Levonorgestrel Butanoate Formulation and Methods Relating Thereto

This invention is a potential subcutaneous or intramuscular progestin-only, injectable contraceptive for women. Forty-five percent (45%) of pregnancies in the United States are unintended. In this group, one-third of reproductive age women are obese – increasing the risk of diabetes, hypertension and venous thromboembolism (VTE). All these are conditions for which most hormonal methods are contraindicated. Thus, additional safe and effective injectable contraceptive options are needed. A subcutaneous formulation may be self-injected without the need of a skilled care provider or medical office visit. Levonorgestrel butanoate (LB) serves as a pro-drug to deliver Levonorgestrel (LNG) to serum after hydrolysis of the ester. It addresses the demand for estrogen-free contraception with no increased risk of VTE. The lack of increased risk is a benefit for all women, especially those obese. 

Injectables have lower failure rates than combined hormonal birth control pills or patches or progestin-only pills (POP). Also, POPs require strict adherence to a daily administration schedule. Currently, the only injectable contraceptive on the U.S. market is depomedroxyprogesterone acetate (DMPA). While popular, DMPA contraceptive with certain risks. DMPA may cause weight gain, moodiness, and a decrease in bone mineral density leading to a higher risk of bone fracture.  

Levonorgestrel butanoate (LB) is a butyl prodrug of levonorgestrel, a widely-used steroidal progestin. It was in development as a long-acting injectable contraceptive since the 1980s by the World Health Organization (WHO) in collaboration with institutions around the world, including NICHD. However, conventional LB formulations, including the WHO formulation, exhibit undesirable stability issues reducing contraceptive activity and the ability to large-scale manufacture.  

NICHD developed an injectable pharmaceutical formulation of LB with a potential for self-administration. The formulation promotes increased stability through a longer lasting and more concentrated dosage than previous LB formulations. This invention also involves a unique manufacturing process requiring only one vendor for more efficient production. NICHD is testing this formulation in an ongoing Phase I subcutaneous study. Results so far indicate promise as a long-lasting, reversible, injectable female contraceptive. Further, there is a competitive advantage as patients in the Phase I study thus far did not report some side effects associated with other contraceptive agents such as DMPA; e.g., weight gain or mood swings. 

Competitive Advantages:

• Safer for women with high-risk conditions
• Self-subcutaneous and reversible injectable
• Long-lasting contraceptive effects
• Increased stability relative to previous formulations
• Amenable to large-scale manufacture relative to previous formulations
• Estrogen free contraceptive
• Progestin only self-injectable contraceptive

Commercial Applications:

• Injectable contraceptive use by humans
• Use in the treatment of progestin-related diseases