Surgery – Female reproductory tract shields – supports – or birth...
Reexamination Certificate
2001-11-06
2004-06-01
Brown, Michael A. (Department: 3764)
Surgery
Female reproductory tract shields, supports, or birth...
C128S832000, C128S833000
Reexamination Certificate
active
06742520
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
Applicant claims priority under 35 U.S.C. §119 of BELGIUM Application No. 9900331 filed on May 7, 1999. Applicant also claims, priority under 35 U.S.C. §120 of PCT/BE00/00036 filed on Apr. 13, 2000. The international application under PCT article 21(2) was not published in English.
FIELD OF THE INVENTION
The present invention relates to an intrauterine device comprising a support and an ingredient releasing element for releasing an active ingredient, the active ingredient comprising copper and a steroid selected from the group consisting of natural progesterone, levonorgestrel and desogestrel. The copper has a surface area in the range 100 to 250 mm
2
, and the steroid is releasable at a release rate within the following range, as a function of the steroid used:
for natural progesterone
5 to 35
&mgr;g/day;
for levonorgestrel
2 to 14
&mgr;g/day;
for desogestrel
0.1 to 0.7
&mgr;g/day.
The invention has high contraceptive efficacy and significantly reduced side effects.
PRIOR ART
Intrauterine contraceptive devices are generally constituted by a support and an active ingredient released from the support.
The support is either a substantially rigid support, for example T or V-shaped, held in the uterus by dint of its shape, or a readily deformable thread or loop held in the uterus by anchoring into the wall at the fundus of the uterus.
Copper is traditionally employed as the active ingredient in intrauterine devices. Depending on the supports employed, the copper is either in the form of a coiled wire or a collar mounted on a rigid support, or in the form of elements that may or may not be hollow that are assembled together, generally by a filament, to constituent a non-rigid assembly in the form of a thread. An intrauterine device of that latter type is, for example, disclosed in the present Applicant's Belgian patent BE-A-901 652. In that publication, the intrauterine device is constituted by hollow copper elements, pierced through and disposed end-to-end to form a longitudinal channel allowing the passage of a needle, those elements being connected into a non-rigid assembly, the assembly being integral with a filament provided with a means for anchoring it in the tissue of the uterus, which can be inserted using a needle.
When copper is used as an active ingredient, until now it has been considered that the larger the surface area of copper exposed in the uterus, i.e., the larger the number of copper ions liberated into the uterus per unit time, the better the contraceptive action of the intrauterine device. This is despite the fact that copper ions are known to have a perturbing effect on homeostasis of the endometrium, in particular its coagulation capacity, and are thus capable of causing heavy bleeding during periods. This perturbing effect is, however, accepted in order to guarantee the contraceptive activity of the device. As a result, the surface area of the copper exposed in the uterus is not generally less than 250 mm
2
. Trials carried out with conventional T or V-shaped intrauterine devices having a reduced copper surface area of 200 mm
2
show a failure rate (undesirable pregnancies) of 3%, which is unacceptable.
The use of steroids from the progesterone family (progesterone and progestins) as the active ingredient in the uterus is also known. Such substances have until now been contained either in a silicone support in the form of a rod, or in a porous polymer support in the form of a fibre, with characteristics that are ascertained so as to provide a release rate for the active ingredient that is suitable for the desired contraceptive activity. An intrauterine device of that type has been described in European patent EP-B-0 445 150, which is also in the name of the present Applicant.
Steroids from the progesterone family used in the uterus as an active contraceptive ingredient comprise natural progesterone and progestins, examples of which are levonorgestrel, norgestimate, gestodene, desogestrel, medroxyprogesterone acetate, etc . . .
The skilled person is well aware that such steroids do not all have the same degree of activity, and so some necessitate the use of high release rates than others. Thus, for example, when the porous polymer support contains natural progesterone, release rates until now have been in the range 50 to 100 &mgr;g/day; for levonorgestrel, the release rate range is 20 to 30 &mgr;g/day, while for desogestrel, a release rate range of 1 to 5 &mgr;g/day will not be exceeded.
Such quantities of steroids, considered until now to be necessary to guarantee a satisfactory contraceptive action, are capable of having undesirable side effects, such as systemic effects: mood changes, headaches, nausea, acne, functional ovarian cysts, or local effects: prolonged weak bleeding or amenorrhea.
Finally, intrauterine devices with a stronger contraceptive effect have been produced by combining natural progesterone and copper. Such a device has been described in German patent DE-A-4 125 575.
In that document, it is known to use a device with a copper surface area of 250 mm
2
and a progesterone release rate of 65 &mgr;g/day. This substantially corresponds to the copper surface areas and progesterone release rates used until now in intrauterine devices employing just one of those constituents.
Finally, EP-A-0 117 163 discloses the use of copper and progesterone together, combined with aminoisocaproic acid. That document teaches that in 1983, a copper-progesterone-aminoisocaproic acid combination was known to involve a synergistic effect between the constituents.
DE-A-4 125 575 teaches that in 1993, there was no incompatibility or contrary effects in a limited combination of copper and progesterone, since the combination was effective when the components were used in their normal quantities.
AIM OF THE INVENTION
We have now surprisingly, discovered that at the contraceptive level, there exists a synergistic effect between copper and a progestin, this effect being of a level such that, while ensuring extremely high contraceptive efficacy, the doses of the constituents, copper and a progestin, can be reduced to values such that their side effects are considerably reduced, if not completely eliminated.
This complete or almost complete absence of side effects is particularly significant in the field of contraception. While the effectiveness of the intrauterine device is guaranteed, and this is at a high level in the device of the invention, for the comfort of the user and thus for the intrauterine device to be readily accepted, its use involves a minimum of disadvantages and as few perturbations as possible.
The present invention concerns an intrauterine device for putting this discovery into practice.
In its preferred embodiments, the invention also aims to provide an intrauterine device that not only has the advantages mentioned above, but which also protects the uterus against sexually transmitted ascending infections.
REFERENCES:
patent: 4180064 (1979-12-01), Heller et al.
patent: 4326511 (1982-04-01), Zimerman
patent: 4353363 (1982-10-01), Sopena Quesada
patent: 4708134 (1987-11-01), Wildemeersch
patent: 5417223 (1995-05-01), Aarnio et al.
patent: 4125575 (1995-04-01), None
patent: 0117163 (1984-08-01), None
patent: 2555893 (1985-06-01), None
Brown Michael A.
Collard & Roe P.C.
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