Pharmaceutical dosage unit for treating climacteric complaints and osteoporosis.

DESCRIPTION OF THE INVENTION

0001The present invention is concerned with an oral pharmaceutical dosage unit for the prevention or treatment of climacteric complaints and symptoms, and osteoporosis, which comprises at least one alkali metal sulfate of a conjugated estrogen selected from the group consisting of estrone, equilin, 17α-dihydro-equilin, 17α-estradiol, equilenin, 17β-­dihydro-equilin, and 17β-dihydro-equilenin and a progestational compound. The present invention also relates to pharmaceutical preparations comprising one or more of these pharmaceutical dosage units.

BACKGROUND OF THE INVENTION

0002A dosage unit for oral application for the prevention or treatment of climacteric complaints comprising at least one of the above estrogens has been disclosed in U.S. Patent 4,154,820. This U.S. patent further discloses the use of a progestin concomitantly or sequentially with the dosage unit comprising the estrogen.

0003European Patent Application 136,011 discloses many progestational compounds for use as agents for preventing or treating climacteric complaints together with an estrogen.

0004Many pharmaceutical preparations used in practice exhibit side-effects, such as a negative influence on the high density lipid (HDL)- and triglyceride concentration in the blood and irregular withdrawal bleeding.

0005Surprisingly, we found that a combination of at least one of the above estrogens and desogestrel does not exhibit these drawbacks. The withdrawal bleedings is absent or regular, which avoids the excessive stimulation of the endometrium. Furthermore, metabolic parameters like HDL- and triglyceride concentration remain practically at the same level as if the dosage unit according to the present invention was not administered. Accordingly, the composition of the present invention is very suitable for the prevention or treatment of climacteric complaints, especially for the prevention or treatment of vasomotoric complaints and osteoporosis.

0006Use of the above estrogens and desogestrel sequentially or concomitantly appear to synergistically increase the beneficial effects while decreasing the risks. By applying an effective amount of the above estrogens bone loss is prevented and climacteric complaints are suppressed. By applying an effective amount of desogestrel during a certain period, side effects that would otherwise be caused by the administration of the above estrogens are avoided without adding other side effects, such as androgen side effects.

0007Desogestrel has been disclosed in U.S. Patent 3,927,046. However, the use of this compound for the prevention or treatment of climacteric complaints and/or osteoporosis in women has not been disclosed.

SUMMARY OF THE INVENTION

0008The present invention relates to a pharmaceutical composition in the form of a dosage unit to be administered orally for the prevention or treatment of climacteric complaints and/or osteoporosis in women, comprising at least one alkali metal sulfate of a conjugated estrogen selected from the group consisting of estrone, equilin, 17α-dihydro-­equilin, 17α-estradiol, equilenin, 17β-dihydro-equilin and 17β-dihydro-equilenin and desogestrel as the active ingredients. It also relates to a pharmaceutical preparation comprising one or more of these pharmaceutical dosage units.

0009In the preferred embodiment the estrogen employed is a combination of sodium estrone sulfate, sodium equilin sulfate and 17α-dihydro-equilin sodium sulfate, more preferably in a weight ratio of about 6:3:1.

0010A dosage unit preferably comprises 0.1-3.0 mg and more preferably 0.2-2.50 mg estrogen, and preferably 25-300 µg and more preferably 50-250µg desogestrel.

0011The simplest way to prevent or to treat climacteric complaints and/or osteoporosis in women is to administer one dosage unit according to the present invention every day without interruption. For this purpose dosage units, each containing the same amount of estrogen and the same amount of desogestrel, may be packaged in a simple way without indicating any particular order in which the dosage units should be taken. A suitable way of packaging is in a tube or a bottle. In this case the preparation does not contain other dosage units except those according to the present invention.

0012If regular withdrawal bleeding is preferred, e.g. after one, two or three months, a pharmaceutical preparation comprising at least two phases may be used, the first phase consists of at least 11, preferably 11-100 and more preferably 11-15 dosage units comprising the estrogen compound but no desogestrel, and the second phase comprising 11-15 dosage units according to the present invention including desogestrel. Preferably, the preparation comprises two or three phases.

0013If the preparation comprises two phases, each phase more preferably comprises 13-15, most preferably 14 successive dosage units.

0014A preparation comprising three phases preferably has a first and a second phase of 11-13 dosage units and a third phase consisting of a period wherein no dosage units are taken or a third phase comprising placebo dosage units. The third phase comprises 2-6 days without dosage units or 2-6 placebos. Preferably, the third phase comprises 4 days without dosage units or 4 placebos. The use of placebos is preferred in view of its convenience to the user.

0015For preparations comprising two or more phases, dosage units are taken one each day in the order indicated on the packaging or in the enclosed leaflet.

0016In preparations comprising two or more phases the amount of estrogen and the amount of desogestrel in each dosage unit in which desogestrel is present are preferably both the same for ease of manufacture. However, the amounts of each ingredient can vary within the limits set forth above.

0017Active ingredients in addition to those already mentioned in the dosage units and preparations according to the present invention may be included. In the preferred embodiment, however, dosage units and preparations exclusively comprising the estrogen component and desogestrel as the active ingredients are preferred.

0018For purposes of describing the invention, except in the examples, the term "dosage units" is meant to indicate tablets or other conventional pills, capsules, coated tablets and granules. The oral dosage units, which may have a total weight of 50-300 mg, are obtained by mixing the desired quantity of desogestrel and estrogen using the normal pharmaceutically acceptable aids such as fillers, binders, disintegrating agents, coloring agents, flavors, anti-­oxidants and lubricants, and bringing the mixture into the form of a pharmaceutical moulding, which may be coated or used for filling capsules.

0019Dosage units according to the present invention may be prepared in the same way as the dosage units in U.S. Patent 4,154,820, which is included herein by reference. Of course, desogestrel should be added as well. Dosage units comprising estrogens only and placebos may be prepared in the same way.

0020It is recommended that the placebos and the tablets in the other phases be distinguished from each other by giving them different shapes and/or colors.

0021Date indications should be provided on the packages in which preparations according to the invention are packed, indicating the date on which each dosage unit should be taken.

0022The preparation can be packed in a tube or box or in strip packaging. In the event a small box is used, which can have circular, square or other shape, the tablets are accommodated separately therein, usually along the periphery of the box, with a series of date indications, either adjustable or not, corresponding to the days on which each of the tablets is to be taken marked on the box.

0023Another practical form of packaging is strip packaging or push-through packaging whereby each tablet is sealed in a separate compartment and where, on the strip or the packaging, date indications or other sorts of indications are provided to show the sequence in which the tablets should be taken.

0024The invention will now be explained with the aid of the following examples, which are directed to specific preferred embodiments of the invention and are to be construed as illustrative but not limiting as to the scope of the invention defined in the appended claims.

EXAMPLE 1

0025Tablets, containing the amounts of conjugated estrogens (sodium estron sulfate, sodium equilin sulfate and sodium 17α-dihydro-equilin sulfate, weight ratio 6:3:1), desogestrel, tromethamine, dl-α-tocopherol and sodium citrate given in Table 1 and 25.0 mg starch, 60.0 mg microcrystalline cellulose, 4.0 mg hydroxypropyl methylcellulose, 6.0 mg stearic acid, 1.5 mg silicon dioxide, 2.0 mg magnesium stearate and an amount of lactose sufficient to make the total weight of the completed tablet 200.0 mg, were prepared by blending together the lactose, starch, microcrystalline cellulose and hydroxypropyl methylcellulose; granulating this blend by adding alcoholic solution of dl-α-tocopherol and 5 desogestrel followed by adding an aqueous solution of conjugated estrogens, tromethamine and sodium citrate; drying; milling; lubricating with stearic acid, magnesium stearate and silicon dioxide and compressing into tablets. <tables id="tabl0001" num="0001"><table frame="all"><title>Table 1</title><tgroup cols="10" colsep="1" rowsep="1"><colspec colnum="1" colname="col1" colwidth="15.75mm" /><colspec colnum="2" colname="col2" colwidth="15.75mm" /><colspec colnum="3" colname="col3" colwidth="15.75mm" /><colspec colnum="4" colname="col4" colwidth="15.75mm" /><colspec colnum="5" colname="col5" colwidth="15.75mm" /><colspec colnum="6" colname="col6" colwidth="15.75mm" /><colspec colnum="7" colname="col7" colwidth="15.75mm" /><colspec colnum="8" colname="col8" colwidth="15.75mm" /><colspec colnum="9" colname="col9" colwidth="15.75mm" /><colspec colnum="10" colname="col10" colwidth="15.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col1" align="center">Tablet</entry><entry namest="col2" nameend="col2" align="center">1</entry><entry namest="col3" nameend="col3" align="center">2</entry><entry namest="col4" nameend="col4" align="center">3</entry><entry namest="col5" nameend="col5" align="center">4</entry><entry namest="col6" nameend="col6" align="center">5</entry><entry namest="col7" nameend="col7" align="center">6</entry><entry namest="col8" nameend="col8" align="center">7</entry><entry namest="col9" nameend="col9" align="center">8</entry><entry namest="col10" nameend="col10" align="center">9</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">conjugated estrogens (mg)</entry><entry namest="col2" nameend="col2" align="char" char=".">0.30</entry><entry namest="col3" nameend="col3" align="char" char=".">0.30</entry><entry namest="col4" nameend="col4" align="char" char=".">0.30</entry><entry namest="col5" nameend="col5" align="char" char=".">0.625</entry><entry namest="col6" nameend="col6" align="char" char=".">0.9</entry><entry namest="col7" nameend="col7" align="char" char=".">1.25</entry><entry namest="col8" nameend="col8" align="char" char=".">2.5</entry><entry namest="col9" nameend="col9" align="char" char=".">0.625</entry><entry namest="col10" nameend="col10" align="char" char=".">0</entry></row><row><entry namest="col1" nameend="col1" align="left">desogestrel (mg)</entry><entry namest="col2" nameend="col2" align="char" char=".">0.075</entry><entry namest="col3" nameend="col3" align="char" char=".">0.100</entry><entry namest="col4" nameend="col4" align="char" char=".">0.150</entry><entry namest="col5" nameend="col5" align="char" char=".">0.150</entry><entry namest="col6" nameend="col6" align="char" char=".">0.150</entry><entry namest="col7" nameend="col7" align="char" char=".">0.150</entry><entry namest="col8" nameend="col8" align="char" char=".">0.150</entry><entry namest="col9" nameend="col9" align="char" char=".">0</entry><entry namest="col10" nameend="col10" align="char" char=".">0</entry></row><row><entry namest="col1" nameend="col1" align="left">tromethamine (mg)</entry><entry namest="col2" nameend="col2" align="char" char=".">0.20</entry><entry namest="col3" nameend="col3" align="char" char=".">0.20</entry><entry namest="col4" nameend="col4" align="char" char=".">0.20</entry><entry namest="col5" nameend="col5" align="char" char=".">0.417</entry><entry namest="col6" nameend="col6" align="char" char=".">0.6</entry><entry namest="col7" nameend="col7" align="char" char=".">0.833</entry><entry namest="col8" nameend="col8" align="char" char=".">1.667</entry><entry namest="col9" nameend="col9" align="char" char=".">0.417</entry><entry namest="col10" nameend="col10" align="char" char=".">0</entry></row><row><entry namest="col1" nameend="col1" align="left">dl-ã-tocopherol (mg)</entry><entry namest="col2" nameend="col2" align="char" char=".">0.1</entry><entry namest="col3" nameend="col3" align="char" char=".">0.1</entry><entry namest="col4" nameend="col4" align="char" char=".">0.1</entry><entry namest="col5" nameend="col5" align="char" char=".">-</entry><entry namest="col6" nameend="col6" align="char" char=".">0.1</entry><entry namest="col7" nameend="col7" align="char" char=".">0.1</entry><entry namest="col8" nameend="col8" align="char" char=".">0.2</entry><entry namest="col9" nameend="col9" align="char" char=".">-</entry><entry namest="col10" nameend="col10" align="char" char=".">-</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">sodium citrate (mg)</entry><entry namest="col2" nameend="col2" align="char" char=".">-</entry><entry namest="col3" nameend="col3" align="char" char=".">-</entry><entry namest="col4" nameend="col4" align="char" char=".">-</entry><entry namest="col5" nameend="col5" align="char" char=".">0.6</entry><entry namest="col6" nameend="col6" align="char" char=".">-</entry><entry namest="col7" nameend="col7" align="char" char=".">-</entry><entry namest="col8" nameend="col8" align="char" char=".">-</entry><entry namest="col9" nameend="col9" align="char" char=".">0.6</entry><entry namest="col10" nameend="col10" align="char" char=".">0.6</entry></row></tbody></tgroup></table></tables>

Example 2

0026Pharmaceutical preparations from dosage units prepared in Example 1: <tables id="tabl0002" num="0002"><table frame="all"><title>Table 2</title><tgroup cols="7" colsep="1" rowsep="1"><colspec colnum="1" colname="col1" colwidth="22.50mm" /><colspec colnum="2" colname="col2" colwidth="22.50mm" /><colspec colnum="3" colname="col3" colwidth="22.50mm" /><colspec colnum="4" colname="col4" colwidth="22.50mm" /><colspec colnum="5" colname="col5" colwidth="22.50mm" /><colspec colnum="6" colname="col6" colwidth="22.50mm" /><colspec colnum="7" colname="col7" colwidth="22.50mm" /><thead valign="top"><row><entry namest="col1" nameend="col1" align="center">Pharmaceutical preparation</entry><entry namest="col2" nameend="col2" align="center">1</entry><entry namest="col3" nameend="col3" align="center">2</entry><entry namest="col4" nameend="col4" align="center">3</entry><entry namest="col5" nameend="col5" align="center">4</entry><entry namest="col6" nameend="col6" align="center">5</entry><entry namest="col7" nameend="col7" align="center">6</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">1st phase</entry><entry namest="col2" nameend="col2" align="left">12 x tablet 8</entry><entry namest="col3" nameend="col3" align="left">13 x tablet 8</entry><entry namest="col4" nameend="col4" align="left">14 x tablet 8</entry><entry namest="col5" nameend="col5" align="left">70 x tablet 8</entry><entry namest="col6" nameend="col6" align="left">12 x tablet 8</entry><entry namest="col7" nameend="col7" align="left">60 x tablet 6</entry></row><row><entry namest="col1" nameend="col1" align="left">2nd phase</entry><entry namest="col2" nameend="col2" align="left">12 x tablet 4</entry><entry namest="col3" nameend="col3" align="left">12 x tablet 4</entry><entry namest="col4" nameend="col4" align="left">14 x tablet 4</entry><entry namest="col5" nameend="col5" align="left">14 x tablet 4</entry><entry namest="col6" nameend="col6" align="left">12 x tablet 4</entry><entry namest="col7" nameend="col7" align="left">-</entry></row><row><entry namest="col1" nameend="col1" align="left">3rd phase</entry><entry namest="col2" nameend="col2" align="left">4 x tablet 9</entry><entry namest="col3" nameend="col3" align="left">5 x tablet 9</entry><entry namest="col4" nameend="col4" align="left">-</entry><entry namest="col5" nameend="col5" align="left">-</entry><entry namest="col6" nameend="col6" align="left">4 x nothing</entry><entry namest="col7" nameend="col7" align="left">-</entry></row><row rowsep="0"><entry namest="col1" nameend="col7" align="justify">"-" means not applicable</entry></row><row rowsep="0"><entry namest="col1" nameend="col7" align="justify">"nothing" means that the 3rd phase consists of a period during which no tablets are taken.</entry></row></tbody></tgroup></table></tables>