Development of Norelgestromin Dissolving Bilayer Microarray Patches for Sustained Release of Hormonal Contraceptive

Abstract

Microarray patches (MAPs) offer a noninvasive and patient-friendly drug delivery method, suitable for self-administration, which is especially promising for low- and middle-income country settings. This study focuses on the development of dissolving bilayer MAPs loaded with norelgestromin (NGMN) as a first step towards developing a future potential drug delivery system for sustained hormonal contraception. The fabricated MAPs were designed with the appropriate needle lengths to penetrate the stratum corneum, while remaining minimally stimulating to dermal nociceptors. Ex vivo assessments showed that the MAPs delivered an average of 176 ± 60.9 μg of NGMN per MAP into excised neonatal porcine skin, representing 15.3 ± 5.3% of the loaded drug. In vivo pharmacokinetic analysis in Sprague Dawley rats demonstrated a Tmax of 4 h and a Cmax of 67.4 ± 20.1 ng/mL for the MAP-treated group, compared to a Tmax of 1 h and a Cmax of 700 ± 138 ng/mL for the intramuscular (IM) injection group, with a relative bioavailability of approximately 10% for the MAPs. The MAP-treated rats maintained plasma levels sufficient for therapeutic effects for up to 7 days after a single application. These results indicate the potential of NGMN-loaded dissolving bilayer MAPs, with further development focused on extending the release duration and improving bioavailability for prolonged contraceptive effects.

Introduction

According to recent estimates by the United Nations, approximately 164 million women who want to avoid pregnancy are not using safe, modern contraception [1]. Additionally, nearly 85 percent of these women live in low- and middle-income countries [2]. Almost half of all pregnancies globally (121 million) are unintended, which may lead to significant health, economic, and psychosocial costs. Many factors influence a woman’s ability to use contraception, including societal and health system- and product-related factors [3].

Recent analysis of unmet need revealed that a lack of awareness of and access to contraception are no longer cited as the leading causes of poor contraceptive usage [4]. Additionally, although a range of both short-term and long-acting contraceptive methods exist, high rates of method discontinuation are being observed [5]. Women who have access to contraception may not use or may discontinue use for several reasons, including changes in relationship status or fertility intentions, concerns over side effects, and opposition from others [5]. Thus, the definition of unmet need should include both women who do not have access to appropriate preventive methods and those who are dissatisfied with their current method [6].

Among the reversible contraceptive methods, hormonal drug delivery systems represent the broadest array of products, including multiple types of oral pills, injectables, and transdermal patches, as well as vaginal rings, implants, and hormone-releasing intrauterine devices [1,7]. These products differ in the types of hormones delivered and the dosing regimen. User-initiated methods such as oral pills, transdermal patches, and vaginal rings require daily, weekly, or sometimes monthly dosing. Injectables provide 2 to 3 months of protection, and in most countries require a clinic visit for administration but can also be self-administered. Methods such as intrauterine devices and implants provide long-term protection (3 to 8 years) and require a provider to insert the product [8,9].

Nonetheless, there remain product-specific concerns that may impact patient nonuse, noncompliance, or discontinuation of these methods, which affects their overall success rates. For example, when considering options that require daily use for effective protection, like oral pills, the cost of the medication and strict adherence requirements are common challenges. Concerns regarding other longer-acting methods include cost, injection site pain, the need for frequent clinic visits (for injectables), and the need for surgical procedures to insert and remove implants. Since the effectiveness of user-initiated methods depends on patient compliance and adherence to product use, new drug delivery systems are needed to address user concerns and provide women and girls with increased options of contraception that fit with their needs and lifestyles [10].

Microarray patches (MAPs), also known as microneedle patches, are under development for the delivery of drugs and vaccines, including for the prevention of pregnancy [11,12,13]. Dissolving MAPs, in particular, consist of an array of water-soluble or biodegradable polymers and the drug(s) that dissolve and release their payload upon exposure to interstitial fluid in the skin [14,15]. MAPs are minimally invasive devices that are inserted into the skin through applied pressure, facilitating drug delivery in a way that is typically perceived as less painful than needles and syringes [16,17,18].

Contraceptive MAPs can be formulated for the controlled release of the drug and are considered easy to use [12,19]. Once a user has been trained to apply MAPs correctly, they can potentially be self-applied at home whenever subsequent dosing is required [20]. This is especially beneficial for women and girls in low- and middle-income countries, where there is great need for contraceptive options that do not require frequent health care visits, as access to health facilities and trained health care providers may be limited, particularly in more rural areas.

There are studies in the literature that support the potential feasibility of MAPs as a long-acting contraceptive delivery platform. One study highlighted the possibility of a controlled release of levonorgestrel for 6 months in vitro through the development of a core–shell MAP made from biodegradable poly(lactic-co-glycolic acid) (PLGA) and polylactic acid (PLA) polymers [21]. Another study demonstrated preclinical in vivo success in the development of contraceptive MAPs that can deliver a sustained release of levonorgestrel through the detachment and embedding of biodegradable PLGA and PLA microneedles into the skin for at least 1 month [22]. Other studies have also highlighted the use of other hormonal contraceptive drugs, including etonogestrel and progesterone, as well as biodegradable materials, including silk fibroin, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and hydroxypropyl cellulose, to fabricate MAPs with a range of other delivery efficiencies and durations of protection [23,24,25].

Considering the current contraceptive MAP landscape, we designed a dissolving bilayer MAP that aimed to deliver an in vivo sustained release of norelgestromin (NGMN) for a 1- to 3-month duration of protection. Feedback on the ideal duration provided by end users in several studies that assessed MAP product preferences and potential acceptability influenced this target; women in several low- and middle-income countries expressed a desire for MAPs that could protect users for up to 1, 3, or 6 months [26,27,28]. Additionally, NGMN was chosen as the candidate drug for this MAP, since it is already marketed in a conventional transdermal patch format, as Mylan Pharmaceuticals’ Xulane® (delivered with ethinyl estradiol), potentially simplifying the regulatory approval process for such a product. However, unlike the Xulane patch, which was designed to be worn and reapplied every week [29], our MAP was designed to be removed after a short application period of 20 min to 1 h, while still aiming to maintain long-term therapeutic effects.

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Materials

Norelgestromin was purchased from Toronto Research Chemicals, Inc. (Toronto, ON, Canada). PVA of molecular weight 9 to 10 kDa, 80% hydrolyzed (PVA 10K), and of molecular weight 31 to 50 kDa, 87% to 89% hydrolyzed (PVA 50K), was purchased from Sigma-Aldrich (Dorset, UK). PVP K-29/32 of molecular weight 58 kDa was provided by Ashland (Kidderminster, UK). A liquid silicone elastomer mix was purchased from Nusil Technology (Buckinghamshire, UK). Ultrapure water was obtained from a water purification system (Elga PURELAB DV 25, Veolia Water Systems, Dublin, Ireland). All other chemicals and materials were of analytical reagent grade and supplied by Sigma-Aldrich.

Vora, L.K.; Tekko, I.A.; Volpe Zanutto, F.; Sabri, A.; Choy, R.K.M.; Mistilis, J.; Kwarteng, P.; Kilbourne-Brook, M.; Jarrahian, C.; McCarthy, H.O.; et al. Development of Norelgestromin Dissolving Bilayer Microarray Patches for Sustained Release of Hormonal Contraceptive. Pharmaceutics 2024, 16, 946. https://doi.org/10.3390/pharmaceutics16070946