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Fig. 1

PLA/PLGA microspheres loaded with LNG for controlled drug delivery (photo courtesy of Dr. Linglin Feng, Shanghai Institute of Planned Parenthood Research).

Fig. 2

Optical microscope image of porous silicon microparticles, approximately 40 μm in diameter (photo courtesy of Dr. Michael Sailor, University of California San Diego).

Fig. 3

Monodispersed microparticles fabricated using PPF technology (photo courtesy of Orbis Biosciences, Inc.).

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A longer-acting injectable contraceptive that lasts for 6 months would be a valuable addition to the contraceptive method mix and ideal for women who are interested in spacing births and/or uncertain about their future reproductive plans. Here we review past applications of drug delivery technologies to injectable contraceptives as well as recent advancements in sustained drug delivery technologies that hold promise for the development of a new longer-acting injectable contraceptive product.

Study design

A global landscape analysis was conducted, promising sustained drug delivery technologies, and research opportunities and partnerships were established with experts in the fields of contraception and drug delivery to identify new approaches in developing a longer-acting injectable contraceptive product.


The landscape analysis confirmed that a number of existing polymer systems, such as poly-lactic-co-glycolic acid and poly(epsilon-caprolactone), remain promising candidates for application to a longer-acting injectable product. Novel polymers and materials also hold promise for achieving longer release profiles and/or having other advantages over existing polymer systems, but products using these materials could potentially have longer roads to regulatory approval. Additionally, recent advancements in the manufacturing process of microspheres may benefit the development of a longer-acting injectable contraceptive.


The design of any new injectable product must take into account the limitations of current injectable contraceptives and address concerns that women may have for a longer-acting product. FHI 360 is supporting several research collaborations for proof of concept of various drug delivery approaches for achieving longer-acting product that fits an established target product profile.

1. Introduction

The unequivocal role of long-acting reversible contraceptives (LARCs) in reducing the rates of unintended pregnancies has been demonstrated in numerous research studies and is well documented [, , , ]. In recognition of their unique place in public health programs, especially in developing countries, international donors, service providers and philanthropic organizations have devoted major attention and resources in increasing worldwide access to LARCs [, ]. In some cases, however, currently available LARCs are either unaffordable or do not meet women's needs or preferences []. New reversible products with durations between the current 3-month injectable contraceptives and contraceptive implants and intrauterine devices would fill an important gap in the existing contraceptive method mix and would increase choices for women.

Injectable contraception has been a cornerstone of international family planning programs for decades. Currently, over 40 million women worldwide use injectable contraceptives to prevent pregnancy []. In sub-Saharan Africa, more than one third of modern method contraceptive users rely on injectable contraceptives []. Depending on the formulation, currently available injectables are effective for 1–3 months, requiring women to return to their provider monthly or quarterly; this is recognized as a significant disadvantage of these methods []. Despite the broad and increasing use of injectables, discontinuation and late return rates for reinjection are high, frequently due to users' difficulty complying with reinjection schedules [].

Previous research has demonstrated that injectable contraceptives with a longer interval between injections lead to better adherence and continuation rates when compared to those with shorter intervals. Ruminjo et al. showed that the 1-year continuation rate was higher for a 3-month injectable depot medroxyprogesterone acetate (DMPA) than for 1-month Cyclofem; the main difference stated by study participants was logistical difficulty in making frequent clinic visits []. South African researchers compared DMPA 150 mg given every 3 months and DMPA 450 mg given every 6 months and demonstrated a significantly better acceptability of the 6-month regimen due, primarily, to convenience and reduced travel costs []. These findings are echoed by research on the acceptability of longer-acting injectable (LAI) formulations in other therapeutic areas [].

A LAI contraceptive that lasts for 6 months would be a valuable addition to the method mix and ideal for women who are interested in spacing births and/or uncertain about their future reproductive plans. In addition to advantages for users, these methods would reduce the patient load burden on clinical facilities and community-based programs. Here we review past applications of drug delivery technologies to injectable contraceptives and review advancements in sustained drug delivery technologies that hold promise for the development of a new LAI contraceptive product.

2. Background

A substantial amount of research has been conducted in the last four decades to develop a longer-acting platform for the release of contraceptive progestins using an injectable method of administration. Historically, two approaches have been used to extend duration of efficacy following the single administration of a contraceptive drug: those involving the active pharmaceutical ingredient (API) and those involving the delivery system. The API approach involves identifying new chemical entities with longer duration of efficacy, using a higher dose or altering the method of administration. In an effort to develop an alternative progestin-only injectable that would produce a superior pharmacokinetic profile, have fewer side effects and potentially have longer duration of action than 3-month DMPA and 2-month norethisterone (NET) enanthate (EN), the World Health Organization Special Programme of Research in Human Reproduction launched a major initiative in 1975 aimed at the chemical synthesis and screening of a large number of progestin derivatives []. This effort focused on creating long-acting esters of known steroids [norethisterone and levonorgestrel (LNG)] that would be formulated as 3- to 6-month injections to be used in women. Hundreds of compounds were synthesized and screened as part of this large-scale initiative and several compounds proved to be promising and longer acting than DMPA and NET-EN, including LNG butanoate (LNG-B), LNG cyclopropyl-carboxylate and LNG cyclobutyl-carboxylate. However, because of financial constraints, only LNG-B has been advanced to the dose-finding stage of clinical testing [].

Higher doses of a known drug may also provide a longer effect. For example, higher doses of DMPA (300/400 mg) administered every 6 months provided effective contraceptive protection in a clinical trial setting (this higher-dose DMPA formulation was never marketed) [, , ]. An alternate route of administration may be another way of extending duration of action of an injectable steroid. For example, subcutaneous administration of 104 mg DMPA is characterized by slower absorption and more sustained release when compared to intramuscular injection (im) of 150 mg DMPA [White White Söfft Söfft Söfft Vita Womens Womens White Vita Vita Söfft Womens Vita Womens Womens White Vita Söfft gXAqpA].

The delivery system approach uses innovative technologies to control the rate of drug release to achieve a longer period of efficacy. The use of biodegradable polymers in the form of microspheres and in situ forming depots in other therapeutic areas have effectively reduced the dose of API compared to more frequently administered suspensions of the same drug []. Similarly, as described below, these systems have demonstrated the potential to extend the release of contraceptive hormones in order to achieve a longer duration of action from a single injection without increasing the dose of API.

3. Past research

Microspheres are a drug delivery technology used in drug products for a wide variety of clinical indications. Fabricated as either solid spheres with a uniform dispersion of API in a polymer matrix or a hollow polymer structure encapsulating the API of interest, these biodegradable structures can be loaded with a wide array of drugs, including hormones and other small molecules, proteins and nucleic acids (Fig. 1). Once injected into the body, microspheres provide a more uniform release of an API for up to several weeks or months from the site of injection through diffusion of the drug through the polymer matrix and/or by gradual degradation of the polymer matrix over time. Controlling the rate and duration of release of API from microspheres is rather complex but can be achieved through modification of the polymer composition, the molecular weight of the polymers, the microsphere particle size and amount of API loaded into the microspheres, among other variables [].

Fig. 1

PLA/PLGA microspheres loaded with LNG for controlled drug delivery (photo courtesy of Dr. Linglin Feng, Shanghai Institute of Planned Parenthood Research).

Over the past three decades, a number of microsphere formulations using various biodegradable materials were evaluated for controlled delivery of contraceptive hormones in a preclinical setting. Three months of sustained release of LNG was demonstrated in mice using a biodegradable polymer, poly(3-hydroxybutyrate) []. Poly(epsilon-caprolactone) (PCL), a synthetic biodegradable polymer that exhibits slow degradation properties, has been used in an injectable formulation to control the release of LNG alone and LNG combined with ethinyl estradiol (EE) [, ]. The same polymer was previously used to release LNG from the biodegradable implant, Capronor []. This product, developed by RTI International, with support from the National Institutes of Health, was a single, tubular implant able to achieve up to 1 year of ovulation suppression. Despite showing promise for being an effective contraceptive [, , ], its further development was impeded by difficult removal of the implant after a period of time and a long release tail [].

Microspheres composed of the synthetic polyesters poly(glycolide) (PLG), poly(lactide) (PLA) and their copolymer poly-lactic-co-glycolic acid (PLGA), however, have become the most common polymers due to their biocompatibility, biodegradability and mechanical strength. PLGA became well known after Lupron Depot (Abbott Laboratories, Abbott Park, IL, USA), a 1–3 monthly formulation of PLGA microspheres releasing leuprolide acetate for the treatment of advanced prostate cancer in men and endometriosis and fibroids in women and became the first PLGA microsphere product to be approved by the Food and Drug Administration in 1989. Since then, PLGA has been used in a number of other drugs, including Vivitrol (Alkermes, Waltham, MA, USA) for treatment of alcohol dependence and Sandostatin LAR Depot (Novartis, Basel, Switzerland) for treatment of acromegaly, among others.

In contraceptive research, PLG, PLA and PLGA have shown promise for the controlled release of LNG both in vitro and in vivo [, , , , , ]. Additionally, PLGA microspheres have been evaluated in vivo for delivery of Nestorone, a potent contraceptive progestin being developed by the Population Council in a variety of formulations. Results from this formulation demonstrated effective serum levels of the progestin for up to 28 days, albeit with highly variable serum levels detected up to 196 days []. The most notable progress with PLGA was achieved with microspheres releasing NET that produced a promising release profile and a pharmacodynamic response of up to 6 months in animal and early clinical studies [, ]. Later, a 90-day injectable formulation containing either 65 or 100 mg NET (NET-90) was shown to be effective in two larger clinical trials [, ]. However, manufacturing issues with the product scale-up ultimately halted further progress with the NET-90 product.

In situ forming biodegradable systems have also been shown to be effective for sustained drug delivery of contraceptive hormones. These types of delivery systems consist of a drug and biodegradable polymer suspended in a biocompatible organic solvent. They are prepared as fluid formulations but form a semisolid or gel depot at the site of injection after administration []. A number of methods are employed to establish the in vivo depot. These include a solvent removal method that relies on water penetration in situ to separate the organic solvent from the biodegradable polymer carrier (a process referred to as “phase separation”), the introduction of chemicals to cross-link polymer monomers and the use of thermosensitive biodegradable triblock copolymers, which polymerize at body temperature to form a gel []. In situ forming systems are able to provide extended release profiles, some significantly longer than microsphere formulations. One successful application of in situ forming systems is the Atrigel® Delivery System (QLT, Inc., Vancouver, Canada) that utilizes the phase separation method to precipitate a depot of a PLGA matrix enclosing the API. Eligard® (Sanofi US, Bridgewater, NJ, USA) uses the Atrigel® system to deliver leuprolide acetate for palliative treatment of advanced prostate cancer, endometriosis and fibroids, with dosing available for 1, 3, 4 or 6 months.

Several groups have investigated the potential of in situ forming biodegradable depots for sustained delivery of contraceptive steroids in animals. Gao et al. studied various oil and gel formulations both in vitro and in vivo, demonstrating over 5 weeks of estrous suppression in rats receiving formulations with LNG or EE [, ]. The use of an injectable gel matrix composed of PLGA was also assessed in cotton-top tamarins for sustained delivery of LNG, with duration of effectiveness reaching 28 weeks [].

4. Current trends

Except for a few isolated research activities, large-scale funding and coordinated efforts to develop a LAI contraceptive based on biodegradable polymers have been suspended or stopped altogether for various reasons, including technical and funding challenges. Also, the introduction in the mid-late 90s of single and two-rod contraceptive implants that last for 3–5 years, but which are relatively easy to remove, temporarily diminished donor interest in this area. However, limited access to medical care in low-resource settings has recently reignited interest of the donor and research communities in longer-term contraceptive options that are easy to administer and do not require removal. Additionally, the recent positive changes in the political and financial climate in the family planning arena worldwide have resulted in renewed interest in contraceptive research and development []. Combined, these trends contribute to an environment favorable to the development of new and improved contraceptive products. Moreover, with the increased popularity and success of injectable contraceptives in recent years [], the case for the development of a new LAI contraceptive product is strong. This may be achieved by capitalizing on new developments in controlled release drug delivery for other indications that have occurred in the last decade as well as developing alternative lower-dose formulations to the currently approved suspensions.

In 2011, with financial support from the Bill & Melinda Gates Foundation, FHI 360, began work to develop a LAI contraceptive product. The main goal of this project is to bring to market a safe and effective injectable method that would provide 7 months of contraceptive protection (6 months plus a 1-month window for reinjection) to women in the developing world. Through this initiative, FHI 360 conducted a landscape analysis of promising sustained drug delivery technologies and research opportunities and established partnerships with experts in the fields of contraception and drug delivery.

The landscape analysis confirmed that PLGA remains a promising synthetic polymer that can be applied to the development of a LAI contraceptive product. Degradation rates of this polymer can be manipulated by adjusting the ratios of PLA and poly(glycolic acid), a characteristic that makes PLGA a polymer of choice for use in a longer-acting drug delivery product. PCL, in spite of the challenges experienced with developing the Capronor product, remains a promising polymer that could be used in a LAI product. In addition to exhibiting slower degradation relative to other biodegradable polymers, the use of PCL in microsphere formulations is advantageous due to its permeability to small drug molecules, biocompatibility and exceptional ability to form blends with other polymers.

The use of novel polymers and materials is appealing for the development of a longer-acting product, given the unique chemical properties that could potentially achieve longer release profiles and/or have other advantages over the use of PLGA and PCL. One alternative, for example, are polyanhydrides that have been assessed for parenteral delivery of drugs for a variety of indications including local anesthetic agents, anticancer agents, antibiotics and growth hormone. A major advantage of this class of polymer is the ease of varying the rate of degradation and release by adjusting the ratio of its prepolymer monomers [].

An alternative material to polymers for use in controlled drug delivery applications is porous silicon (Si), which can be loaded with a wide range of molecules (Fig. 2). Porous Si is produced by electrochemical “etching” of crystalline silicon wafers, resulting in porous silicon microparticles with precise pore size and distribution. In addition to being able to vary the microparticle pore size and volume, advantages to the system include large surface area of the microparticles, the ability to modify the surface to control drug release properties, resorbability and biocompatibility []. The degradation product of porous Si microparticles is orthosilicic acid [Si(OH)4], which is the natural form of Si found in the body and is readily excreted by the kidneys. Porous Si has been investigated for controlled delivery of various drugs as well as proteins, enzymes and genes, with release profiles reaching weeks to several months [].

Fig. 2

Optical microscope image of porous silicon microparticles, approximately 40 μm in diameter (photo courtesy of Dr. Michael Sailor, University of California San Diego).

In addition to new materials, advancements in the manufacturing process of microspheres may benefit the development of a LAI contraceptive. A major limitation to more traditional emulsion-based methods of microparticle fabrication such as spray drying, solvent evaporation and solvent extraction is the production of broad particle size distributions. Microsphere particle size has a significant impact on release and degradation profiles as smaller particles tend to degrade and release loaded drug faster due to larger surface-to-volume ratio. Therefore, formulations that have a narrower microsphere particle size distribution will allow greater control over the API release profile including decreasing the initial burst release and shortening the “tail” of the release profile (i.e., the period when blood levels of the API are still detectable but not sufficient enough to be effective). Recent work has been carried out to narrow the particle size distribution through the development of new manufacturing methods. One such innovation, called Precision Particle Fabrication (PPF), is able to create monodispersed, drug-loaded microparticles by using acoustic excitation to produce uniform-sized droplets of a polymer-containing solution in a nonsolvent carrier stream []. This technology has been used to create precise particle sizes with a wide range of polymers containing a number of different drugs, including rhodamine B and piroxicam, with release profiles reaching several months with certain formulations (Fig. 3) [, ].

Fig. 3

Monodispersed microparticles fabricated using PPF technology (photo courtesy of Orbis Biosciences, Inc.).

Application of these various innovative materials, technologies and approaches holds significant promise to develop a LAI contraceptive product.

5. Path forward

Despite the potential user and programmatic advantages of a 6-month injectable, a potential challenge to broad use may be concern over the “irreversibility” of these systems. If women using such a product develop serious side effects, such as hormonally responsive cancers or other conditions in which hormonal therapies would be contraindicated, the method could not be discontinued immediately. Also, less serious side effects such as irregular menstrual bleeding could be a source of dissatisfaction, but users could not discontinue immediately. To address this potential concern, a shorter duration of contraceptive protection was chosen over longer-term duration (i.e., 6 months versus 12 or 18 months) to guide the LAI product development process. Patient counseling about possible side effects including bleeding disturbances will remain an important tool to prevent user dissatisfaction with the new LAI product and future discontinuation [, ]. In addition, biodegradable drug delivery systems have been historically characterized by a long release tail []. Long periods of subtherapeutic drug levels at the end of product duration could make it difficult to predict return of fertility for women who want to conceive, a concern often cited by users and medical professionals as a serious downside of current injectable options.

The design of any new injectable product must take into account these concerns. Additionally, as the majority of injectable contraceptive users are in developing areas of the world, design and manufacturing of the product must ensure affordability and stability under extremes in temperature and humidity and must allow for easy storage and distribution in low-resource settings. To this end, FHI 360 developed a target product profile that will guide development of a 6-month contraceptive product. The goal is for the method to provide effective levels of drug for 7 months (6-month duration with a 1-month grace period to return for reinjection), a predictable return of fertility (well defined “tail”) and acceptable side effects and contraindications. The final product should be easily suited for self-administration and/or administration by lower cadres of health care workers in developing settings to facilitate wide uptake of the method (e.g., a disposable prepackaged syringe or autodisable injection system similar to Uniject™).

Developing a product that meets these requirements is a difficult task. While newer APIs may offer advantages over the currently approved progestins in terms of side effects, our goal for a first-generation LAI is to utilize a well-established contraceptive hormone. To facilitate regulatory approval, the choice of APIs that are, or soon will be, approved by a stringent regulatory authority seems prudent. With this in mind, LNG and etonogestrel (ENG), which are well-characterized progestins with robust safety profiles and a history of use in longer-acting contraceptive methods, are the drugs of first choice [, ]. From the newer generation of progestins, Nestorone being developed by the Population Council in other presentations could be a promising candidate due to its unique biologic profile and clinical performance [, ]. Marketing approval for a Nestorone-containing contraceptive vaginal ring is pending [].

The use of new polymer systems, while promising, may require extensive toxicity and carcinogenicity studies to obtain regulatory clearance that may substantially prolong the approval process. As with selection of the API, the first generation of a LAI will likely utilize well-characterized PLG, PLA, PLGA and PCL that have been approved and used in existing marketed drug products.

Another important consideration for the development and introduction of a LAI contraceptive is whether recent controversy regarding a possible association between hormonal contraceptives and HIV acquisition could impact introduction or acceptability of a new injectable product []. Product developers will need to carefully monitor emerging evidence in this area, as well as how new findings may influence public opinion.

As part of the LAI project, FHI 360 is supporting research collaborations at the Shanghai Institute of Planned Parenthood Research, Orbis Biosciences, Inc., the University of California San Diego and the University of Tennessee Health Science Center. These groups are investigating the following drug delivery systems: (1) PLA/PLGA microspheres releasing LNG, (2) PLGA microspheres releasing ENG, (3) nanostructured porous silicon microparticles releasing various contraceptive steroids and (4) an in situ gelling PLGA/PLA suspension releasing LNG, respectively. Interim results of these studies will be available in 2015, and final results will be available in 2016. The goal is to develop and bring to market a 6-month injectable within 10–15 years and possibly sooner. An injectable that lasts 6 months would provide women with greater choice, offer an intermediate duration of efficacy between short- and long-acting reversible methods, improve continuation and compliance and ultimately help reduce rates of unintended pregnancy around the world.


Support for this work was provided by FHI 360 with funds from the Bill & Melinda Gates Foundation, although the views expressed in this publication do not necessarily reflect those of FHI 360 or the foundation. We would like to thank Dr. Linglin Feng at Shanghai Institute of Planned Parenthood Research, Dr. Nathan Dormer at Orbis Biosciences, Inc., Dr. Michael Sailor at the University of California San Diego and Dr. Tao Lowe at the University of Tennessee Health Science Center and their respective research groups for their important contributions to this manuscript and the Longer Acting Injectable project. We also wish to express our gratitude to Lex Smith and Gregory S. Kopf for their review of the manuscript and guidance throughout the writing process.


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