Abstract:
The invention pertains to a process for the preparation of a high-purity composition of (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one. The process provides for a composition with less than 0.5% of (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one. This composition can be used as a source for the preparation of stable pharmaceutical dosage units.

Description:
CROSS-REFERENCE TO RELATED APPLICATION  
       [0001]    This application is a continuation of U.S. Ser. No. 09/787,215, filed May 17, 2001, which is the national phase of PCT International Application No. PCT/EP99/07768, filed Oct. 11, 1999, now International Publication No. WO 00/23460, with a publication date of Apr. 27, 2000, the contents of both of which is incorporated by this reference. 
     
    
     
       TECHNICAL FIELD  
         [0002]    The invention relates to a high-purity composition comprising (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one, a method for the preparation of this compound for use in the pharmaceutical composition, as well as a pharmaceutical composition prepared by admixing a pharmaceutically suitable carrier and the high-purity composition.  
         BACKGROUND  
         [0003]    The compound (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one (Tibolone) having the structural formula 1:  
                         
 
           [0004]    is known, for example from U.S. Pat. Nos. 3,340,279 and 4,701,450. The method described in these patents leads to a compound having combined oestrogenic, progestagenic and androgenic characteristics. This compound is used in medicaments having gonadomimetic, ovulation-inhibiting or immuno-modulating action.  
           [0005]    Compositions comprising Tibolone and a pharmaceutically acceptable solid carrier have been described in European Patent application 389,035, which disclosure is incorporated herein by reference. Tablets are available on the European market under the name of Livial®.  
           [0006]    The known tablets can be stably stored very well for, typically, two years at ambient temperature. A sufficiently humid atmosphere (e.g., 50-70% relative humidity) makes for a better storage stability than a relatively dry atmosphere (e.g., 45% relative humidity or below that).  
           [0007]    A problem in the preparation of pharmaceutical dosage units is that during their preparation, the relative amount of impurities may increase. In particular, the amount of one of the impurities which is already present in the bulk preparation, i.e., (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one (Org OM38) tends to increase during the process of making pharmaceutical dosage units. It is furthermore known that the amounts of Org OM38 in compositions comprising Tibolone increase upon storage.  
           [0008]    The end of shelf life specification with respect to the amount of Org OM38 formed during storage is 5%. A minimum acceptable shelf life period for these dosage units is one year.  
           [0009]    The customary amount of Tibolone in the known dosage unit is 2.5 mg in tablets or capsules of 100 mg total weight, i.e., 2.5%. For the sake of providing therapies better tailored to an individual woman&#39;s needs, it is desired to provide dosage units having a lower amount.  
           [0010]    However, adaptation of a known formulation by simply including a lower amount of Tibolone further decreases the stability of the dosage unit substantially. For example, if a 2.5 mg Tibolone dosage unit has a shelf life of, for example, two to three years at room temperature, the same unit upon lowering the amount of Tibolone to, for example, 0.3 mg can only be kept at 4° C. for a period of 6 to 12 months. Such a lower stability is unacceptable in daily practice.  
           [0011]    One of the possibilities to also keep the amount of Org OM-38 below a desired level after a prolonged storage time is to limit the amount initially present in the bulk preparation. Thus, a need exists to synthesize high-purity Tibolone batches with a low contamination content of Org OM-38.  
           [0012]    During the last step of the synthesis of Tibolone, a solution of (7α, 17α)-3,3-dimethoxy-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one in a mixture of pyridine and ethanol is mixed with a solution of oxalic acid in water and the mixture is stirred for three hours at approximately 30° C. The solution is then poured out in a mixture of pyridine and water and the resulting suspension is filtered. The crystals are washed with a mixture of water and pyridine and subsequently, the crystals are dried under vacuum at 40° C. to give (7α, 17α)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one (see also van Vliet et al (1986), Recl. Trav. Chim. Pays-Bas 105, 111-115).  
           [0013]    As this compound has a lower stability than the corresponding (7α, 17α)-17-hydroxy-7-methyl-19-nor-pregn-4-en-20-yn-3-one, there is always formed a small percentage of the latter compound via acid catalyzed isomerization. Furthermore, this isomerization takes place at higher temperatures and upon long-term storage of the crystals.  
         SUMMARY OF THE INVENTION  
         [0014]    Unexpectedly, it has been found that the rate of formation of Org OM38 during drying and storage in a specific batch can be decreased if crystals of Tibolone are washed with water and are allowed to age for at least 24 hours in the presence of water. Thus, the Tibolone is left for at least 24 hours under wet conditions. Preferentially, the crystals are left under these conditions for a period of at least three days. There is no limit to a maximum period but a period of three to six days is best suited. The aging temperature is preferably room temperature.  
           [0015]    Thus, according to the procedure of the present invention, highly pure Tibolone with a low Org OM38 impurity is obtained by including a delay of several days before drying. The procedure reliably results in batches of Tibolone having a low Org OM38 content. A further advantage is that these batches have an excellent stability. Furthermore, these batches do not form additional amounts of the latter compound upon heating or long-term storage.  
           [0016]    The invention provides dosage forms having a lower content of Tibolone (which are more prone to stability problems than regular dosage forms) that can be suitably kept for a prolonged period of time. The present invention further provides for high-purity batches of Tibolone. The invention also improves upon the storage stability, i.e., enhances the shelf life of the dosage units.  
           [0017]    The crystal formation procedure of the present invention can be combined perfectly well with the last step of the Tibolone synthesis wherein (7α, 17α)-3,3-dimethoxy-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one in a mixture of pyridine and ethanol is mixed with a solution of oxalic acid in water. In general, this reaction proceeds under mild acidic conditions in the presence of an organic solvent and water within a pH range of 3 to 5, preferentially 3.5 to 4.5. The acid preferentially is a weak organic acid having a pKa value in the range of 1 to 5, such as, citric acid, malonic acid, oxalic acid, dichloroacetic acid and acetic acid, optionally buffered with a base such as pyridine. As the organic solvent, for example, ethanol, methanol, acetone, 2-propanol or tetrahydrofuran, can be used. The solution is then poured out in water, which is made slightly alkaline by addition, for example, of a low amount of pyridine. After filtering the suspension, the crystals are washed with a mixture of water made slightly alkaline by, for example, pyridine. Before drying, the crystals are left wet for at least 24 hours.  
           [0018]    Inclusion of the crystal aging step according to the invention results in bulk Tibolone batches with a low Org OM38 content. Routinely, batches are obtained with an Org OM38 content of less than 0.5%. Often, even batches with less than 0.25% or even 0.1% of Org OM38 are obtained. Thus, high-purity compositions with Tibolone having less than 0.5% of Org OM38, preferably 0.25%, more preferably 0.10% of Org OM38 form part of the present invention. The amount of Org OM38 is calculated as the percentage (w/w) of the total amount of the bulk substance including some minor impurities. The amount of Tibolone usually is more than 98%.  
           [0019]    The batches of these high-purity Tibolone compositions with their low initial Org OM38 content are perfectly well suited to be used as a source for the preparations of pharmaceutical formulations. This guarantees a formulation with a low initial Org OM38 content and, therefore, improves its storage properties. Pharmaceutical preparations prepared with high-purity Tibolone usually result in preparations with less than 1% of Org OM38, often even less than 0.7% of Org OM38, and these preparations are less prone to increase in Org OM38 content during storage.  
           [0020]    As indicated herein, the amount of Org OM38 in a dosage form also depends upon the concentration of the active substance, the amount of impurity increasing as the amount of Tibolone in the dosage unit decreases. Therefore, by using the high-purity Tibolone as the active substance, dosage units can now be prepared with a lower amount of Tibolone and still have an acceptable shelf life. Thus, the invention also relates to pharmaceutical dosage units, which can be prepared by admixture of a pharmaceutically suitable solid carrier and the high-purity composition of the present invention.  
           [0021]    A typical known formulation for Tibolone is a 100 mg dosage unit having 2.5 mg of Tibolone contained therein, a relatively small amount (e.g., approximately 1% by weight) of pharmaceutically acceptable auxiliaries, and a carrier making up the body of the tablet. The carrier typically is composed of 10% by weight of starch, for example, potato starch, and 90% by weight of lactose.  
           [0022]    Due to the excellent stability properties of dosage units with a lower amount of active substance than the present commercially available tablets of 2.5 mg active substance, the present invention now makes it also possible to provide for stable dosage units comprising Tibolone in an amount of less than 2.50 mg, preferably 1.25 mg or less, more preferably 0.625 mg or less. At a shelf life of 1.5 years, preferably two years, these dosage units still comprise less than 5% of OM38 (relative to the amount of Tibolone).  
           [0023]    It is another aspect of the present invention to provide dosage units comprising Tibolone in amounts of less than 2.50 mg, preferably 1.25 mg or less, more preferably 0.625 mg or less and comprising at a shelf life of six months, less than 3%, preferably 2% of OM38. The shelf life preferably is extended up to one year, preferably 1.5 years, more preferably, two years.  
           [0024]    As used herein, “shelf life” means storage during a specified period under temperature conditions varying from 2° C. to 25° C. Dosage units can be packed, e.g., in push-through packs (PTP, blister) and are preferably stored in the dark (e.g., enclosed in cartons). Alternatively, they might also be stored in bottles, for example, high-density polyethylene bottles.  
           [0025]    The pharmaceutical dosage units of the present invention will generally take the form of tablets or capsules, but other solid or dry pharmaceutical preparations may also be utilized.  
           [0026]    Methods for making such dosage units are well known. For example, in the standard English language text, Gennaro et al.,  Remington&#39;s Pharmaceutical Sciences  (18th ed., Mack Publishing Company, 1990, see especially, Part 8, “Pharmaceutical Preparations and Their Manufacture”), methods of making tablets, capsules and pills and their respective components are described.  
           [0027]    Tablets and capsules are prepared of granulates using dry or wet granulation techniques as disclosed in  The Theory and Practice of Industrial Pharmacy  (3rd ed.), L. Lachman, H. A. Lieberman and J. L. Kanig (1986) p 1-99 and 293-345.  
           [0028]    The aim of granulation is to improve the flowability and compressibility of the powder mixture. Wet granulation forms the granules by binding the powders (a mixture of a diluent and disintegrant) together with an adhesive. The wet granulation technique employs a solution, suspension or slurry containing a binder, which is usually added to the powder mixture; however, the binder may be incorporated dry to the powder mix and the liquid may be added by itself. The wet granulation process is performed in mixers/kneaders or fluid bed systems.  
           [0029]    Usually an amount of water is incorporated in the basic granulate ranging from 5.5% to 7%. Preferably, the amount of water incorporated is at least 6%.  
           [0030]    After granulation, the mass is dried to the desired water content using fluid bed dryers, tray dryers, vacuum dryers or other suitable dryers.  
           [0031]    To attain a good distribution of the active (Tibolone) over the total mass, the active is premixed with a part of the granulate, sieved using an oscillating sieve, a high-speed sieve or other suitable sieving equipment. Next this mixture is mixed with the remaining part of the granulate and a lubricant. This mixture is compressed to tablets, or filled into capsules.  
           [0032]    The following examples are illustrative for the invention and should in no way be interpreted as limiting the scope of the invention.  
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
     EXAMPLES  
     Example 1  
       [0033]    A solution of (7α, 17α)-3,3-dimethoxy-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one (15 kg) in a mixture of pyridine (630 ml) and ethanol (315 liters) was mixed with a solution of oxalic acid (750 gr) in water (90 liters). The mixture was stirred for two hours at approximately 30° C. The solution was poured out in a mixture of pyridine (1350 ml) and water (300 liters) and the resulting suspension was filtered. The crystals were washed with a mixture of water and pyridine and dried under vacuum at 40° C. to give (7α, 17α)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one containing 0.6% of the corresponding (7α, 17α)-17-hydroxy-7-methyl-19-norpregn-4-en-20-yn-3-one as indicated by HPLC analysis. A stress test was performed at 45° C. (duration one month) which indicated a 0.4% increase of the latter compound.  
       Example 2  
       [0034]    A solution of (7α, 17α)-3,3-dimethoxy-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one (15 kg) in a mixture of pyridine (630 ml) and ethanol (315 liters) was mixed with a solution of oxalic acid (375 gr) in water (90 liters). The mixture was stirred for three hours at approximately 30° C. The solution was poured out in a mixture of pyridine (1350 ml) and water (300 liters) and the resulting suspension was filtered. The crystals were washed with a mixture of water and pyridine and allowed to age for three to six days at room temperature. Subsequently, the crystals were dried under vacuum at 40° C. to give (7α, 17α)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one containing ≦0.1% of the corresponding (7α, 17α)-17-hydroxy-7-methyl-19-norpregn-4-en-20-yn-3-one as indicated by HPLC analysis. A stress test was performed at 45° C. (duration one week) which indicated a &lt;0.1% increase of the latter compound.  
       Example 3  
       [0035]    The preparation as described in Example 2 was repeated. (7α, 17α)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one was obtained which contained 0.2% of the corresponding (7α, 17α)-17-hydroxy-7-methyl-19-norpregn-4-en-20-yn-3-one as indicated by HPLC analysis. A stress test was performed at 45° C. (duration one week) which indicated a 0.1% increase of the latter compound.  
       Example 4  
       [0036]    A basic granulate was prepared by granulation of a mixture of lactose (diluent), potato starch (disintegrant) and potato starch mucilage (binder) in a fluid bed granulator. The water content of the granulate varied within 5.5% to 6.5%. After granulation, the basic granulate was passed through a conical high-speed sieve. Part of the granulate (10% w/w) was mixed with Tibolone and ascorbyl palmitate using a tumble blender and then passed through a conical high-speed sieve.  
         [0037]    The Tibolone premix and the remainder of the basic granulate were mixed in a ribbon blender. Magnesium stearate was added and mixed. The final granulate was compressed into round tablets.  
         [0038]    The stability of the active compound (Tibolone) in tablets was determined.  
                                                                               TABLE 1                           Content of decomposition product (Org OM38) in percentage of the       declared amount of Tibolone per tablet, in tablets containing a various       amount of Tibolone, after storage at 25° C. and 60% relative humidity.                Concentration of Tibolone per tablet                0.46   0.96   1.92   2.5            Storage time   Amount of Org OM38 formed during storage       (months)   (in percentage of the declared amount of Tibolone)                    0   1.2   0.8   0.5   0.4       6   6.5   3.5   1.8   1.6       12   9.5   5.1   2.7   2.2       18   12.2   6.1   3.3   2.7                  
 
       Example 5  
       [0039]    Tablets of 1.25 mg of Tibolone have been prepared as described in Example 4. The tablets were stored at 25° C. and 60% relative humidity and the decomposition product (Org OM38) was measured.  
                                                                       TABLE 2                           Content of decomposition product (Org OM38) in percentage of the       declared amount of Tibolone per tablet. Stability of three development       tablet batches (1.25 mg of Tibolone per 65 mg) was assessed (storage       at 25° C. and 60% relative humidity).                Batch No.                049514001   049515001   049516001            Storage time   Amount of Org OM38 formed during storage       (months)   (in percentage of the declared amount of Tibolone)                    0   0.7   1.0   1.3       6   2.3   2.6   2.9       12   3.5   3.7   3.8       18   4.3   4.2   4.3       24   5.1   4.9   4.9                  
 
         [0040]    It can be concluded that the shelf life of tablets containing 1.25 mg of Tibolone per tablet of 65 mg is borderline  
       Example 6  
       [0041]    Tibolone as prepared in Example 2 was used as the active compound to prepare tablets as described in Example 4. The amount of Org OM38 formed in several batches during storage was determined.  
                                                                                               TABLE 3                           The stability of six tablet batches (1.25 mg of Tibolone per 65 mg)       was assessed (storage at 25° C. and 60% relative humidity). The amount of water incorporated in       the basic granulate was varied from 6.0% to 6.5%.                Batch No.            Storage   TD96.1128   TD96.1132   TD96.1133   162454001   162455001   162456001            time   Amount of Org OM38 formed during storage       (months)   (in percentage of the declared amount of Tibolone)                    0   0.7   0.5   0.5   0.9   0.8   0.9       6   1.3   1.1   1.1   1.8   1.7   1.8       12   1.8   1.5   1.6       18   2.0   1.5   1.7       Water   6.5   6.5   6.5   6.3   6.1   6.1       content of       the basic       granulate