PHARMACEUTICAL DOSAGE UNIT FOR THE PREVENTION OR TREATMENT OF CLIMACTERIC COMPLAINTS

Abstract: The invention relates to a pharmaceutical dosage unit for oral application for preventing or treating climacteric complaints.

Description: The invention relates to a pharmaceutical dosage unit for oral application for preventing or treating climacteric complaints, which dosage unit contains an oestrogenic compound and a substance which is capable of inducing progestational activity, and to a pharmaceutical preparation which contains several of said dosage units. Such dosage units and preparations are generally known. It has, however, been found that such preparations often have side effects such as an unfavourable effect on the so-called "high density lipid" (HDL) and triglyceride content and irregular abstraction haemorrhages. EP-A-0253607 published on 22 January 1988, after the filing date hereof, discloses the use of a composition comprising 0.5 to 2.0 mg of 17β-estradiol and 25 to 100 µg of desogestrel for use in hormonal replacement therapy for a pre-menopausal woman. Another European patent application, EP-A-0136011, broadly claims a product containing "less than 2.5 mg estrogen and 30 mg progestogen", but does not disclose the use of desogestrel. On page 9 TABLE 1B, PROGESTOGENS, a progestogen relatively equipotent with desogestrel, i.e. "laevonorgestrel", is described as having a daily dosage maximum of 0.075 mg. Neither of these patent applications teaches or discloses the use of a relatively high amount of the potent progestogen, desogestrel, for the treatment of climacteric complaints without concomitant undesirable side effects. It has now been found that a certain combination of 17β-oestradiol and desogestrel do not exhibit said disadvantages. The abstraction haemorrhages are absent or regular so that the endometrium is not at risk (is excessively stimulated). In addition, metabolic parameters such as the HDL and triglyceride content remain at virtually the level such as is found without administering the preparation according to the present invention. As stated, the preparation according to the invention is extremely suitable for preventing or treating climacteric syndrome and, in particular, vasomotor complaints including osteoporosis. 17β-Oestradiol, which is attractive because it is one of the natural oestrogens, and desogestrel appear to supplement each other excellently. By administering a certain quantity of oestradiol, bone loss is prevented and climacteric complaints are suppressed. Administration of a certain quantity of desogestrel during a certain period ensures that the side effects due to the administration of oestradiol are prevented without the administration of desogestrel giving rise to undesirable side effects (e.g. androgenic side effects). The invention therefore relates to a pharmaceutical dosage unit for oral application for treating or preventing climacteric complaints, containing 17β-oestradiol and desogestrel as active constituents and to a pharmaceutical preparation containing several of said dosage units. A dosage unit contains 0.5-2.5 mg, and still more preferably, 0.75-2.25 mg of oestradiol and 100-300 µg, and still more preferably, 100-200 µg of desogestrel. The simplest form of treatment of prevention of climacteric complaints is to administer one dosage unit per day without interruption. For this purpose, the dosage units which, preferably, each contain the same quantity of 17β-oestradiol and each contain the same quantity of desogestrel, may be packaged in a simple manner without indicating the sequence of swallowing to be adopted. A suitable packaging form is, for example, a small bottle or small tube. In this case, the preparation contains no other dosage units than those according to the present invention. If a periodical abstraction haemorrhage, for example after 1, 2 or 3 months, is preferred, use may be made of a pharmaceutical preparation which consists of at least two phases, the first phase comprising at least 11 and preferably 11-100, and still more preferably, 11-15 dosage units containing 17β-oestradiol and the second phase 11-15 dosage units containing 17β-oestradiol and desogestrel. Preferably, the preparation contains two or three phases. If the preparation comprises two phases, both phases consists more preferably of 13-15 and still more preferably of 14 consecutive dosage units. If the preparation comprises three phases, the first and second phase consist preferably of 11-13, and still more preferably, of 12 consecutive dosage units. The third phase, if present, consists of a period in which no dosage units are taken or of placebos. Preferably, the period lasts 2-6 days and, still more preferably, 4 days, or the number of placebos is 2-6 and, still more preferably, 4. The use of placebos is preferred with a view to the convenience of the preparation for the user. Although the presence of active constituents other than 17β-oestradiol and desogestrel in the dosage units and preparation according to the present invention is not excluded, dosage units containing 17β-oestradiol and desogestrel exclusively are preferred. In the case of two-phase and three-phase preparations, the quantity of 17β-oestradiol and desogestrel may also vary over the different dosage units, but the preference is for the same quantity of 17β-oestradiol and desogestrel for each dosage unit. During the period of administration, one dosage unit is administered daily, the sequence being determined by the manner in which the dosage units are arranged in the packaging of the preparation. When mention is made of dosage units in the description (with the exception of the examples), these are understood to mean oral dosage units such as tablets, pills, capsules, dragees and granules. The oral dosage units are produced by mixing the desired quantities of desogestrel and oestradiol with the usual pharmaceutically acceptable auxiliary substances such as fillers, binders, colouring agents, flavourings and lubricants, and converting the mixture into the form of a pharmaceutical moulding or filling capsules therewith. A practical dosage form is the soft gelatin capsule. It may be advisable to distinguish the placebos and the dosage units mutually from each other in the different phases by a different design and/or colour. Daily indications indicating the sequence in which the dosage units have to be taken are preferably provided on the packagings in which the two- and three-phase preparation according to the invention is packaged. The preparation may be packaged in a tube or a small box or in a so-called strip packaging. In the case of a small box, which may have a circular, rectangular or some other shape, the dosage units are separately confined therein, usually around the circumference of the small box, an optionally movable series of daily indications being provided on the small box corresponding to the days on which each of the dosage units has to be taken. Another practical form of packaging is the so-called strip packaging or blister packaging in which each dosage unit is confined in a separate compartment and daily indications or other indications which specify the sequence in which the dosage units should be taken are provided on the strip or the packaging. The invention is explained on the basis of the following examples. Example 1 Tablets containing the quantities of 17β-oestradiol and desogestrel shown in Table 1 below and 0.080 mg of dl-α-tocopherol, 4.000 mg of potato starch, 0.600 mg of colloidal silicon dioxide, 0.200 mg of magnesium stearate, 2.200 mg of polyvinylpyrrolidone and sufficient lactose for the tablets to weigh a total of 80.000 mg were prepared by mixing a solution of desogstrel and tocopherol in acetone with a mixture of oestradiol, polyvinylpyrrolidone and lactose, mixing the granular material with starch after drying, colloidal silicon dioxide and magnesium stearate, and by moulding tablets from the composition thus formed. Example 2 Composition of pharmaceutical preparations containing the tablets prepared in Example 1.

Claims: Claims for the following Contracting States: AT, BE, CH/LI, DE, FR, GB, IT, NL, SE 1. Pharmaceutical dosage unit for oral application for treating or preventing climacteric complaints and especially osteoporosis containing 0.5-2.5 mg or 17β-oestradiol and from greater than 100 to 300 µg of desogestrel as active ingredients. 2. Pharmaceutical preparation containing several dosage units according to claim 1. 3. Pharmaceutical preparation according to claim 2, characterized in that the preparation contains no other dosage units. 4. Pharmaceutical preparation according to claim 2, characterized in that the preparation contains at least 22 dosage units in a particular sequence, the preparation comprising at least two phases, of which the first consists of at least 11 and the second of 11-15 consecutive dosage units, each dosage unit of the first phase containing 17β-oestradiol as active constituent and each dosage unit of the second phase being a dosage unit according to claim 1 or 2. 5. Pharmaceutical preparation according to claim 4, characterized in that the number of dosage units is 22-30 and the first phase consists of 11-15 consecutive dosage units. 6. Pharmaceutical preparation according to claims 4-5, characterized in that the preparation consists of two phases, the first and the second phase containing 14 dosage units. 7. Pharmaceutical preparation according to claims 4-5, characterized in that the first and the second phase contain 12 dosage units and that the preparation also comprises a third phase which consists of 4 placebo dosage units. 8. Pharmaceutical preparation according to claims 2-7, characterized in that the quantity of 17β-oestradiol is the same in each dosage unit in which 17β-oestradiol occurs. 9. Pharmaceutical preparation according to claims 2-8, characterized in that the quantity of desogestrel is the same in each dosage unit in which desogestrel occurs. Claims for the following Contracting States: GR, ES 1. A process of manufacturing oral pharmaceutical dosage units for treating or preventing climacteric complaints, said process characterized by: mixing predetermined quantities of desogestrel and oestradiol with predetermined quantities of pharmaceutically acceptable auxiliary substances, and converting the mixture into the form of a pharmaceutical moulding, each portion of converted mixture containing 0.5 to 2.5 mg of 17β-oestradiol and from greater than 100 to 300 µg of desogestrel. 2. A process of manufacturing oral pharmaceutical dosage units for treating or preventing climacteric complaints, said process characterized by: mixing predetermined quantities of desogestrel and oestradiol with predetermined quantities of pharmaceutically acceptable auxiliary substances, and filling capsules with sufficient mixture so that each capsule contains 0.5 to 2.5 mg of 17β-oetradiol and from greater than 100 to 300 µg of desogestrel.

Inventors: TAX, LAMBERT JOSEPH WILHELM MARIE
Applicants: AKZO N.V.
Application year: 1988
Main classification: A61K31
IPC codes: C07J1, A61P43, A61P19, C07J11, A61K31, A61P5