SI9300687A - Transdermal hormone replacement therapy - Google Patents

Abstract

The present invention provides a method of treating a female in need of hormone replacement therapy comprising transdermally administering to said female a series of alternating phases of from about one to about four days of estrogen dominant activity and phases of from about one to about four days of progestin dominant activity, with the estrogen dominant activity phase consisting of administering a transdermal estrogen substance alone or administering a transdermal estrogen substance and a transdermal progestin substance and the progestin dominant activity phase consisting of administering a transdermal progestin substance and a transdermal estrogen substance, the amount of progesting substance being alternately increased in the progesting dominant activity phase and decreased in the estrogen dominant activity phase to provide the required dominant activity.

Description

Jencap Research Ltd.

Transdermal hormone replacement therapy

The present invention relates to hormone replacement therapy in menopausal or castrated women. Specifically, the present invention relates to a formulation and a process involving transdermal administration.

Estrogen replacement therapy in menopausal women is justified for various reasons. Estrogen replacement is known to dampen heat waves and this wave and night sweats alleviates typical sleep and contributes to the patient's overall well-being. Estrogen replacement protects against loss of calcium from the postmenopausal skeleton, especially from vertebral carcasses, which prevents brittle fractures and weight loss. Various studies now indicate that long-term estrogen therapy is also associated with a reduction in the incidence of classic osteoporosis of the forearm and hip. A further beneficial effect of long-term estrogen use is a reduction in the risk of death from ischemic heart disease, possibly mediated by changes in blood lipoprotein concentrations. Estrogen replacement has also been shown to improve the vascularity and health of the vaginal mucosa and urinary tract. The only major risk factor associated with the administration of estrogen at the doses needed to relieve menopausal symptoms is hyper stimulation of the endometrium and increased risk of endometrial cancer. Progestin supplementation for 13 days each month has been shown to protect the endometrium from these estrogen stimulating effects.

Progestin protects the endometrium by lowering the concentrations of the nuclear estradiol receptor and, therefore, increases the nuclear estrogen bioavailability, resulting in an antimitotic effect and a decrease in DNA synthesis. Progestins also increase the activity of indometric estradiol-17/3-dehydrogenase, an enzyme that metabolizes estradiol to estrone, a less effective estrogen. However, there were concerns about the potential adverse effects of progestin in the suppression of high density lipoprotein cholesterol concentrations. This cholesterol fraction appears to have a protective effect against ischemic heart disease and atherosclerosis. Lowering HDL cholesterol with progestin can negate the long-term beneficial effects of estrogen by reducing the incidence of myocardial infection. Other side effects of progestins include acne, breast tenderness, depression and irritability. Because the side effects of progestins appear to be dose dependent, the dose of progestin used in menopause replacement estrogens is the minimum required to achieve endometrial protection.

Usually hormone replacement consists of continuous (daily or cyclical) (eg days 1-25 every month) administration of estrogen with progestin supplementation for 10-13 days (eg days 13-25 every month). This type of replacement regimen is effective in preventing menopausal symptoms and, at the same time, protects the endometrium from developing hyperplasia or adenocarcinoma. However, cyclical progestin administration leads to a planned bleeding failure or period in 65-75% of women. This bleeding failure is usually not acceptable for patients and can lead to consent problems. Also, because progestin administration follows after 13-16 days of unhindered estrogen therapy with endometrial proliferation and estrogen progestin receptor induction, a high dose of progestin is required to antagonize these effects, resulting in a greater chance of side effects and counter metabolic effects. While continuous regimens of low doses of estrogen and progestin for hormone replacement may avoid the problem of bleeding failure, daily administration of progestin in these regimens induces depletion of both estrogen and progestin receptors, resulting in endometrial atrophy, which may be associated with an outbreak of bleeding. Since abnormal bleeding in postmenopausal women is known to be associated with endometrial carcinoma, this should be investigated with endometrial hypertrophy specimens, usually D&C. Daily administration of progestin also increases the concern that these beneficial effects of estrogen on metabo3 lick HDL cholesterol, adversely affected by HDL cholesterol drop.

In U.S. Pat. No. 5,108,995 describes a regimen that can more effectively protect the endometrium from the risk of estrogen-related endometrial hyperplasia and adenocarcinoma, with a lower dose of progestin, by giving progrestin a short period of time, alternating, with a short period without or with reduced amounts of progestin. The formulation, which gave a low dose of progestin intermittently within one month, achieved the following result: a significant elimination of the absence of bleeding; intermittent enhancement of estrogenic activity and stimulation of endometrial growth and progestin receptors. Thus, the endometrium is more sensitive to subsequent progestin activity, which limits growth by reducing estrogen receptors and increasing 17/3-hydroxysteroid dehydrogenase. Interaction of progestin with progestin receptors induces secretion changes in the endometrium, resulting in denser stroma and endometrial stability. The return of relatively dominant estrogen activity then again stimulates estrogen and progestin receptors and restores endometrial progestin sensitivity. This push / pull activity keeps endometrial activity low, depending on the number of days of estrogen and progestogen activity, and maintains a stable endometrium, resulting in a significant absence of outbreaks or bleeding events. This formulation allows for better progestive effects with less progestin. The dose of progestin is significantly reduced compared to a preparation containing a constant daily dosage of progestin. It is possible to obtain a complete steroid dosage similar to or even lower than that of the above-mentioned cyclic estrogen and progestin administration method for ovarian disorder hormone replacement therapy. A decrease in progestin dosage results in a less negative effect on HDL cholesterol levels.

Transdermal drug delivery systems are known in the art. Some patents in this field relate to the transdermal administration of hormone formulations for various purposes. Examples of such patents are as follows:

U.S. Pat. No. 4,816,258, issued March 28, 1989, by Nedberge et al., Describes a formulation of ethinyl estradiol and left-norgestrel drug for transdermal administration comprising a matrix containing steroids and an amount of glycerololeate to increase skin permeability.

U.S. Pat. No. 5,122,382, issued June 16, 1992, by Gail et al., Describes a composition for transdermal administration comprising estrogen and ST-1435. The formulation delivers certain amounts of steroids per day and includes a skin permeation enhancer.

U.S. Pat. No. 5,023,084, issued June 11, 1991, and U.S. Pat. No. 4,906,169, issued March 6, 1992, both by Chien et al., Describe a combination of estrogen and progestin in a contraceptive formulation with a transdermal unit comprising a support layer, a polymer layer containing hormones and an adhesive layer.

U.S. Pat. No. 4,624,665, issued Nov. 25, 1986, 4,687,481, issued Aug. 18, 1987, 4,834,978, issued May 30, 1989, 4,810,499, issued March 7, 1989, and 4,927,687, issued May 22, 1990, describe a transdermal administration system that is said to be prevents the dose of the drug to be given, caused by accidental rupture of the maintained part, being delayed and ensures effective and prolonged administration of the drug, especially contraceptive steroids. Suitable steroids include norethindrone, norgestrel, estradiol, left norgestrel, and mestranol.

For the benefit of transdermal delivery systems, it is perceived that they primarily exist in the ability to bypass the liver at the first pass of hormones through the body, if not given orally. Gastrointestinal absorption requires passage through the liver in which the metabolism of the drug occurs before the first complete circulatory loop delivers the drug to the target organs (eg, uterus, heart, bones, central nervous system, etc.). The advantage of avoiding the liver is that patients can be given smaller amounts of the drug to achieve the same level of efficacy in the target tissues, reducing adverse metabolic effects (changes in coagulation factors, glucose metabolism, lipids, etc.) that can be encountered in oral mode, (see Transdermal Hormone Replacement, MI Whitehead and L. Schenkel, 1990). It is also thought that avoiding the stomach can prevent some nausea and gastrointestinal problems, which is related to oral estrogen therapy (see Transdermal Administration of Oestrogen / Progestin Hormone Replacement Therapy, MI Whitehead et al. The Lancet, 310-312,10 Feb. 1990).

We believe that the system of continuous transdermal administration generally provides more constant steady-state plasma hormone levels, with no upward or downward deviations (peaks and valleys) than oral administration once daily. The phenomenon of first pass can also be concluded to be exposed to the perceived disadvantage of the transdermal route of administration. This perceived disadvantage is that estrogens actually induce some favorable changes in the lipoprotein profile (eg, stimulate HDL cholesterol growth) and these effects are likely the result of induction of hepatic en5 cymes. A decrease in hepatic drug exposure could be predicted as a decrease in the beneficial effects of these drugs.

However, there are a number of factors that need to be considered in determining whether patients should be treated with hormone therapy orally or transdermally, and typically factors favoring transdermal administration include a patient who is generally very sensitive to pharmacological agents, a rejecting or superficial patient who may have problems with daily dosing regimens, gastrointestinal disorders due to oral estrogen therapy, and lack of oral response. On the contrary, oral choice may be preferred in cases where the patient is perceived to be at high risk for cardiovascular disease, hyperlipidemia, tendency for skin sensitivity and dermatological disorders.

We believe that the use of a transdermal delivery system for US Pat. 5,108,995 increased the benefits of the basic regimen itself due to the perceived benefits of transdermal mode. In addition, we have found that the transdermal delivery system works best with a specific selection of hormones that are best suited for this route of administration.

In one embodiment, the invention provides a method of treating a woman in need of hormone replacement therapy comprising transdermally administering to this woman a series of pharmaceutical patch regimens arranged in alternating phases of dominant hormonal activity from about one day to about four days, these stages being selected from estrogen dominant active phases and progestin dominant active phases, each of these phases comprising at least one patch that is applied and removed according to a particular dominant phase activity, wherein the estrogen dominant active phase contains an amount of substance with sufficient estrogen activity, to accelerate the development of progestin receptors in the endometrium of this woman or the amount of a substance with estrogenic activity sufficient to accelerate the development of progestin receptors in the endometrium of this woman and the amount of a substance with progestin activity; and wherein the progestin-dominant active phases contain an amount of a substance with estrogenic activity and an amount of a substance with progestinic activity sufficient to antagonize the effect of estrogen on this woman's endometrium, and estrogen and progestin are selected from hormones that can be transdermally administered.

The present invention provides a method of treating a woman in need of hormone replacement therapy comprising transdermally administering to this woman a series of pharmaceutical patch regimens arranged in alternating phases of dominant hormonal activity from about one day to about four days, these stages being selected from estrogen dominant active phases and progestin dominant active phases, each of these phases comprising at least one patch which is applied and removed according to a particular dominant phase activity, wherein this estrogen dominant active phase consists of administration of transdermal estrogen only or administration of transdermal estrogen substance and transdermal progestin substance and said progestin dominant active phase consists of administering a transdermal progestin substance and a transdermal estrogen substance, wherein the amount of progestin substance is alternately increased to the progestin dominant active i phase and reduced in the estrogen dominant active phase to provide the required dominant activity.

In another aspect, the present invention provides a pharmaceutical preparation for administration to a woman in need of hormone replacement therapy comprising a series of patch regimens arranged in alternating phases of dominant hormonal activity from about one day to about four days, each of which being selected from estrogen dominant active phases and progestin dominant active phases, each of these phases comprising at least one patch that is applied and removed according to a particular dominant phase activity, said estrogen dominant active phase consisting only of a transdermal estrogen substance or a transdermal estrogen substance and transdermal progestin, and this progestin-dominant active phase consists of transdermal progestin and transdermal estrogen, with the amount of progestin being alternately increased in the progestin-dominant active phase and reduced in the estrogen d ominant active phase, to obtain the required dominant activity.

In another embodiment, the present invention provides a pack comprising a regimen for administering pharmaceutical transdermal patches to a woman in need of hormone replacement therapy, the pack comprising a series of pharmaceutical patch regimens arranged in alternating phases of dominant hormonal activity from about one day to about four days , wherein these phases are selected from estrogen dominant active phases and progestin dominant active phases, these phases comprising at least one patch which is applied and removed according to a particular dominant phase activity, said estrogen dominant active phase consisting solely of transdermal estrogenic substances or transdermal estrogenic substances and transdermal progestin substances and said progestin

Ί The dominant active phase consists of a transdermal progestin substance and a transdermal estrogen substance, whereby the amount of progestin substance is alternately increased in the progestin-dominant active phase and reduced in the estrogen-dominant active phase to obtain the required dominant activity.

In a preferred embodiment of the invention, estrogen and progestin are selected from transdermal estrogens and progestins that provide activity levels equivalent to a transdermal amount of administration from about 25 gg / day to about 150 / g / day, more preferably about 100 μg / day 17- / 3 -estradiol and from about 250 g / day to about 500 gg / day piperazine estrone sulfate and from about 15 gg / day, more preferably from about 25 gg / day to about 1000 gg / day norethindronacetate or from about 5 / g / day to about 150 / g / day of 3-keto-desogestrel, with the proviso that progestin is increased in the progestin-dominant phase relative to the estrogen-dominant phase to produce the necessary dominance.

In a preferred embodiment of the present invention, a first patch, e.g. either the type of adhesive matrix or the type of drug tank (ethanol gel) is prepared so that it contains enough 17- / 3estradiol to give an amount of transdermal administration from about 25 ^ g / day to about 100 ^ g / day. The second patch is prepared either as an adhesive matrix type or drug tank type (ethanol gel) so that it contains enough 17- / 3-estradiol to give the above amount of release and enough norethindronacetate (ΝΕΤΑ) to give a transdermal administration amount of about 25 / w / day to about 1000 / zg / day ΝΕΤΑ, more preferably from about 75 / zg / day to about 500 gg / day, most preferably 75 / zg / day to about 300 / zg / day. In the case of a combination of 17- / 3-estradiol and 3-keto-desogestrel, the amount of 17- / 3-estradiol remains the same as above, while the amount of 3-keto-desogestrel is sufficient to obtain a transdermal administration amount of about 5 / wg / day up to about 150 ^ g / day, more preferably 25 / zg / day to about 150 / zg / day. The application of these patches in the required sequence provides the advantage of the present invention.

Estrogens that can be used as a component in the regimens of the invention may be any of those conventionally available that can be absorbed through the skin. Typically, estrogen can be selected from the group consisting of synthetic and natural estrogens. Synthetic estrogens can be selected e.g. from ethynyl estradiol, micronized estradiol, 17- / 3-estradiol, mestranol, estradiol valerate, 11-nitrato estradiol, 7-α-methyl-11-nitrato-estradiol, piperazine estrone sulfate and quinestranol. Of particular interest is 17α-ethynyl estradiol and its esters and ethers. Estrogen is preferred

17- / 3-estradiol.

The progestin component can be any progestively active compound. So progestin can be selected from progesterone, 17-hydroxyprogesterone, dihydroprogesterone, medroxyprogesterone acetate, norethindrone, norethindrone acetate, norethinodrela, ethinodioldiacetate, norgestrel, left-norgestrel, gestoden, delta-15levonorgesterone, esterogesterone, esterogester 3-keto-desogestrel. Preferred progestins are norethindrone acetate and 3-keto-desogestrel.

The choice of hormones best suited for transdermal administration can be determined by conventional tests used in the skin permeation technique. The most common is the In Vitro Skin Permeation Chamber, which uses hairless mouse skin or human dead skin. There is a lot of information in the literature about these tests and the following references are typical:

a) Kao J, Hall J. Skin Absorption and Cutaneous First Pass Metabolism of Topical Steroids: In Vitro Studies with Mouse Skin in Organ Culture. J. Pharmacol Exp Ther 241 (2), p. 482-487,1987;

b) Tojo K, Lee C. A Method for Predicting Steady-State Rate of Skin Penetration In Vivo. J. Invest Derm 92 (1), p. 105-108,1989;

c) Liu P, Higuchi WI, Song W, Kurihara-Bergstrom T, Good WR. Ouantitative Evaluation of Ethanol Effects on Diffusion and Metabolism of / 3-Estradiol in Hairless Mouse Skin. Pharm Res 8 (7), p. 865-872,1991; and

d) Roy S, Gutierrez M, Chiang C. Permeation of Norethindrone, Norethindrone Acetate and Norethindrone Diacetat Through Cadaver Skin. Pharm Res Suppl 6, p. 1168,1989.

Skin permeability and therefore amounts for transdermal administration are important when selecting suitable hormones, but hormone stability may also be a factor in the formulation. Stability can be determined or measured in two basic ways: by visual monitoring and in vitro degradation.

Visual monitoring for crystal formation is generally done at both the macroscopic and microscopic levels. For in vitro degradation, tests for in vitro release rates are standard in the art. Generally, when these criteria are met, we can easily obtain the quantities required for transdermal administration.

The phases can range from one day to four days, but need not be exactly 24-hour days. However, there are limitations to adequate flexibility, because the absence of hormones for too long can lead to a lack of bleeding; so e.g. for a three-day phase, the total number of hours can be 66 or 78, as opposed to 72 hours. In the preferred mode, the phases comprise about 3 and about 4 days. Other combinations can also be used, such as. 2 and 3, or 1 and 3, or 3 and 3, or 2 and 4, or 1 and 4.

Generally, hormone replacement therapy is given without interruption. However, there may be cases where discontinuation may be desirable and in this case patches containing placebo or any other hormone-free agent may also be included in the package. Examples of suitable hormone-free alternative agents include vitamins such as. iron supplements.

In general, the amounts of estrogen and progestin incorporated into the formulation of the invention depend on the activity of the estrogen or progestin selected. In the formulation of the invention, estrogen is administered continuously, in other words, it is always present in the formulation, while progestin levels are adjusted up or down to produce the required estrogen or progestin dominance. The choice of amounts depends on the type of estrogen or progestin because each hormone has its own specific activity.

Typically, in the formulations described in U.S. Pat. 5, 108,995, the amount of estrogen activity per unit dose may be equivalent in the range of estrogen activity to a minimum of approx. 0.3 mg piperazine estrone sulfate to a maximum of approx. 2.5 mg piperazine estrone sulfate. The amount of progestin activity per unit dose may be equivalent in the range of minimum 0 mg to a maximum of approx. 5 mg norethindrone.

Some of the preferred combinations include the following:

1. Three single doses of 0.75 mg piperazine estrone sulfate, alternating with three single doses of 0.75 mg piperazine estrone sulfate and 0.35 mg norethindrone.

2. Three single doses of 0.75 mg piperazine estrone sulfate and 0.15 mg norethindrone alternately with three single doses of 0.75 mg piperazine estrone sulfate and 0.35 mg norethindrone.

Equivalent dosages for transdermal administration can be determined by measuring blood hormone levels. It is generally believed that the levels of administration observed for the patch formulations of the invention can be labeled as follows. First, each phase should generally consist of a single patch, although a series of patches can be used to make the phase. The size of the patch depends, among other things, on the length of the phase and the capacity of the hormone. For example, 17- / 3-estradiol patches are now available, providing quantities for transdermal administration of about 50 / wg / day. In such a case, the amount of 17-j8-estradiol is 4 mg and the size of the patch is about 18 cm ² , with the actual reservoir being about 10 cm ² . In the case of a patch containing 2 hormones, such as. 17- / 3-estradiol and norethindronacetate, respectively, are 10 mg or more. 30 mg and the effective area of the patch is 26 cm ² to obtain quantities for transdermal administration of about 50 / wg / day for 17- / 3-estradiol and about 250 / w / day for norethindrone acetate. 3-Ketodezogestrel is more effective progestin and the amount incorporated into the patch may range from about 4 mg to about 30 mg to obtain the required daily amounts for transdermal administration. The range for 17-JS-estradiol can be from about 1 mg to about 10 mg (in the adhesive matrix reservoir; this can be changed to another type of patch), and for norethindrone acetate the range can be from about 10 mg to about 100 mg.

The above combinations can also be divided into three-day and four-day groups, starting with either three-day or four-day groups and ending in reverse.

Numerous transdermal patches that are commercially available can be used in the process of the invention. Most importantly, it is important to remember that the sequence of administration is crucial to the present invention and that we need to arrange the patches or their application in a predetermined order to achieve the benefits of the invention. Two such patches are described here for purposes of proof only, and different ones may be used.

In the known system, a solid adhesive matrix of an acrylic copolymer base containing the hormones in dissolved form is used. The system involves the use of a flexible support foil, which may comprise e.g. polyethylene terephthalate. The detachable protective layer forms the second layer (in contact with the adhesive). Polysaccharide, a swelling-capable galactomannan, is added to the adhesive matrix to improve adhesion between the patch surface and hydrated skin throughout the application and to reduce the irritation phenomena caused by occlusal effects. Preferably, they fabricate a three-layer laminate of foil foil, healing matrices and detachable protective layers. Now marketed products of this type are sold under the SYSTEN TTS brand.

A further marketable product is available under the ESTRADERM brand. ESTRADERM ™ is an estradiol transdermal system that has been shown to release estradiol through a rate-limiting membrane continuously after application to intact skin. The ESTRADERM ™ system consists of five layers: a support layer, a drug reservoir, a control membrane, an adhesive layer, and a protective layer, respectively, from the outside to the inside. The qualitative composition of the drug's estraderm reservoir is estradiol, alcohol, and hydroxypropylcellulose.

For transdermal administration, as mentioned earlier, any suitable patch formulation can be selected. The following, which is known to be useful in the administration of hormone formulations, is described in detail in U.S. Pat. No. 4,668,232, issued May 26, 1987, by Cordes and Wolff, the description of which is incorporated herein by reference. In this US patent, the described system is four-layered, comprising an impermeable support or cover layer; a reservoir layer adjacent to a support or cover layer; an adhesive layer that is permeable to hormones and a protective layer that is removed before the application of the patch. As described previously, it is possible to use a three-layer system comprising a cover layer, a healing matrix adhesive layer and a detachable protective layer.

The estrogen patch of the invention can be prepared using an ethanol gel type drug reservoir. The weight of the hormone, preferably 17- / 3-estradiol, may be 4 mg. The patch has an effective area of about 18 cm ² . It can be round in shape with a reservoir spanning approximately 10 cm ^{2 of the} patch. This generally provides an amount for transdermal administration of about 10 / tg / day for 17-S-estradiol.

An estrogen / progestin patch can be prepared using an ethanol gel type drug tank with amounts of hormones, e.g. 10 mg of 17- / 3-estradiol and 30 mg of norethindronacetate. The total contact area of such a patch is approximately 20 cm ² and has the appearance of glasses with joined tanks, each tank containing both drugs. This generally provides an amount for transdermal administration of about 50 / ig / day of 17- / 3-estradiol and about 250 / mg / day of norethindronacetate.

Typically, this preparation is for administration to postmenopausal patients and / or those who are actively symptomatic.

Patches can be packaged, e.g. into cardboard boxes containing multiple transdermal 17/3-estradiol patches and multiple transdermal 17- / 3-estradiol and norethindronacetate patches. Each patch can be sealed individually in a protective bag.

In this case, the first 17- / 3-estradiol patch can be applied for the required number of days (although it is not essential to start this phase), this patch can be removed and one of the 17-S-8-estradiol or norethindronacetate patches applied for the required number of days. The second patch is then removed and the next 17-SS-estradiol patch, etc., applied. Treatment is usually continuous without interruption. Individual patches are usually replaced every 3 or 4 days depending on the particular regimen, although patches can be prepared for application for any combination of days, for a regimen limited to one to four days.

Each new patch is applied to a different location. Preferably, the application sites are clean, dry and undamaged skin areas below the waist. Preferably, the surface of the buttocks, flanks, or abdomen is selected, since these skin areas are least wrinkled as the body moves.

In the following examples, specific embodiments of the present invention are indicated. They are intended only to illustrate the invention and not to limit it in any way. Unless otherwise stated, all parts and percentages are by weight.

EXAMPLE 1

The transdermal patch of 17-jS-estradiol (100 μβ / day) for the three-day phase was administered and replaced with the transdermal patch of 17-β-estradiol (100 μ-g / day) and norethindrone (0.35 mg / day) for the three-day phase. These patches are applied alternately and without interruption.

EXAMPLE 2

The transdermal patch of 17- / 3-estradiol (100 μ-g / day) for the three-day phase is administered and replaced with a transdermal patch of 17- / 3-estradiol (100 μ-g / day) and norethindronacetate (0.35 mg / day) for the three-day phase. These patches are applied alternately and without interruption.

EXAMPLE 3

The transdermal patch of 17- / 3-estradiol (50 μg / day) for the three-day phase is administered and replaced with the transdermal patch of 17- / 3-estradiol (50 μg / day) and norethindronacetate (0.15 mg / day) for the three-day phase . These patches are applied alternately and without interruption.

EXAMPLE 4

The transdermal patch of 17- / 3-estradiol (25 μg / day) for the three-day phase is administered and replaced with a transdermal patch of 17- / 3-estradiol (25 μg / day) and norethindronacetate (0.50 mg / day) for the three-day phase. These patches are applied alternately and without interruption.

EXAMPLE 5

An estrogen patch with an active surface of about 18 cm ^{2 is} prepared using a drug tank, of the ethanol gel type, containing about 4 mg of 17- / 3-estradiol. In appearance, it is round in shape with a reservoir spanning about 10 cm ^{2 of the} patch. This generally provides an amount of transdermal administration of about 10 μg 17- / 3-estradiol / day.

The estrogen / progestin patch is prepared using a drug tank, of ethanol gel type, with amounts of hormones containing 10 mg of 17- / 3-estradiol and 30 mg of norethindronacetate. The total contact area of such a patch is approximately 20 cm ² . The patches look like glasses with two pooled tanks, with each tank containing both medicines. These patches generally provide amounts for transdermal administration of 50 [mu] g of 17-JS-estradiol / day and 250 [mu] g of norethindronacetate / day.

The patches are packed in cardboard boxes containing multiple transdermal 17- / 3-estradiol patches and multiple transdermal 17- / 3-estradiol and norethindronacetate patches. Each patch is sealed individually in a protective bag.

The first 17-8-estradiol patch is applied for 3 days (although it is not essential to start this phase), this patch is removed and one of the 17- / 3-estradiol and norethindronacetate patches is applied for 4 days. Another patch is then removed and the next 17- / 3-estradiol patch, etc. applied. Treatment is continued without interruption. We apply each new patch to a different location. Preferred application sites are clean, dry and undamaged skin areas beneath the waist, preferably the surface of the buttock, flank or abdomen, since these skin areas are least wrinkled as the body moves.

While the present invention is described with reference to its specific embodiments, it should be understood by those skilled in the art that various changes and substitutions with equivalents are possible without departing from the true essence and scope of the invention. In addition, many modifications can be made to adjust the particular state, material or composition of a substance, process, step or stages of the process, or the then-discerning spirit of the invention, without departing from its essence.

Industrial usability

The benefits of transdermal delivery systems are perceived to exist primarily in the ability to bypass the liver when hormones are first passed through the body, unless given orally. This advantage of avoiding the liver is that it is possible to administer a smaller amount of the drug to the patient to achieve the same level of efficacy in the target tissues, reducing adverse metabolic effects (e.g., changes in coagulation factors, glucose metabolism, lipids, etc.) at which can be encountered in oral mode. It is also thought that avoiding the stomach can prevent some of the nausea and gastrointestinal problems associated with oral estrogen therapy. We believe that the system of continuous transdermal administration generally provides more constant steady-state plasma hormone levels, with no upward and downward deviations (peaks and valleys), than oral administration once daily. Estrogen replacement therapy is known to soothe heat waves, and this wave and night sweats alleviates typical sleep and contributes to the patient's overall sense of well-being. Estrogen replacement protects against the loss of calcium from the post-menopausal skeleton, especially from vertebral carcasses, prevents brittle fractures and weight loss. Various studies now indicate that long-term estrogen therapy is also associated with a reduction in the incidence of classic osteoporosis of the forearm and hip. Another beneficial effect of long-term estrogen use is to reduce the risk of death from ischemic heart disease, possibly mediated by a change in blood lipoprotein concentrations. Estrogen replacement has also been shown to improve the vascularity and health of the vaginal mucosa and urinary tract.

Claims (43)

PATENT APPLICATIONS A pharmaceutical pack comprising a regimen for the administration of transdermal patches to a woman in need of hormone replacement therapy, characterized in that it consists of a series of pharmaceutical patch regimens arranged in alternating phases of dominant hormonal activity from about one day to about four days, at each phase being selected from estrogen dominant active phases and progestin dominant active phases, each of said phases comprising at least one patch which is applied and removed according to a particular dominant phase activity, said estrogen dominant active phase consisting solely of the transdermal estrogenic substance or transdermal estrogenic substance and transdermal progestin substance and said progestin dominant active phase consists of transdermal progestin substance and transdermal estrogen substance, the amount of progestin substance being alternately increased to progestin dominant active i phase and reduced in the estrogen-dominant active phase to provide the required dominant activity. A pack according to claim 1, characterized in that each phase is applied with a single patch. A pack according to claim 1, characterized in that each phase with multiple patches is administered. A pack according to claim 1, characterized in that the phases are administered continuously. A pack according to claim 1, characterized in that estrogen and progestin are selected from estrogens to provide activity levels equivalent to a transdermal amount of administration from about 25 / ig / day to about 100 / ig / day 17- / 3-estradiol and from about 25 µg / day to about 1000 µg / day norethindronacetate or from about 5 µg / day to about 150 µg / day 3-keto-desogestrel, with the proviso that progestin is increased in the progestin-dominant phase relative to the estrogen-dominant phase , to produce the necessary dominance. A pack according to claim 1, characterized in that the estrogen dominant phase contains an amount of 17- / 3-estradiol sufficient to provide an amount for transdermal administration of from about 25 / xg / day to about 100 μ-g / day and progestin the dominant phase contains an amount of 17- / 3-estradiol sufficient to provide an amount for transdermal administration of from about 25 gg / day to about 100 gg / day and an amount of norethindronacetate sufficient to provide an amount for transdermal administration of about 25 gg / day to about 1000 gg / day. A pack according to claim 6, characterized in that the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days. A pack according to claim 6, characterized in that the estrogen dominant phase comprises about four days and the progestin dominant phase comprises about three days. A pack according to claim 6, characterized in that the amount of norethidronacetate is sufficient to provide a transdermal administration amount of from about 75 gg / day to about 500 gg / day. A pack according to claim 6, characterized in that the amount of norethindronacetate is sufficient to provide a transdermal administration amount of from about 75 gg / day to about 300 gg / day. A pack according to claim 1, characterized in that the estrogen dominant phase contains an amount of 17- / 3-estradiol sufficient to provide an amount for transdermal administration from about 25 gg / day to about 100 gg / day and the progestin dominant phase contains an amount of 17- / 3-estradiol sufficient to provide an amount for transdermal administration of from about 25 μg / day to about 100 gg / day and an amount of 3-ketodezogestrel sufficient to provide an amount for transdermal administration of about 5 gg / day to about 150 gg / day. A pack according to claim 11, characterized in that the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about 4 days. 13. A pack according to claim 11, characterized in that the estrogen dominant phase is equivalent to about four days and the progestin dominant phase is equivalent to about three days. A pack according to claim 11, characterized in that the amount of 3-keto-desogestrel is sufficient to provide an amount for transdermal administration of from about 25 gg / day to about 150 gg / day. A pack according to claim 1, characterized in that the estrogen-dominant phase contains an amount of 17- / 3-estradiol sufficient to provide an amount for transdermal administration of about 50 / ig / day and the progestin-dominant phase contains an amount of 17- / 3-estradiol, sufficient to provide an amount for transdermal administration of about 50 µg / day and an amount of norethindone acetate sufficient to provide an amount for transdermal administration of about 300 µg / day. A pack according to claim 11, characterized in that the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days. A pack according to claim 11, characterized in that the estrogen dominant phase comprises about four days and the progestin dominant phase comprises about three days. A pack according to claim 1, characterized in that the estrogen dominant phase contains an amount of 17- / 3-estradiol sufficient to provide an amount for transdermal administration of about 50 μg / day and the progestin dominant phase contains an amount of 17- / 3-estradiol , sufficient to provide an amount for transdermal administration of about 50 / xg / day and an amount of norethindronacetate sufficient to provide an amount for transdermal administration of about 150 / xg / day. A pack according to claim 18, characterized in that the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days. A pack according to claim 18, characterized in that the estrogen dominant phase comprises about four days and the progestin dominant phase comprises about three days. A pack according to claim 1, characterized in that each phase comprises a single patch. A pack according to claim 1, characterized in that each phase comprises several patches. 23. Pharmaceutical preparation for administration to a woman in need of hormone replacement therapy, characterized in that it comprises a series of patch regimens arranged in alternating phases of dominant hormonal activity from about one day to about four days, each of said phases being selected from estrogen dominant active phases and progestin-dominant active phases, each of said phases comprising at least one patch that is applied and removed according to a particular dominant phase activity, said estrogen dominant phase consisting solely of transdermal estrogen or transdermal estrogen and transdermal progestin substance and said progestin dominant active phase consists of a transdermal progestin substance and a transdermal estrogen substance, the amount of the progestin substance being alternately increased in the progestin dominant active phase and reduced in the estrogen dominant active phase, to provide the necessary dominant activity. 24. Use of a pharmaceutical patch regimen in the preparation of a medicament for the treatment of a woman in need of continuous hormone replacement therapy, the patch regimen comprising a series of patches arranged in alternating phases of dominant hormonal activity from about one day to about four days, wherein each of said phases is selected from estrogen-dominant active phases and progestin-dominant active phases, each said phase comprising at least one patch that is applied and removed according to a particular dominant phase activity, said estrogen dominant phase consisting of administering only transdermal estrogen substance or administration of transdermal estrogen substance and transdermal progestin substance and said progestin dominant active phase consists of administration of transdermal progestin substance and transdermal estrogen substance, whereby the amount of progestin substance is alternately increased into lines Stin dominant active phase and reduced in estrogen dominant active phase to provide the required dominant activity. Use according to claim 24, characterized in that each phase is administered with a single patch. Use according to claim 24, characterized in that each phase is administered with multiple patches. Use according to claim 24, characterized in that the phases are administered continuously. Use according to claim 24, characterized in that estrogen and progestin are selected from estrogens and progestins, which provide activity levels equivalent to the amount for transdermal administration from about 25 / wg / day to about 100 / w / day 17- / 3- estradiol and from about 25 / wg / day to about 1000 / w / day norethindrone acetate or from about 5 pg / day to about 150 gg / day 3-keto-desogestrel, with the proviso that progestin is increased in the progestin-dominant phase relative to estrogen the dominant phase, to produce the necessary dominance. Use according to claim 24, characterized in that the estrogen dominant phase contains an amount of 17-β3-estradiol sufficient to provide an amount for transdermal administration of from about 25 µg / day to about 100 µg / day and the progestin dominant phase contains an amount of 17- / 3-estradiol sufficient to provide an amount for transdermal administration of from about 25 ^ g / day to about 100 ^ g / day and an amount of norethindrone acetate sufficient to provide an amount for transdermal administration of about 25 μg -g / day to about 1000 / ig / day. Use according to claim 24, characterized in that the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days. Use according to claim 24, characterized in that the estrogen dominant phase comprises about four days and the progestin dominant phase comprises about three days. Use according to claim 24, characterized in that the amount of norethindronacetate is sufficient to provide an amount for transdermal administration of from about 75 µg / day to about 500 µg / day. Use according to claim 24, characterized in that the amount of norethindronacetate is sufficient to provide an amount for transdermal administration of from about 75 µg / day to about 300 µg / day. Use according to claim 24, characterized in that the estrogen-dominant phase contains an amount of 17-SS-estradiol sufficient to provide an amount for transdermal administration from about 25 / xg / day to about 100 ^ g / day and the progestin-dominant phase contains an amount of 17- / 3-estradiol sufficient to provide an amount for transdermal administration of from about 25 ^ g / day to about 100 / ig / day and an amount of 3-ketodezogestrel sufficient to provide an amount for transdermal administration of about 2 / ig / day to about 150 ^ g / day. Use according to claim 34, characterized in that the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days. Use according to claim 34, characterized in that the estrogen dominant phase is equivalent to about four days and the progestin dominant phase is equivalent to about three days. Use according to claim 34, characterized in that the amount of 3-keto-desogestrel is sufficient to provide an amount for transdermal administration of from about 25 µg / day to about 150 µg / day. Use according to claim 24, characterized in that the estrogen dominant phase contains an amount of 17- / 3-estradiol sufficient to provide an amount for transdermal administration of about 50 / ig / day and the progestin dominant phase contains an amount of Υ1-βestradiol, which it is sufficient to provide an amount for transdermal administration of about 50 µg / day and an amount of norethindronacetate sufficient to provide an amount for transdermal administration of about 300 µg / day. Use according to claim 38, characterized in that the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days. Use according to claim 38, characterized in that the estrogen dominant phase comprises about four days and the progestin dominant phase comprises about three days. Use according to claim 24, characterized in that the estrogen dominant phase contains an amount of 17- / 3-estradiol sufficient to provide an amount for transdermal administration of about 50 μg / day and the progestin dominant phase contains an amount of Υ1-β · estradiol sufficient to provide an amount for transdermal administration of approx 50 μ-g / day and an amount of norethindronacetate sufficient to provide an amount for transdermal administration of about 150 μ-g / day. Use according to claim 41, characterized in that the estrogen dominant phase comprises about three days and the progestin dominant phase comprises about four days. Use according to claim 41, characterized in that the estrogen dominant phase comprises about four days and the progestin dominant phase comprises about three days.