DE10134768A1 - Pharmaceutical combination preparations containing aromatase inhibitors and substances with an estrogenic effect and their use - Google Patents

Abstract

The invention relates to pharmaceutical combination preparations comprising aromatase inhibitors and substances with an estrogenic effect and their use for a selective estrogen replacement therapy (SERT (selective estrogen replacement therapy, in particular in the case of climacteric complaints and their side effects. Estrogenic substances, if appropriate, are preferred as substances with an estrogenic effect The combination preparations according to the invention are preferably used for menopausal complaints, in particular for the treatment and prevention of postmenopausal osteoporosis and breast cancer, and for other long-term consequences which can be caused by a lack of estrogen.

Description

The invention relates to pharmaceutical combination preparations comprising aromatase inhibitors and substances with estrogen Effect as well as their use to a selective estrogen Replacement therapy (SERT (selective estrogen replacement therapy), especially for menopausal symptoms and their side effects. As substances with estrogen Effect are preferred estrogens, optionally also in Combination with progestogens. The invention Combination preparations are preferred for climacteric complaints and prevention postmenopausal osteoporosis, while increasing in contrast to long-term therapy with ERT / HRT alone Breast cancer risk does not, as it stimulates the Breast gland due to increased estrogen tissue concentrations avoid.

The hormone replacement therapy to mitigate climacteric Complaints is a generally accepted one Treatment method and short-term treatment the relationship between treatment risk and success is clear the side of successful therapy.

However, such a clear statement is for long-term therapies not possible. Relationships between estrogen intake and Cancers have been discussed over and over again. In particular is long-term treatment with an increasing risk of breast cancer connected. This relationship has been established in epidemiological Studies with women over a period of 5 years and treated for longer.

So stimulate estrogens, often against climatic Discomfort and post menopause treatment for  Osteoporosis can be used to grow Breast tumor cells both in the pre and in the postmenopausal phase.

The invention was therefore based on the object to provide pharmaceutical preparations which a Long-term treatment in the form of an estrogen replacement therapy allow and not increase the risk of breast cancer or even belittle it.

The object of the invention is achieved by a combination preparation of at least one aromatase inhibitor and at least one Dissolved substance with estrogenic effect. It has shown, that such a combination preparation to a selective Estrogen replacement therapy (SERT (selective estrogen replacement therapy) can be used.

Even after menopause, the levels of estradiol are in the Breast tumor tissues are those of tumors that stop before the Ovarian function occur similarly, however, the plasma Estrogen level in postmenopausal women 10 to 50 times lower than in premenopausal women (Yue, W. et al., Determinants of tissue estradiol levels and biologic responsiveness in breast tumors. Breast Cancer Res Treat (Netherlands), 1998, 49 Suppl 1 pS1-7, discussion S33-7).

The invention is based on the knowledge that the Breast estrogen content is not a sole consequence of Estrogen plasma level and passive diffusion of the Hormones, but rather a result of active ones Mechanisms like an autonomous intracellular Estrogen synthesis from steroid hormone precursor compounds (metabolic precursors). This is how estrogens come from postmenopausal woman predominantly from the aromatization of Androgen precursor compounds in peripheral adipose tissue. The specific hormonal situation of postmenopausal women with growing production of ovarian and adrenal  Androgen precursor compounds are likely to promote that Accumulation of newly synthesized estrogen in breast tissue.

With the combination preparation according to the invention Use of at least one aromatase inhibitor on the one hand endogenous estrogen synthesis from androgen precursor compounds in tissues with high aromatase activity, e.g. B. that Breast tissue is reduced.

The accompanying hormone therapy with at least one estrogen on the one hand, acting substance prevents one additional estrogen deficiency, which is the result of aromatase Inhibition would occur, and on the other hand, keeps the Estrogen plasma levels in the menopause, especially at postmenopausal women, high enough that through Suppressed estrogen deficiency suppressed become.

Aromatase inhibitors in the sense of the present invention are all those compounds that prevent the formation of estrogens their metabolic precursors by inhibiting the enzyme Prevent aromatase (inhibition of biosynthesis). As Aromatase inhibitors are therefore all compounds that are suitable as substrate for the aromatase, such as for example that in Jounal of Clinical Endocrinology and Metabolism. 49, 672 (19979) described testolactone (17α- Oxa-D-homoandrost-1,4-diene-3,17-dione), which is described in "Endocrinology" 1973, Vol. 92, No. 3, page 874 described connections Androsta-4,6-diene-3,17-dione, Androsta-4,6-diene-17β-ol-3-one acetate, androsta-1,4,6-triene-3,17-dione, 4-androstene-19-chloro 3,17-dione, 4-androsten-3,6,17-trione, which is described in DE-A1 31 24 780 19-alkynylated steroids described in DE-A1 31 24 719 described 10- (1,2-propadienyl) steroids, which in EP-A1 0 100 566 described 19-thioandostrane derivatives, the in "Endocrinology" 1977, Vol. 100, No. 6, page 1684 and in US-A 4,235,893 4-androsten-4-ol-3,17-dione and its esters, the 1-methyl- described in DE-A1 35 39 244  15α-alkyl-andostra-1,4-diene-3,17-diones, which are described in DE-A1 36 44 358 described 10β-alkynyl-4,9 (11) estradiene derivatives and the 1,2β-methylene-6- described in EP-A1 0 250 262 methylene-4-androstene-3,17-dione.

Preferably in the invention Combination preparation selective aromatase inhibitor used. Selective aromatase inhibitors are compounds which act as a substrate for the aromatase and in the No dosage other than the aromatase used Affect enzymes in a clinically relevant manner.

Typical aromatic aromatase inhibitors are, for example the steroidal compounds 1-methyl-andostra-1,4-diene-3,17- dione (DE-A1 33 22 285; atamestane), 4-hydroxy-4-androsten- 3,17-dione (Formestan) as well as the non-steroidal Compounds (RS) -5- (4-cyanophenyl) -5,6,7,8-tetrahydro imidazo- (1,5α) -pyridine, hydrochloride (Cancer Res., 48, p. 834-838, 1988; Fadrozole), 4- [cyan-α (1,2,4-triazol-1-yl) - benzyl] benzonitrile (CGS 20267), 5- [cyclopentylidene (1- imidazolyl) methyl] thiophene-2-carbonitrile (EP-A1 0 411 735; Pentrozole), 2,2 '- [5- (1H', 2 ', 4-triazol-1-yl-methyl) -1,3- phenylene] -bis (2'-methylpropionitrile) (Arimidex) and (6- [1- (4-chlorophenyl) -1,2,4-triazol-1-yl) methyl] -1-methyl-1H- benzotriazole, dihydrochloride (vorozole).

The list of selective aromatase inhibitors is not complete, including others mentioned in the cited documents Connections, as well as other connections that the Requirements are considered.

They are manufactured according to methods known per se and assembled and available depending on the application preferably in oral form, as an injection or as Long-term drug available. The aromatase inhibitors can according to the invention as single doses or as depot forms be administered.  

Through the targeted administration of a, preferably selective, Aromatase inhibitor becomes an excessive burden on the Breast tissue by estrogens from the metabolic Avoiding conversion of androgens. This is particularly true in the postmenopause is important, as part of a Counter regulation due to ovarian estrogen deficiency, androgens are increasingly formed. The simultaneous Decrease in SHBG, a binding protein for steroid hormones, increases the proportion of free androgens in the plasma and favors an increase in androgen concentration in the mammary gland tissue. Hormone substitution treatment can also be used Lower the SHBG level, especially if the estrogen is combined with a progestogen that androgenic partial effects.

Generally the daily dosages are for one Aromatase inhibitor at 100 mg - 600 mg. With a daily dose of 200 mg is the target area generally well hit.

As substances with an estrogenic effect in the sense of the invention all known substances can be used for the standard hormone replacement therapy in the menopause Elimination of estrogen failure symptoms can be used can. These are preferably preparations which Estrogens or preparations containing estrogens and progestogens exhibit.

All natural and synthetic come as estrogens estrogen-active known compounds in question.

As natural estrogens, these are in particular estradiol as well as its longer-acting esters such as valerate etc. or estriol. Furthermore, synthetic estrogens are like Ethinyl estradiol, 14α, 17α-ethano-1,3,5 (10) -estratriene-3,17β- diol, 14α, 17α-ethano-1,3,5 (10) estratriene-3,16α, 17β-triol or to name the 15,15-dialkyl derivatives of estradiol.  

Estratriene-3-amidosulfonates are also derived from Estradiol or ethinyl estradiol and 14α, 17α- Methylene sterols from the tarran series and the corresponding 3-amidosulfonate derivatives mentioned.

Preparations containing estrogens in combination with progestogens contain or have the gestagens alone are also well known.

Gestagens are preferably selected from the group of compounds:
Gestoden, progesterone, desogestrel, 3-ketodesogestrel, levonorgestrel, lynestrenol, norgestimate, norethisterone, norethisterone acetate, chlormadinone acetate, drospironenone, cyproterone acetate or dienogest.

It is known that estrogens and progestogens also lie as Combination preparations before, such. B. as single-phase preparations or as graduated combination preparations or as Sequence preparations (estrogen (1st phase) and estrogen / progestogen (2nd phase) and are suitable according to the invention.

The list of estrogens and progestogens that can be used is not complete, also other connections that the Requirements are considered.

The substances with estrogenic effects are used in standard Dosages administered (e.g. estradioal orally 0.5-2.0 mg / day, conjugated estrogens 0.3-1.25 mg / day) to reduce the estradiol Balancing plasma levels and on a premenopausal Level. In individual cases, higher dosages are also used administered.

Suitable dosages are based on body weight, age and Constitution of the patient, taking the necessary daily dose can be applied by single or multiple dispensing, set.  

The substances with estrogenic effects can be administered intravenously, subcutaneously, intramuscularly, orally, intranasally or intravaginally be administered.

The administration of aromatase inhibitors and estrogen-acting Substances on the patient can be simultaneously and / or occur sequentially in time. It takes into account the kinetics of the individual substances and is chosen so that effective Plasma levels of the aromatase inhibitor, such as that for the Hormone replacement therapy used hormones can be achieved. Simultaneously and sequentially in time means that optionally the aromatase inhibitor over a certain one Period is administered and then treatment with Aromatase inhibitors and estrogen-active substance (s) is continued.

The pharmaceutical combination preparation according to the invention is suitable for selective estrogen replacement therapy, especially for long-term treatment for menopause Complaints, preferably in the postmenopausal phase. On the one hand, side effects that occur are Menopause, such as B. osteoporosis, is avoided, too any lost bone mass is rebuilt, and on the other hand, the risk becomes breast cancer at the same time lowered.

The invention therefore also relates to the use of the Combination preparation according to the invention to a selective Estrogen replacement therapy (SERT), especially for treatment of climacteric complaints, preferably for Long-term therapy of postmenopausal side effects, due to a lack of estrogen.  

The pharmaceutical combination preparation according to the invention is made by the aromatase inhibitors and substances with estrogenic effects together or separately with the usual pharmaceutical carrier, auxiliary and / or Additives are formulated, the dosage forms of the individual active ingredients do not have to be identical. It is z. B. quite possible that the one active ingredient of Combination drug is administered orally during the other active ingredient is administered subcutaneously.

These pharmaceutical compositions and Combination preparations can be used for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular Application may be provided.

The combination preparations of the invention are with the usual solid or liquid carriers or Diluents and the commonly used pharma Zeutisch-technical auxiliaries according to the desired type of application with a suitable dosage in manufactured in a known manner. The preferred preparations exist in a dosage form that is oral Application is suitable. Such dosage forms are for example tablets, film-coated tablets, coated tablets, capsules, Pills, powders, solutions or suspensions or else Form depot.

Of course, parenteral preparations such as Injection solutions into consideration. Furthermore, be as Preparations, for example, suppositories and agents called for vaginal use.

Appropriate tablets can be mixed, for example of the active ingredient with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, Mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin,  Lubricants such as magnesium stearate or talc and / or agents to achieve a depot effect like carboxylpolymethylene, Carboxylmethylcellulose, cellulose acetate phthalate or Polyvinyl acetate. The tablets can too consist of several layers.

Correspondingly, coated tablets can be coated analogously to the Cores usually produced in tablets Dragee coatings used means, for example Polyvinylpyrrolidone or shellac, gum arabic, talc, Titanium oxide or sugar. It can also the coated tablet consists of several layers, the Excipients mentioned above for the tablets can be used can.

The solutions or suspensions can additionally taste-improving agents such as saccharin, cyclamate or Sugar and z. B. flavorings such as vanillin or Orange extract included. You can also Suspen auxiliaries such as sodium carboxymethyl cellulose or Contain preservatives such as p-hydroxybenzoates.

Furthermore, capsules can be produced, for example, by adding inert carriers like milk sugar or sorbitol and encapsulated in gelatin capsules.

Suitable suppositories can be found, for example Mix with the appropriate carriers such as Neutral fats or polyethylene glycol or their derivatives produce.

The invention also relates to the packaging unit which comprises at least two components. It contains the Active substances made up together or spatially separated and as a further component an information note on  simultaneous and / or sequential application the dosage forms.

The invention is intended to be illustrated in more detail below by examples are explained without restricting them to them.

example 1

Combination preparation for menopausal women who do not need endometrial protection by progestogens (e.g. after hysterectomy) for continuous daily administration:

• a) Estrogen preparation
  daily dosage unit depending on the preparation e.g. B. 1-2 mg of estradiol-17β or 0.625 mg of a conjugated estrogen in one dose and
• b) aromatase inhibitor
  z. B. 200 mg of atamestane in one dose.

Example 2

Combination preparation for perimenopausal women with an intact uterus for a 28-day cycle:

• a) Estrogen preparation
  daily dosage unit depending on the preparation e.g. B. 1-2 mg estradiol-17β or 0.625 mg of a conjugated estrogen in one dose,
• b) progestin preparation for 10-14 days (sequential addition) daily dosage unit depending on the respective Progestin preparation z. B. 5 mg MPA, 1 mg NETA, 75-150 µg LNG, 1 mg CPA or 50 µg gestoden in one dose and
• c) aromatase inhibitor
  z. B. 200 mg of atamestane in one dose.

Example 3

Combination preparation for postmenopausal, non-hysterectomized women for continuous daily administration:

• a) Estrogen preparation
  daily dosage unit depending on the preparation e.g. B. 1-2 mg estradiol-17β or 0.625 mg of a conjugated estrogen in one dose,
• b) progestogen preparation
  daily dosage unit depending on the progestogen preparation z. B. 5 mg MPA, 1 mg NETA, 75-150 ug LNG, 1 mg CPA or 50 ug Gestoden or lower in one dose and
• c) aromatase inhibitor
  z. B. 200 mg of atamestane in one dose.

List of abbreviations

MPA = medroxyprogesterone acetate
NETA = norethisterone acetate
LNG = Levonorgestrel
CPA = cyproterone acetate

Claims (8)

1. Pharmaceutical combination preparation comprising at least an aromatase inhibitor and at least one substance estrogenic effect. 2. Combination preparation according to claim 1, characterized characterized that the aromatase inhibitor is a selective Is an aromatase inhibitor, preferably atamestane, formestane, Pentrozole, Arimidex, Fadrozole, CGS 20267 or Vorozol. 3. Combination preparation according to claim 1 or 2, characterized characterized that the substance with estrogenic effects an estrogen or an estrogen in combination with one Gestagen represents. 4. Combination preparation according to claim 3, characterized characterized that the estrogen from the group of natural estrogens or synthetic estrogens or their derivatives is selected. 5. Combination preparation according to claim 3, characterized characterized that the progestogen from the group of Gestoden, progesterone, desogestrel, 3- compounds Ketodesogestrel, levonorgestrel, lynestrenol, norgestimate, Norethisterone, norethisterone acetate, chlormadinone acetate, Drospironenone, cyproterone acetate or dienogest selected is. 6. Process for the manufacture of a pharmaceutical Combination preparation according to one of claims 1-5, characterized in that at least one Aromatase inhibitor and a substance with an estrogenic effect together or separately from each other with usual pharmaceutical carriers, auxiliaries and / or additives formulated.   7. Use of at least one aromatase inhibitor and at least one substance with an estrogenic effect selective estrogen replacement therapy. 8. Use according to claim 7 for the treatment of climacteric complaints, especially for Long-term therapy of postmenopausal Side effects related to estrogen deficiency are due.