Intrauterine drug delivery for contraception and gynecological treatment : innovative, intrauterine drug delivery systems for contraception, hormone replacement therapy and other female health needs

There is a need for the development of new, improved birth control methods that are easy to use, have few side effects, and do not require consistent daily attention or application prior to every act of intercourse. Long-acting contraceptive methods, which eliminate the need for such daily activity and for some specific action at the time of coitus, are designed to meet this need. However, developing a new contraceptive is a major challenge. It is generally estimated that it takes 10 to 15 years to develop a new method and bring it to the market, at a cost of US$ 300-500 million, or even much more. Thus, industry is reluctant to risk such a long-term investment. Both risk and investment can be reduced, though, by taking small steps, so that small improvements to existing contraceptives could result in a giant leap forward. This thesis describes the development of new intrauterine drug delivery products, which are designed to provide improved methods for the prevention and treatment of gynecological conditions, improvements to birth control methods, and higher levels of safety, user acceptability, compliance, and quality of life for women. The development of frameless intrauterine systems is such an attempt to improve on the performance and acceptability of established intrauterine contraception. Both the frameless GyneFix® intrauterine device (IUD) and the frameless FibroPlant® levonorgestrel-releasing intrauterine system (LNG-IUS) possess features that could solve potentially major problems encountered with conventional IUDs (e.g., expulsion, abnormal or excessive bleeding, and pain). However, the performance of frameless devices depends on proper anchoring of the device, which requires specific technical skills not required for the insertion of conventional IUDs. Nevertheless, proficiency in the insertion of GyneFix® and FibroPlant® devices is easily acquired, if the medical provider follows the procedural instructions strictly. For less technically skilled providers, whether he or she is an obstetrician/gynecologist, general practitioner, or nurse-midwife, the Femilis® and Femilis® Slim LNG-IUS, which use a new, simplified, push-in insertion technique for T-shaped devices, can be an excellent contraceptive option. This current research, described in this thesis, paves the way for new developments. The frameless copper and LNG-releasing IUDs/IUSs and framed LNG-IUS are only the beginning of a series of innovative developments in this field. New compounds, such as progesterone antagonists and selective progesterone receptor modulators (SPRMs), could be incorporated into polymeric drug delivery platforms for use in the uterus, cervix, or vagina, or subdermally. These novel systems could extend the treatment indications and help women who, up until now, could rely only on invasive techniques for cure or relief of their condition. It is likely that current and new hormone-releasing intrauterine systems could also be useful for bleed-free contraception in HIV-positive (HIV+) women. Finally, a word about the underuse of the IUD. Women in highly developed countries where the IUD/IUS is used less often, such as the USA and the Netherlands, could benefit from the advantages that IUDs/IUSs offer. However, there is also a great need for this technology in the low- and middleincome countries. The current underuse of the IUD is mainly due to a combination of individual factors and misinformation. IUDs are largely misunderstood. In addition, service delivery, political, religious, and commercial factors all play a vital role in their disuse. We must also take into account that IUDs and IUSs are the most cost-effective, reversible method of contraception. One important reason for the underuse of the IUD is the fear of insertion pain. There is no doubt that the acceptability and popularity of the method could be enhanced by giving attention to the patient’s physical and psychological comfort during insertion. It is usually not necessary to provide pain relief for insertion of an IUD/IUS, particularly in parous women, but some women, mostly nulliparous women, may need it. IUD providers should realize that no woman likes to suffer during the insertion of an IUD, and severe discomfort may create a negative attitude towards the method

Continuous combined parenteral estrogen substitution and intrauterine progestogen delivery: The ideal HRT combination?

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Ease of insertion, contraceptive efficacy and safety of new T-shaped levonorgestrel-releasing intrauterine systems

Objective: The objective of the study was to evaluate ease of insertion, contraceptive performance and safety, in parous and nulliparous women, of two new T-shaped levonorgestrel (LNG)-releasing intrauterine systems (LNG-IUS), Femilis (TM) (parous women) and Femilis (TM) Slim (nulliparous women), releasing 20 mu g of LNG per day. An ancillary objective was to evaluate expulsion and user continuation. Design and Methods: An open, prospective, noncomparative study (interim analysis). Two hundred thirty-five insertions were performed in fertile women seeking contraception. Of these, 143 (60.8%) parous women were fitted with Femilis and 92 (39.2%) nulliparous women were fitted with Femilis Slim. The LNG-IUS was inserted using a simplified push-in technique (without folding the cross-arms in the insertion tube). Results: This paper is the first report with the Femilis LNG-IUS. The push-in technique of insertion was considered simple and safe. Insertion was reported "easy" in virtually all women (97.9%). Pain at insertion was absent in 24.7% and "mild" in 67.7% of women. With respect to pain, there were no statistical differences between the parous and nulliparous group. At the time of study analysis, the total number of women-months of use was 1769.7. Seventy-six women had the Femilis IUS in place for periods in excess of 1 year. The study was well followed up with lost to follow-up of only two women. No pregnancies were observed. There was one expulsion in the nulliparous and one in the parous group. Ten removals were performed for medical reasons (mainly bleeding and pain). One pelvic infection occurred in a nulliparous woman caused by Chlamydia trachomatis, which was resolved without removing the IUS. There were no other serious adverse events reported. Both Femilis and Femilis Slim were well tolerated, which resulted in a high continuation rate (94.04%). Conclusion: The Femilis LNG-IUS is an effective contraceptive and is easily inserted. The simple and safe insertion procedure could be an advantage for use by nonspecialist providers such as nurses, midwives, general practitioners, and for those not inserting intrauterine devices regularly. Femilis Slim could be an attractive long-term contraceptive option in young and adolescent women

Femilis® 60 Levonorgestrel-Releasing Intrauterine System–-A Review of 10 Years of Clinical Experience

Objective The aim of this study was to update the clinical experience with the Femilis® 60 levonorgestrel-releasing intrauterine system (LNG-IUS), now up to 10 years in parous and nulliparous women, particularly with regard to ease and safety of insertion, contraceptive performance, retention, acceptability, continuation of use, impact on menstrual blood loss (MBL), and duration of action. Study Design Using the Femilis® 60 LNG-IUS releasing 20 μg of levonorgestrel/day, the following studies were conducted: an open, prospective noncomparative contraceptive study, an MBL study, a perimenopausal study, a study for the treatment of endometrial hyperplasia, and early cancer of the uterus, a residue study. Results A total of 599 Femilis LNG-IUS were inserted in various clinical trials, the majority for contraceptive purposes. The total exposure in the first and second contraceptive studies, covering 558 parous and nulliparous women, was 32,717 woman-months. Femilis has high contraceptive effectiveness as only one pregnancy occurred. Expulsion of the LNG-IUS was rare with only two total and no partial expulsions (stem protruding through the cervical canal) occurred. Femilis was well tolerated, with continuation rates remaining high. Several MBL studies were conducted, totaling 80 heavy and normal menstrual bleeders, using the pictorial bleeding assessment chart method or the quantitative alkaline hematin technique. Virtually all women responded well with strongly reduced menstrual bleeding. Amenorrhea rates were high, up to 80% after three months, and ferritin levels simultaneously increased significantly. The Femilis LNG-IUS was tested in 104 symptomatic perimenopausal women for seamless transition to and through menopause, adding estrogen therapy when required. Patient tolerability appeared high as >80% requested a second and a third LNG-IUS. Twenty women presenting with nonatypical and atypical hyperplasia and one woman presenting with early endometrial carcinoma were treated with Femilis LNG-IUS. All histology specimens showed full regression, and patients remained in remission without signs of hyperplasia or cancer at yearly and ongoing follow-up examinations up to 10 years. Residual content of LNG was measured in 37 women having the Femilis LNG-IUS for up to 10 years. In 10 of the 102 women who had the Femilis 60 in situ for 10 years between 20% and 30% of the original 60 mg was recovered confirming the long duration of action of the Femilis 60 LNG-IUS. Conclusion These studies suggest that the Femilis 60 LNG-IUS releasing 20 μg of LNG/day is an effective, well-tolerated, and well-retained contraceptive both in parous and in nulliparous women. The design of the LNG-IUS, with flexible transverse arm(s) length of 28 mm, allows for a simplification of the insertion technique and training requirements facilitating the use by nonspecialist providers in either developed or developing countries. For nulliparous women, additional evaluation of devices with a 24 mm transverse arm(s), as it relates to tolerability, retention, and continuation of use, still needs to be undertaken