WO2000028995A1

WO2000028995A1 - Graduated progestin contraceptive

Info

Publication number: WO2000028995A1
Application number: PCT/US1999/025705
Authority: WO
Inventors: Roger M. Boissonneault
Original assignee: Warner Chilcott Laboratories Ireland Limited
Priority date: 1998-11-12
Filing date: 1999-11-03
Publication date: 2000-05-25
Also published as: EP1148884A1; AU1518900A; EP1148884A4

Abstract

Contraceptive methods and delivery systems involving few undesirable side effects during administration are based on novel multi-phasic norethindrone/ethinyl estradiol combinations, wherein the amount of norethindrone is increased substantially stepwise over the phases.

Description

GRADUATED PROGESTIN CONTRACEPTIVE

Field of the invention

The present invention generally relates to a contraceptive method and delivery system, and in particular a contraceptive method and delivery system involving novel multi-phasic norethindrone/ethinyl estradiol combinations, wherein the amount of norethindrone is increased substantially stepwise over the cycle.

Background of the Invention

The study of the prevention of pregnancy in human females has led to the evolution of many hormone-based compositions. Some compositions contain both estrogenic and progestogenic compounds. Such compositions, referred to herein as "estrogen/progestogen combinations", are highly effective in controlling ovulation and conception.

U.S. Patent No. 4,390,531 discloses the use of norethindrone as the progestogenic component in one type of estrogen/progestogen combination. However, such combinations are generally associated with high incidence of breakthrough bleeding.

U.S. Patent No. 3,733,407 discloses a product which attempts to mimic the phases of the natural menstrual cycle by varying the progestational component.

U.S. Patent No. 4,962,098 discloses contraceptive methods and delivery systems based on novel triphasic estrogen/progestogen combinations, wherein the amount of estrogen is increased stepwise over the three phases.

It is known that the use of graduated estrogen tends to minimize estrogen exposure early in the cycle. Estrogen is then increased during the cycle to grow the endometrium and add stability to the endometrium. In some prior art contraceptive methods the user is exposed to relatively large amounts of estrogen (on the order of about 35 meg), especially near the end of the cycle. The use of such relatively large amounts of estrogen tends to increase the safety risks for the user.

In some prior art contraceptive methods (Ortho-Novum 777) the progestin dose was increased in a step-like fashion every seven days, to mimic the natural menstrual cycle. However, such prior art methods do not teach or suggest that estrogen dosage may thereby be minimized, and in such methods the estrogen dosage remains at relatively high levels (on the order of 30 to 35 meg).

Summary of the Invention

It has been discovered that several unwanted side effects generally associated with the administration of known contraceptive schemes may be minimized when the compositions used correspond to phases comprising, in sequence, about 0.4 to 1.0 mg norethindrone and about 10 to 30 meg ethinyl estradiol in a first phase (Phase I), about 0.5 to 1.2 mg norethindrone and about 10 to 30 meg ethinyl estradiol in a second phase (Phase II), about 0.75 to 1.5 mg norethindrone and about 10 to 30 meg ethinyl estradiol in a third phase (Phase III), and a suitable quantity of placebo in an inactive phase (Phase IV).

The present invention, in a preferred embodiment, may be characterized in that the amount of norethindrone is increased with each succeeding phase. That is, the amount of norethindrone is increased for each composition with different compositions being used in each phase. With current low dose oral contraceptives, cycle control is problematic mid to late cycle. By increasing the amount of norethindrone in pharmacologic doses during mid to late cycle, this problem is ameliorated.

The present invention, in a preferred embodiment, may be administered in a variety of cycles, including 22 day to 35 day cycles, with 23 to 25 day cycles being preferred. Preferably, the first phase will be about four to six days, the second phase will be about five to seven days, the third phase will be about ten to fifteen days, and the pill free interval will be about three to seven days.

Detailed Description of the Preferred Embodiments

The following detailed description is of the best presently contemplated mode of carrying out the invention. This description is not to be taken in a limiting sense, but is made merely for the purpose of illustrating the general principles of the invention. The scope of the invention is best defined by the appended claims.

In its preferred embodiment, the present invention includes a method and a kit for the use of a graduated multi phase, sequentially-administered combination of compositions.

In a preferred embodiment, the compositions employed in accordance with the present invention contain in Phase I about 0.4 to 1.0 mg norethindrone and about 10 to 30 meg ethinyl estradiol, in Phase II about 0.5 to 1.2 mg norethindrone and about 10 to 30 meg ethinyl estradiol, and in Phase III about 0.75 to 1.5 mg norethindrone and about 10 to 30 meg ethinyl estradiol. The amount of norethindrone is preferably increased stepwise over the three compositions.

In a preferred embodiment of a method in accordance with the present invention, a first composition is administered for about five days and comprises about 0.4 mg norethindrone and about 20 meg ethinyl estradiol, a second composition is administered for about six days and comprises about 0.70 mg norethindrone and about 20 meg ethinyl estradiol, and a third composition is administered for about thirteen days comprising 1.0 mg norethindrone and about 20 meg ethinyl estradiol.

In one preferred embodiment, the invention is directed to a method of contraception comprising the steps of sequentially administering, to a female of child bearing age: for about four to about six days, a first composition comprising about 0.4 to 1.0 mg norethindrone and about 10 to 30 meg ethinyl estradiol, for about five to seven days, a second composition comprising about 0.5 to 1.2 mg norethindrone and about 10 to 30 meg ethinyl estradiol, for about ten to fifteen days, a third composition comprising 0.75 to 1.5 mg norethindrone and about 10 to 30 meg ethinyl estradiol, wherein the amount of norethindrone is increased stepwise by the amount of 0.30 mg in each step.

In another embodiment, the invention is directed to a graduated multiphase combination and contraceptive kit comprising a package comprising daily dosages of a Phase I composition comprising norethindrone and ethinyl estradiol, a Phase II composition comprising norethindrone and ethinyl estradiol, and a Phase III composition comprising norethindrone and ethinyl estradiol, wherein the amount of norethindrone is increased in a substantially stepwise fashion over the three compositions.

A pill free interval, which comprises one or more placebos, may be used in conjunction with the other three compositions.

The compositions may be consumed or administered in a numeric sequence with the Phase I composition being used first, the Phase II composition being used second, etc. The method and kit described herein can be employed as part of a larger scheme for contraception or treatment of gynecological disorders. While the sequence in which the combinations are administered is generally important to their operation, variations in timing and dosage may be tolerated when medical considerations so dictate.

The present invention provides several advantages over prior art methods which employ estrogen/progestogen combinations. Principal among its advantages are ease of administration and the benefits of graduated progestin, i.e., maintaining low overall estrogen exposure while increasing progestogen mid to late cycle which results in increased stability of the developing and mature endometrium. In contrast to known contraceptive techniques, the present invention maintains a relatively low level of estrogen throughout the entire cycle. In a preferred embodiment, the estrogen level is maintained at a substantially constant dosage of about 20 meg throughout the cycle. The user is not required to be exposed to dosages as high as 35 meg at the end of the cycle, as in some prior art techniques. By thereby reducing estrogen exposure, the present invention tends to increase safety of the present invention in contrast to other prior art contraceptives.

Nor does the present invention require that the progestin dose must be increased in a step-like fashion every seven days, to mimic the natural menstrual cycle. Since cycle control is problematic mid to late cycle, the present invention makes use of stepwise pharmacologic increases in norethindrone (graduated norethindrone), rather than attempting to mimic natural physiology

In further contrast to known contraceptive methods, the present invention tends to reduce side effects, such as breakthrough bleeding, that occur with existing low dosage pills. In a preferred embodiment of the present invention the active pill taking period is increased from about 21 days to between about 23 and 25 days. Extending the third phase (highest progestin dose) results in improved cycle control. Reducing the pill free interval, number of placebo pills, should also improve the overall efficacy of the regimen.

The following table describes representative example of compositions, administration times and drug contents in accordance with a preferred embodiment of the present invention. The table sets forth relevant values for one preferred embodiment, or configuration, for administration to the system to females. TABLE

Phase Administration Norethindrone Ethinyl Placebo, mg

Interval, Days , mg Estradiol, meg

1 5 0.4 20 0

II 6 0.7 20 0

III 13 1.0 20 0

IV 4 0 0 0

The table above is presented for illustrative purposes only. For example, the present invention encompasses the substitution of functionally equivalent amounts and kinds of reagent(s) in these schemes.

In addition, the present invention encompasses the use of other conventional additives, e.g., fillers, colorants, polymeric binders, and the like. In general, there are a wide variety of pharmaceutically-acceptable additives which may be used in one or more of the compositions without significantly interfering with the function of the active components.

Examples of suitable carriers with which the compositions can be administered include, without limitation, lactose, starch, cellulose derivatives and the like used in suitable amounts. Lactose is a preferred carrier. Mixtures of carriers may also be used.

One example of the norethindrone which may be used in the present invention is Noriutin™, a product believed to be (or have been) manufactured by Parke-Davis. One example of the ethinyl estradiol which may be used in the present invention is Estinyl™, a product manufactured by Schering Plough.

In some embodiments of the invention the norethindrone component may be completely or partially replaced with one or more alternative components, including, for example, norethindrone acetate, norgestrel, desogestrel or norgestimate. In some embodiments of the invention the ethinyl estradiol component may be completely or partially replaced with one or more alternative components, including, for example mestranol.

As used herein, the designation "meg" refers to micrograms and "mg" to milligrams.

While the preferred embodiment of the present invention is described as one employing four phases, another embodiment may employ only three. Phase IV is not essential to the operation of the other three phases. Thus, a method or kit which does not contain the Phase IV component is operable and, in fact, may be preferred when suitable factors, e.g., economy, dictate the non-use of the Phase IV component.

The terms "method" and "kit" as used herein may include any drug delivery systems via the use of which the 3- or 4-phase scheme outlined above can be effectively administered to human females. Combinations of various dosage forms may also be used.

A unique dosage pattern, i.e., a unique sequence of administrations of a novel norethindrone/ethinyl estradiol combination has been discovered which minimizes certain side effects, notably breakthrough bleeding, commonly associated with conventional low dosage pills.

The presently disclosed embodiments are to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims, rather than the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

What is claimed is:

1. A method of contraception comprising the steps of sequentially administering to a female of child bearing age: for about four days to about six days, a first composition comprising about 0.4 to 1.0 mg norethindrone and about 10 to 30 meg ethinyl estradiol, for about five days to about seven days, a second composition comprising about 0.5 to 1.2 mg norethindrone and about 10 to 30 meg ethinyl estradiol, for about ten days to about fifteen days, a third composition comprising about 0.75 to 1.5 mg norethindrone and about 10 to 30 meg ethinyl estradiol, wherein norethindrone is increased stepwise by an amount of 0.30 mg in each step.

2. The method of claim 1 comprising the step of administering, for about three days to about seven days, a fourth composition comprising at least one placebo.

3. The method of claim 1 wherein the first composition comprises about 0.4 mg norethindrone and about 20 meg ethinyl estradiol, the second composition comprises about 0.7 mg norethindrone and about 20 meg ethinyl estradiol, and the third composition comprises about 1.0 mg norethindrone and about 20 meg ethinyl estradiol.

4. The method of claim 1 wherein the first composition is administered for about five days and comprises about 0.4 mg norethindrone and about 20 meg ethinyl estradiol, the second composition is administered for about six days and comprises about 0.7 mg norethindrone and about 20 meg ethinyl estradiol, and the third composition is administered for about thirteen days and comprises about 1.0 mg norethindrone and about 20 meg ethinyl estradiol.

5. The method of claim 4 wherein the compositions are administered in combination with a suitable carrier.

6. A method of contraception comprising the steps of sequentially administering to a female of child bearing age: for a first period of days, a first composition comprising an amount of norethindrone and an amount of ethinyl estradiol, for a second period of days, a second composition comprising an amount of norethindrone and an amount of ethinyl estradiol, the second composition comprising an amount of norethindrone approximately 0.30 mg greater than the amount of norethindrone in the first composition, for a third period of days, a third composition comprising an amount of norethindrone and an amount of ethinyl estradiol, the third composition comprising an amount of norethindrone approximately 0.30 mg greater than the amount of norethindrone in the second composition.

7. A method of contraception comprising the steps of sequentially administering to a female of child bearing age: for a first period of days, a first composition comprising an amount of norethindrone and an amount of ethinyl estradiol, for a second period of days, a second composition comprising an amount of norethindrone and an amount of ethinyl estradiol, the second composition comprising an amount of norethindrone approximately 0.30 mg greater than the amount of norethindrone in the first composition and an amount of ethinyl estradiol approximately equal to the amount of ethinyl estradiol in the first composition, for a third period of days, a third composition comprising an amount of norethindrone and an amount of ethinyl estradiol, the third composition comprising an amount of norethindrone approximately 0.30 mg greater than the amount of norethindrone in the second composition and an amount of ethinyl estradiol approximately equal to the amount of ethinyl estradiol in the second composition.

8. The method of claim 6 or 7 comprising the step of administering, for a fourth period of days, a fourth composition comprising at least one placebo.

9. The method of claim 6 or 7, wherein the first period of days comprises four to six days, the second period of days comprises five to seven days, and the third period of days comprises ten to fifteen days.

10. The method of claim 9, wherein the first period of days comprises five days, the second period of days comprises six days, and the third period of days comprises thirteen days.

11. The method of claim 6 or 7, wherein the first composition comprises about 0.4 to 1.0 mg norethindrone and about 10 to 30 meg ethinyl estradiol, the second composition comprises about 0.5 to 1.2 mg norethindrone and about 10 to 30 meg ethinyl estradiol, and the third composition comprises about 0.75 to 1.5 mg norethindrone and about 10 to 30 meg ethinyl estradiol.

12. The method of claim 11, wherein the first composition comprises about 0.4 mg norethindrone and about 20 meg ethinyl estradiol, the second composition comprises about 0.7 mg norethindrone and about 20 meg ethinyl estradiol, and the third composition comprises about 1.0 mg norethindrone and about 20 meg ethinyl estradiol.

13. The method of claim 8, wherein the fourth period of days comprises about three to seven days.

14. A contraceptive kit, comprising: a first plurality of daily dosages of a first composition comprising an amount of norethindrone and an amount of ethinyl estradiol, a second plurality of daily dosages of a second composition comprising an amount of norethindrone and an amount of ethinyl estradiol, the second composition comprising an amount of norethindrone approximately 0.3 mg greater than the amount of norethindrone in the first composition, and a third plurality of daily dosages of a third composition comprising an amount of norethindrone and an amount of ethinyl estradiol, the third composition comprising an amount of norethindrone approximately 0.3 mg greater than the amount of norethindrone in the second composition.

15. A contraceptive kit, comprising: a first plurality of daily dosages of a first composition comprising an amount of norethindrone and an amount of ethinyl estradiol, a second plurality of daily dosages of a second composition comprising an amount of norethindrone and an amount of ethinyl estradiol, the second composition comprising an amount of norethindrone approximately 0.3 mg greater than the amount of norethindrone in the first composition and an amount of ethinyl estradiol approximately equal to the amount of ethinyl estradiol in the first composition, and a third plurality of daily dosages of a third composition comprising an amount of norethindrone and an amount of ethinyl estradiol, the third composition comprising an amount of norethindrone approximately 0.3 mg greater than the amount of norethindrone in the second composition and an amount of ethinyl estradiol approximately equal to the amount of ethinyl estradiol in the third composition.

16. The kit of claim 14 or 15 comprising a fourth plurality of daily dosages of a fourth composition comprising at least one placebo.

17. The kit of claim 14 or 15, wherein the first plurality of daily dosages comprises four to six daily dosages, the second plurality of daily dosages comprises five to seven daily dosages, and the third plurality of daily dosages comprises ten to fifteen daily dosages.

18. The kit of claim 17, wherein the first plurality of daily dosages comprises five daily dosages, the second plurality of daily dosages comprises six daily dosages, and the third plurality of daily dosages comprises thirteen daily dosages.

19. The kit of claim 14 or 15, wherein the first composition comprises about 0.4 to 1.0 mg norethindrone and about 10 to 30 meg ethinyl estradiol, the second composition comprises about 0.5 to 1.2 mg norethindrone and about 10 to 30 meg ethinyl estradiol, and the third composition comprises about 0.75 to 1.5 mg norethindrone and about 10 to 30 meg ethinyl estradiol.

20. The kit of claim 19, wherein the first composition comprises about 0.4 mg norethindrone and about 20 meg ethinyl estradiol, the second composition comprises about 0.7 mg norethindrone and about 20 meg ethinyl estradiol, and the third composition comprises about 1.0 mg norethindrone and about 20 meg ethinyl estradiol.

21. The kit of claim 16, wherein the fourth plurality of daily dosages comprises about three to seven daily dosages.