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Title:  Low dose estrogen interrupted hormone replacement therapy

United States Patent:  6,747,019

Issued:  June 8, 2004

Inventors:  Casper; Robert F. (Toronto, CA); Shangold; Gary A. (Califon, NJ); Ausmanas; Militza K. (Lake Forest, IL)

Assignee:  Jencap Research, Ltd. (Toronto, CA); Ortho-McNeil Pharmaceutical, Inc. (Raritan, NJ)

Appl. No.:   134455

Filed:  April 30, 2002

Abstract

A hormone replacement therapy, comprising a plurality of daily doses of a pharmaceutical preparation, the doses being administered continuously and consecutively in alternating phases of three daily doses, a relatively dominant estrogenic activity phase comprising three daily doses of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol per day, and a relatively dominant progestagenic activity phase of a combination of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol and a substance exhibiting progestogenic activity equivalent to about 90 .mu.g per day of norgestimate.

SUMMARY OF THE INVENTION

It has now been discovered that a selected dosage regimen within the broad class proposed in the aforementioned US Patents, provides unexpected benefits that are of major significance for the patient.

The remarkable finding of the regimen is that maximum symptom relief, in particular hot flushes, is obtained with the regimen and this relief is equivalent to that for a regimen of the same type where the estrogen level is 100 percent higher. It was unexpected that symptom relief would be the same for both estrogen levels in this type of regimen.

The advantage of the present regimen over those of the same class with higher estrogen levels is that it offers an increased margin of safety because of its lower estrogen level, while providing the same symptom relief.

The regimen of the present invention was also compared with a known HRT regimen sold under the brand names KLIOGEST.RTM. and KLIOSEM.RTM. and known for its effective symptom relief. This known product contains 100 percent higher estrogen than the present formulation. Symptom relief was equivalent in both regimens.

The present invention provides, in one aspect, a pharmaceutical preparation for administration to a female in need of hormone replacement therapy, comprising a plurality of doses for consecutive administration in alternating phases, the phases consisting of a relatively dominant estrogenic activity phase comprising three daily doses or an equivalent thereof, of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol, and a relatively dominant progestogenic activity phase comprising three daily doses or an equivalent thereof, of a combination of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol and a substance exhibiting progestogenic activity equivalent to about 90 .mu.g per day of norgestimate.

In a more preferred form of the pharmaceutical preparation of the invention, there is provided a pharmaceutical preparation for administration to a female in need of hormone replacement therapy comprising a plurality of daily doses for consecutive administration, the doses being administered consecutively in alternating phases, the phases comprising a relatively dominant estrogenic activity phase comprising three consecutive daily doses of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol, and a relatively dominant progestogenic activity phase comprising three consecutive daily doses of a combination of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol and a substance exhibiting progestogenic activity equivalent to about 90 .mu.g per day of norgestimate.

In another aspect of the invention, there is provided a package containing a pharmaceutical preparation for administration to a female in need of hormone replacement therapy, comprising a plurality of doses for consecutive administration arranged in alternating phases, the phases consisting of a relatively dominant estrogenic activity phase comprising three daily doses or an equivalent thereof, of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol, and a relatively dominant progestogenic activity phase comprising three daily doses or an equivalent thereof, of a combination of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol and a substance exhibiting progestogenic activity equivalent to about 90 .mu.g per day of norgestimate.

In a more preferred form of the pharmaceutical package of the invention, there is provided a pharmaceutical package containing a pharmaceutical regimen for administration to a female in need of hormone replacement therapy, the doses being arranged for consecutive administration in alternating phases, the phases consisting of a relatively dominant estrogenic activity phase comprising three consecutive daily doses of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol, and a relatively dominant progestogenic activity phase comprising three consecutive daily doses of a combination of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol and a substance exhibiting progestogenic activity equivalent to about 90 .mu.g per day of norgestimate.

In yet another aspect the invention provides a method of treating a female in need of hormone replacement therapy comprising administering to said female a pharmaceutical regimen comprising a plurality of doses arranged in alternating phases, the phases comprising a relatively dominant estrogenic activity phase comprising three daily doses or an equivalent thereof, of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol, and a relatively dominant progestogenic activity phase comprising three daily doses or an equivalent thereof, of a combination of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol and a substance exhibiting progestogenic activity equivalent to about 90 .mu.g per day of norgestimate.

In yet another aspect the invention provides a use of an estrogenically active substance and a progestogenically active substance in the preparation of a medicament, characterized in that the medicament is for hormone replacement therapy for administration to a female in need of such therapy, the medicament comprising a plurality of doses for consecutive administration in alternating phases the phases consisting of a relatively dominant estrogenic activity phase comprising three daily doses or an equivalent thereof, of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol, and a relatively dominant progestogenic activity phase comprising three daily doses or an equivalent thereof, of a combination of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol and a substance exhibiting progestogenic activity equivalent to about 90 .mu.g per day of norgestimate.

In a preferred form of the invention there is provided a use of an estrogenically active substance and a progestogenically active substance in the preparation of a medicament, characterized in that the medicament is for hormone replacement therapy for administration to a female in need of such therapy, the medicament comprising a plurality of daily doses for consecutive administration in alternating phases, the phases consisting of a relatively dominant estrogenic activity phase comprising three consecutive daily doses of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol, and a relatively dominant progestogenic activity phase comprising three consecutive daily doses of a combination of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol and a substance exhibiting progestogenic activity equivalent to about 90 .mu.g per day of norgestimate.

DETAILED DESCRIPTION OF THE INVENTION

In a preferred form of all aspects of the invention, the substance exhibiting progestogenic activity is selected on the basis that it binds to progestin receptors, demonstrates poor affinity for androgen receptors and has a lack of affinity for sex-hormone-binding globulin (SHBG).

In its most preferred form, the invention provides a therapy or regimen in which the three daily doses in the relatively dominant estrogenic activity phase comprise about 1 mg per day of 17.beta.-estradiol, and in the relatively dominant progestogenic activity phase comprise about 1 mg per day of 17.beta.-estradiol and about 90 .mu.g per day of norgestimate.

Generally the formulation of the invention will consist of a single oral tablet taken once daily. On days one through three of therapy, the tablet contains 17.beta.-estradiol. On days four through six of therapy, the tablet contains both 1.0 mg. 17.beta.-estradiol and 90 .mu.g or 0.09 mg of norgestimate. This unique regimen consisting of a pattern of three days of 17.beta.-estradiol only followed by three days of 17.beta.-estradiol plus norgestimate is repeated continuously throughout therapy.

DEFINITIONS

A Female in Need of Hormone Replacement Therapy

Generally this would include a female of child bearing age or older in whom ovarian estrogen and progesterone production has been interrupted either because of natural menopause, surgical, radiation, or chemical ovarian ablation or extirpation or premature ovarian failure.

A Relatively Dominant Estrogenic Activity Phase

A Relatively Dominant Progestogenic Activity Phase

One may start the regimen with either phase, although the relatively dominant estrogenic activity phase is the preferred starting phase.

The word relative defines the activity of a phase with respect to any immediately preceding phase and any immediately following phase.

The only activity of the phase is the estrogenic activity and therefore it is dominant in this phase, and this activity is relative to the other estrogenic activity of the phase where a progestogenically active substance is present also. In the relatively dominant progestogenic activity phase the dominant hormone activity is the progestogenic activity, and again this activity in this phase is dominant relative to its activity in the other phase.

In the relatively dominant estrogenic activity phase, the estrogen stimulates endometrial growth and progestogen receptors. Consequently, the endometrium is more sensitive to subsequent progestogen activity that limits growth by decreasing estrogen receptors and increasing 17.beta.-hydroxysteroid dehydrogenase. Interaction of progestogen in the second relatively dominant estrogenic activity phase with progestogen receptors induces secretory changes in the endometrium, which results in a denser stroma and endometrial stability. A return to relatively dominant estrogenic activity then again stimulates estrogen and progestogen receptors and renews endometrial sensitivity to progestogen. This push/pull activity keeps endometrial activity within a low range depending on the number of days of estrogenic and progestogenic activity [see Cameron, Sharon T., et al, Continuous transdermal oestrogen and interrupted progestogen as a novel bleed-free regimen of hormone replacement therapy for postmenopausal women, British Journal of Obstetrics and Gynaecology, October 1997, Vol. 104, pp. 1184-1190]. In this instance, the relatively dominant estrogenic activity phase lengths that have been found to maximize this push/pull activity are three days for each relatively dominant estrogenic activity phase.

A Substance Exhibiting Estrogenic Activity and a Substance Exhibiting Progestogenic Activity

Any substance that exhibits appropriate estrogenic activity may be used in the present invention. As indicated the preferred estrogen is 17.beta.-estradiol. Other suitable estrogens include 17.alpha.-ethinylestradiol, esters and ethers of 17.alpha.-ethinylestradiol such as, for example, 17.alpha.-ethinylestradiol 3-dimethylamino propionate, 17.alpha.-ethinylestradiol 3-cyclopentyl ether (quienestrol) and 17.alpha.-ethinylestradiol 3-methyl ether (mestranol). Natural estrogens such as estrone, estrone sulfate, estrone sulfate piperazine salt, estradiol and estriol, and their esters, as well as the synthetic estrogens, may also be employed. The selection of the estrogen and the dose level will generally follow from the literature, which is well known to the person skilled in the art. The dose level is dependent on the cyclophasic regimen. The discussion that follows about the selection of a progestogen and its dose level may be used as a guide in the selection of the estrogen.

The preferred progestogen is norgestimate. Norgestimate is also known under its chemical name D-17.beta.-acetoxy-.beta.-ethyl-17.alpha.-ethinyl-gon-4-en-3-one oxime. While other progestogens may be used in place of norgestimate, in selecting a suitable progestogen, and in particular norgestimate, selection criteria include degree of affinity for progestogen receptor, absence of affinity for androgen receptor and whether the progestogen displaced androgen from human sex-hormone-binding globulin (SHBG) [see Phillips, Audrey et al., Preclinical evaluation of norgestimate, a progestin with minimal androgenic activity, Am J Obstet Gynecology, October 1992, October 1992, Volume 167, Number 4, Part 2, pp. 1191-1196]. In the case of norgestimate, it binds to progestin receptors, it demonstrates very poor affinity for androgen receptors and it has a lack of affinity for SHBG. All of these effects make it similar to natural progesterone.

Other progestogens may be employed in the present therapy regimen as long as they meet the criteria set forth above for the selection of norgestimate. In essence, the progestogen must have a profile that is similar to norgestimate. Possible choices of those progestogens that meet these requirements include desogestrel, dydrogesterone, medroxyprogesterone acetate, norethynodrel, cyproterone acetate, chlormadinone acetate, magestrol acetate, 17 D-acetyl norgestimate, dienogest, trimegestone, drosperinone and nomagestrel. Examples of progestogens that do not have a suitable profile include norethindrone and norgestrel. The literature contains descriptions of numerous progestogens and based on the criteria set out above, the person skilled in the art may make a suitable choice.

As stated the preferred dose for norgestimate is about 90 .mu.g. Equivalent doses for other progestogens may be determined by the person skilled in the art by reference to the literature, for example the standard text Treatment of the Menopausal Woman, Basic and Clinical Aspects, Ed. Lobo, Rogerio A., Raven Press, New York, pp73-80. Dosage selection is made with reference to hormone potency and the nature of the regimen, which is cyclophasic and does allow for lower levels of hormones. Examples of suitable equivalent doses include about 54 .mu.g/day of desogestrel, about 180 .mu.g/day of 3-keto-desogestrel, about 90 .mu./day of 17D-acetyl norgestimate, about 180 .mu.g/day of cyproterone acetate, about 720 .mu.g/day of dienogest, about 1080 .mu.g/day of drosperinone and about 27 .mu.g/day of gestogen. When making a choice of dose level, it would be a matter of routine experimentation for the person skilled in the art to take the equivalent dose level in the selected hormone and then to test a few doses around that level in order to refine the dose level.

Three Daily Doses or an Equivalent Thereof

The daily doses of the present invention may be administered in any convenient form. Preferred, as set out earlier is a single daily tablet, but any other suitable form may be employed. The single tablet is preferred as it reduces the likelihood that the patient will get confused. The words "an equivalent thereof" are meant to cover administrative forms that do not comprise daily doses, for example a transdermal form.

Generally speaking, the formulations are prepared according to conventionally known procedures in accordance with the desired method of administration. Different amounts of the active ingredients may be required in different types of formulations but it is essential that the amount of estrogenically active substance and progestationally active substance be selected so as to provide the dose equivalency for the regimen as described above. The percentage of active ingredients may vary according to the potency of the hormone, the delivery system or method of administration and is chosen in accordance with conventional methods known in the art.

The estrogen and progestogen compositions can be administered by way of any art recognized means as practiced in the pharmaceutical arts. For example, the estrogen and progestogen alone or in combination may be so formulated so that it can be administered orally, via a skin patch for transdermal absorption, by intramuscular injection, contained within an inert matrix which is implanted within the body and in a depot state, or intravaginally in a matrix that slowly releases the active compositions (such implants are taught for example in U.S. Pat. Nos. 4,957,119 and 5,088,505).

Pharmaceutical compositions containing compounds of the invention may further comprise pharmaceutically acceptable carriers and be in either solid or liquid form. Solid preparations include powders, tablets, dispersible granules, capsules, etc. The carrier may also be one or more substances, which act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents as well as encapsulating materials. Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, peptin, dextrin, starch, methylcellulose, sodium carboxylmethylcellulose, and the like. Liquid form preparations include solutions, which are suitable for oral or parenteral administration, or suspensions and emulsions suitable for oral administration.

Sterile water solutions of the active component or sterile solutions of the active components in solvents comprising water, ethanol, or propylene glycol are examples of liquid preparations suitable for parenteral administration. Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable flavorants, coloring agents, stabilizers and thickening agents as required. Aqueous suspensions for oral use can be made by dispersing the active component in water together with a viscous material such as a natural or synthetic gum, methylcellulose, sodium carboxymethyl-cellulose, and other suspending agents known to the pharmaceutical formulation art. Other solid dosage forms include topical dosage forms which include solutions, powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, creams, gels or jellies and foams; and parenteral dosage forms which include solutions, suspensions, emulsions or dry powder comprising an effective amount of estrogen or estrogen and progestogen as taught in this invention.

Various conventional techniques for preparing pharmaceutical compositions including solutions, suspensions, tablets or caplets can be employed, as would be known to those skilled in the art and as is disclosed for example by Remington's Pharmaceutical Sciences, Mack Publishing Co., Part 8, Chapters 76-93, Pharmaceutical Preparations and Their Manufacture, pp. 1409-1677 (1985).

The pharmaceutical formulations may be provided in kit form containing preferably multiples of three unit dosages, each constituting a relatively dominant estrogenic activity phase and in a suitable form, for example, caplets or tablets. The kit may comprise a dial package or a foil strip as is well known in the art. The kit would typically contain an even number of doses for each phase arranged in an even number of relatively dominant estrogenic activity phases. Thus the unit dosages would be arranged in each package in multiples of six so that an even number of phases would be present in each package.

The term "unit dosage form" as used herein refers to physically discrete units suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The term "doses" as used herein broadly encompasses the term unit dosage form or dosage units as well as continuous dosing of compositions by depot or other methods.

A Combined Preparation

This term is meant to indicate that the therapy or formulation is meant to comprise both an estrogenically active substance and a progestogenically active substance. Only the relatively dominant progestogenic activity phase involves both substances delivered in combination.

Consecutively

Generally hormone replacement therapy is administered on a daily basis, every day to a patient. This is the case in the present invention, but there may be instances where hormone free days could be desirable. In such a case, dosages containing placebo or any other hormone-free agent may be included in the regimen. Examples of suitable alternative hormone-free agents include vitamins and/or iron supplements. It should be noted that the phases are consecutively administered to the patient.

The active ingredients are usually compounded with the chosen carrier and in for example the case of a tablet form, placed in a tablet molding apparatus to form the tablets which are subsequently packaged in accordance with the chosen regimen.

In the oral form of the formulation, the package would have the daily dosages arranged for proper sequential administration. Data indications may be provided on the packaging. The packaging may be a tube or box or a strip. The box may be circular, square, or otherwise shaped with the tablets for example being accommodated separately therein for ease of administration. Date indications may appear adjacent each tablet corresponding with the days on which each tablet is to be taken. Some indication of the sequence in which the tablets are to be taken preferably appears on the packaging regardless of its form.

Claim 1 of 24 Claims

We claim:

1. A pharmaceutical preparation for administration to a female in need of hormone replacement therapy, comprising a plurality of doses for administration in alternating relatively dominant estrogenic activity phases, the relatively dominant estrogenic activity phases consisting of a relatively dominant estrogenic activity relatively dominant estrogenic activity phase comprising three consecutive daily doses or an equivalent thereof, of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol, and a relatively dominant progestogenic activity phase comprising three consecutive daily doses or an equivalent thereof, of a combination of a substance exhibiting estrogenic activity equivalent to about 1 mg per day of 17.beta.-estradiol and a substance exhibiting progestogenic activity equivalent to about 90 .mu.g per day of norgestimate.




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