National Partnership for Women & Families

Monthly Women's Health Research Review

Study Evaluates Research on Developing New Longer-Acting Injectable Contraceptives

Summary of "Towards the Development of a Longer-Acting Injectable Contraceptive: Past Research and Current Trends," Halpern et al., Contraception, Feb. 25, 2015.

"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," according to Vera Halpern and colleagues at FHI 360.

The researchers note that while long-acting reversible contraceptives (LARCs) have played an "unequivocal role" in reducing global rates of unintended pregnancy, LARCs remain unaffordable or unsuitable for some "women's needs or preferences." The researchers write that a "longer-acting injectable (LAI) … 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," while also helping to "reduce the patient load burden on clinical facilities and community-based programs."

In this study, the authors "review[ed] past applications of drug delivery technologies to injectable contraceptives and review[ed] advancements in sustained drug delivery technologies that hold promise for the development of a new LAI contraceptive product."

Background



According to the study, two methods historically have been used to "extend duration of efficacy following the single" dose of contraceptive medications -- those using:

~ Active pharmaceutical ingredients (APIs); and

~ Delivery systems.

The researchers note that the API approach identifies "new chemical entities" that have longer efficacy durations by using higher doses or by altering administration methods. For example, the World Health Organization Special Programme of Research in Human Reproduction in 1975 launched a large-scale effort to develop new compounds for use in three- and six-month LAIs, but only one of the new compounds they created, levonorgestrel butanoate (LNG-B), "advanced to the dose-finding stage of clinical testing."

Meanwhile, the researchers note that the "delivery system approach uses innovative technologies to control the rate of drug release to achieve a longer period of efficacy." Some of "these systems have demonstrated the potential to extend the release of contraceptive hormones ... to achieve a longer duration of action from a single injection without increasing the dose of API."

Review of Past Research

The researchers explain how a drug delivery technology called microspheres can be manipulated to help "[c]ontro[l] the rate and duration of release of API." They note that "[o]ver the past three decades, a number of microsphere formulations using various biodegradable materials were evaluated for controlled delivery of contraceptive hormones."

For example, the researchers wrote that a biodegradable implant called Capronor was developed via one microsphere formulation to provide "up to 1 year of ovulation suppression," although "its further development was impeded by difficult removal" and other factors. However, the authors noted that another set of microsphere formulations -- currently "the most common polymers" -- has since been used in health care products that have been successful, including treatments for prostate cancer and fibroids. These polymers also "have shown promise for the controlled release of" levonorgestrel (LNG), the researchers write.

The researchers add that another sustained drug delivery technology, called in situ forming biodegradable systems, has "also been shown to be effective for ... contraceptive hormones." Specifically, they note that these systems have been used successfully in products that palliatively treat advanced prostate cancer, fibroids and endometriosis, and that they have been "investigated [for] the potential ... for sustained delivery of contraceptive steroids in animals."

Review of Current Trends

The researchers note that most "large-scale funding and coordinated efforts to develop a LAI contraceptive" using "biodegradable polymers have been suspended or stopped altogether for various reasons, including technical and funding challenges." In addition, the introduction of contraceptive implants that last from three to five years in the mid- to late-1990s "temporarily diminished donor interest" in developing LAIs. However, limited access to health care in low-income areas "has recently reignited" donor and researcher interest because such options would be "easy to administer and do not require removal." According to the researchers, interest in LAI development has also been stoked by positive developments in the global "political and financial climate in the family planning arena," as well as "the increased popularity and success of injectable contraceptives."

According to the researchers, developing new LAIs could "be achieved by capitalizing on new developments in controlled release drug delivery" currently used in other medical treatments "as well as [by] developing alternative lower-dose formulations to the currently approved" LAIs. For example, FHI 360 in 2011 launched a project that aims "to bring to market a safe and effective [LAI] that would provide 7 months of contraceptive protection (6 months plus a 1-month window for reinjection) to women in the developing world."

The researchers write that existing polymers and new materials -- such as novel polymers and "[a]n alternative material to polymers" called porous silicon -- look promising for new LAI development. "In addition to new materials, advancements in the manufacturing process of microspheres may benefit the development of a LAI contraceptive," the researchers write, adding that one such process, which narrows microsphere particle size distribution, could "allow greater control over" how and when APIs are released.

Further Development

The researchers cite several factors that should be considered in "[t]he design of any new" LAI.

For example, they note that for future LAIs, "a shorter duration of contraceptive protection [might be better than] longer-term duration (i.e., 6 months versus 12 or 18 months)" because the "irreversibility" of the methods could cause concern. Specifically, they note that "[i]f 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."

The researchers write that developers should also consider how biodegradable drug delivery systems traditionally have had a long release tail -- "the period when blood levels of the API are still detectable but not sufficient enough to be effective" -- which can pose difficulties "for women who want to conceive." Further, novel LAIs should be developed to withstand extreme temperatures and humidity to "allow for easy storage and distribution in low-resource settings."

According to the researchers, FHI 360 to this end has "developed a target product profile that will guide development of a 6-month contraceptive product." Specifically, the product should be effective "for 7 months (6-month duration with a 1-month grace period ... for reinjection), a predictable return of fertility (well defined 'tail') and acceptable side effects." Further, the 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."

The researchers suggest that the new LAI "utilize a well-established contraceptive hormone," such as LNG, or a polymer "that [has] been approved and used in existing marketed drug products." The researchers add that developers also should "monitor emerging evidence" on the possible association between HIV acquisition and hormonal contraceptives.

The researchers note that FHI 360 aims to "bring to market a 6-month injectable within 10-15 years," noting that such an injectable "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."