA. However, the effervescent patch backing formulation was consistent throughout both preclinical and clinical studies.
“The active patch was not administered to human participants, who were only tested with placebo patches. The pharmacological profile of the device was only tested in mice and may not be completely translatable to humans,” cautions Alex Polyakov, Consultant Obstetrician, Gynecologist and Fertility Specialist at the Reproductive Biology Unit at the Royal Women's Hospital in Melbourne.
Good separation of microneedles was observed, with 92% of needles separated from the backing within the wear time of less than one minute. All participants reported either “no pain” or “slight pain” that was much less than that caused by a conventional hypodermic injection. No tenderness or swelling was observed at the patch application site at any time.
A closer look at limitations and future considerations
“It must be pointed out that the authors did not invent a new contraceptive drug, but rather used a very old one in a novel application device. While levonorgestrel has a very good safety and effectiveness record, it has certain side effects that are also well recognized and which are likely to be unaffected by the new administration process,” says Polyakov.
“Two of the most bothersome side-effects of levonorgestrel-containing long term contraceptives are irregular bleeding and undesired psychological effects,” he adds.
One hundred percent of participants said they would prefer the monthly microneedle patch compared to a monthly hypodermic injection, whereas 90% said they would favor the patch over a daily contraceptive pill.
Gino Pecoraro also provided expert comment on the findings: “Patient acceptability across multiple continents was high and women reported liking the idea of self-administration of long-acting reversible contraceptives without need for doctor visits, invasive injections, implants or IUD insertions. A number reported a preference for longer acting (3- or 6-month patches) and this needs further study as does contraceptive efficacy and cost.”
“If successful, this delivery system can be expanded for many more drugs (not just hormones) and is certainly worthy of further development," Pecoraro concludes.
Reference: Li, et al. (2019) Long-acting reversible contraception by effervescent microneedle patch. Science Advances. DOI: 10.1126/sciadv.aaw8145